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## **Meet the editors**

Doctor Sandro Misciagna was born on March 15, 1969 in Italy. He received degree in medicine in 1995 and in Neurology in 1999 at Catholic University in Rome. From 1993 to 1995 he attended research laboratory involving in cerebellar functions in mice. From 1994 to 2003 he attended Neuropsychological department of Catholic University involving in human cognitive and behavioural disorders, writing various publications and book chapters. In 2003 he took PhD in Neuroscience. He has been teacher of clinical neuropsychology, neurology, neurological and cognitive rehabilitation mainly at Catholic University. As clinician he has worked as neurologist in Alzheimer's clinics, Neuropsychiatric clinics and Neuropsychological departments. Currently he works as clinical neurologist and neuropsychologist at rehabilitation department of Don Gnocchi Foundation in Rome.

Dr. Cosgrove is an Associate Professor of Psychiatry and Diagnostic Radiology at Yale University. She uses PET brain imaging to examine the chemical changes that occur during the recovery from tobacco smoking and alcohol dependence in human subjects and in preclinical models.

Dr. Yoder utilizes PET to study neurochemistry in both humans and small animal models of psychiatric and neurological disorders. Dr. Yoder's background is in neuropharmacology and neurochemistry, with additional training in PET tracer kinetic modeling. The main focus of her laboratory is understanding the role of dopamine in cognitive processes that subserve addiction and pain disorders. Dr. Yoder's scope of research also includes traumatic brain injury, Alzheimer's Disease, and other dementias. Molecular targets of interest include dopaminergic receptors (primarily to study relative changes in dopamine levels), markers for neuroinflammation, amyloid and tau, and tracers for blood flow and glucose utilization.

Dr. Brad Christian serves as faculty with the departments of Medical Physics and Psychiatry at the University of Wisconsin-Madison where he serves as Director of PET Physics and Co-director of the Waisman Brain Imaging Core Laboratory. His research focuses on developing and translating novel PET methods for the study of neurodevelopment and neuropsychiatric illness. This involves using PET methodologies to investigate neurochemical changes in the brain and studying novel radioligands to characterize neurotransmitter-protein interactions and how they are influenced by development, genes, environment and drugs.

Contents

**Preface VII**

Todd Faasse

Karmen K. Yoder

Sandro Misciagna

**Section 1 PET Instrumentation and Imaging Processing 1**

Chapter 1 **Implementation of TOF-PET Systems on Advanced Reconfigurable Logic Devices 3**

Sánchez, J.M. Benlloch and M.J. Rodríguez

**Acquisition and Image Management 31**

Chapter 5 **How to Study Smoking and Drinking with PET 103**

Chapter 3 **Basic PET Data Analysis Techniques 63**

**Emission Tomography 85**

Chapter 7 **Pathological Gambling: PET Studies 177** Daniela Santoro and Stefano Pallanti

Chapter 2 **Positron Emission Tomography-Computed Tomography Data**

**Section 2 PET Applications in Neurological and Behavioral Research 83**

Chapter 4 **Functional Imaging Studies of Human Cognition Using Positron**

Evan D. Morris, Molly V. Lucas and Kelly P. Cosgrove

Chapter 6 **PET Imaging of the Serotoninergic 5-HT1A System 151** Amélie Lothe, Sandrine Bouvard and Philippe Ryvlin

J. Torres, R. García, A. Aguilar, J. Soret, J. Martos, A.J. González, F.

### Contents



#### **X** Contents

#### **Section 3 PET Imaging in Clinical Oncology 189**

Chapter 8 **PET – Assessment of Oncologic Treatment Response 191** Inga S. Grills and Victor S. Mangona

Preface

image quality.

tinue to be low.

onds or even a single breath hold.

FDG PET shows greatest potential as a clinical tool.

(

Positron emission tomography (PET) is a minimally invasive method and relatively safe di‐ agnostic procedure of nuclear medicine imaging that uses short-lived radiopharmaceutical

The majority of radioactive isotopes used in medical imaging decay by releasing energy as single gamma rays (photons). PET is based on use of radioisotopes which decay by emitting a positively charged electron (positron) from the nucleus. The positron collides with a nega‐ tively charged electron, resulting in two high-energy photons (511 kiloelectron-volts, KeV) that travel in opposite directions. The high-energy photon is subjected to less absorption or scatter by tissue than in comparatively lower-energy photons released during conventional imaging, meaning potential image degradation with PET is less likely, so there is superior

Charged particle accelerators (e.g. generators and cyclotrons) produce the radiopharmaceut‐

13N-NH3 and 15O-H2O. PET radiotracers are generally used in microgram quantities, so the incidence of adverse reactions to very small amounts of labelled molecules is likely to con‐

The first successful PET scan using the radionuclide 2-[18F]fluoro-2-deoxy-D-glucose

18FDG), a radio-labelled analogue of glucose, was applied in 1976 by Reivich et al. After that time several PET centres concentrated on studying brain metabolism and brain function. The methodology for PET whole body imaging was only developed in early 1990s and since that time there have been improvements in both scanner performance and processing tech‐ niques. The number of detector elements has increased from about 20 to about 20,000, the axial field of view from about 2 to about 20 cm, the spatial resolution has improved from

Modern PET instrumentation are also multi-modality scanners, combining high-perform‐ ance state-of-the-art PET and Computed Tomography (CT) scanners in a single device. These instruments provide near-perfect registration of both images of anatomy (with CT) and in vivo functions (with PET). Spiral CT scanners incorporated into PET-CT devices are extremely fast, potentially allowing the completion of a whole-body scan in a matter of sec‐

Most clinical PET imaging uses the FDG and are a potentially valuable means of diagnosis for a range of clinical conditions including oncology, cardiology and neuropsychiatric disor‐ ders. During the 1990s international experience recognized that oncology is the area where

C-CO2, 11C-methionine,

ical used for PET scanning that includes primarily 18FDG, but also <sup>1</sup>

about 25 to about 5mm and the sensitivity has increased about 1000 fold.

to detect and assess perfusion and metabolic activity in various organs and systems.

#### Chapter 9 **PET-CT in Anal Cancer: Indications and Limits 235** Massimiliano Mistrangelo and Adriana Lesca

Chapter 10 **Early Prediction of Tumor Response: A Future Strategy for Optimizing Cancer Treatment 257** Shigeto Ueda and Toshiaki Saeki

### Preface

**Section 3 PET Imaging in Clinical Oncology 189**

**VI** Contents

Inga S. Grills and Victor S. Mangona

Chapter 9 **PET-CT in Anal Cancer: Indications and Limits 235** Massimiliano Mistrangelo and Adriana Lesca

> **Optimizing Cancer Treatment 257** Shigeto Ueda and Toshiaki Saeki

Chapter 8 **PET – Assessment of Oncologic Treatment Response 191**

Chapter 10 **Early Prediction of Tumor Response: A Future Strategy for**

Positron emission tomography (PET) is a minimally invasive method and relatively safe di‐ agnostic procedure of nuclear medicine imaging that uses short-lived radiopharmaceutical to detect and assess perfusion and metabolic activity in various organs and systems.

The majority of radioactive isotopes used in medical imaging decay by releasing energy as single gamma rays (photons). PET is based on use of radioisotopes which decay by emitting a positively charged electron (positron) from the nucleus. The positron collides with a nega‐ tively charged electron, resulting in two high-energy photons (511 kiloelectron-volts, KeV) that travel in opposite directions. The high-energy photon is subjected to less absorption or scatter by tissue than in comparatively lower-energy photons released during conventional imaging, meaning potential image degradation with PET is less likely, so there is superior image quality.

Charged particle accelerators (e.g. generators and cyclotrons) produce the radiopharmaceut‐ ical used for PET scanning that includes primarily 18FDG, but also <sup>1</sup> C-CO2, 11C-methionine, 13N-NH3 and 15O-H2O. PET radiotracers are generally used in microgram quantities, so the incidence of adverse reactions to very small amounts of labelled molecules is likely to con‐ tinue to be low.

The first successful PET scan using the radionuclide 2-[18F]fluoro-2-deoxy-D-glucose ( 18FDG), a radio-labelled analogue of glucose, was applied in 1976 by Reivich et al. After that time several PET centres concentrated on studying brain metabolism and brain function.

The methodology for PET whole body imaging was only developed in early 1990s and since that time there have been improvements in both scanner performance and processing tech‐ niques. The number of detector elements has increased from about 20 to about 20,000, the axial field of view from about 2 to about 20 cm, the spatial resolution has improved from about 25 to about 5mm and the sensitivity has increased about 1000 fold.

Modern PET instrumentation are also multi-modality scanners, combining high-perform‐ ance state-of-the-art PET and Computed Tomography (CT) scanners in a single device. These instruments provide near-perfect registration of both images of anatomy (with CT) and in vivo functions (with PET). Spiral CT scanners incorporated into PET-CT devices are extremely fast, potentially allowing the completion of a whole-body scan in a matter of sec‐ onds or even a single breath hold.

Most clinical PET imaging uses the FDG and are a potentially valuable means of diagnosis for a range of clinical conditions including oncology, cardiology and neuropsychiatric disor‐ ders. During the 1990s international experience recognized that oncology is the area where FDG PET shows greatest potential as a clinical tool.

On current clinical practice the disease areas covered by PET are: (1) differentiation of be‐ nign from malignant lesions in the case of isolated lung nodules, (2) preoperative staging of non-small cell lung cancer, (3) guiding biopsy to the highest area in primary brain tumours, (4) diagnosis of radiation necrosis, residual or recurrent mass in patients treated with radio‐ therapy for malignant glioma, (5) diagnosis of suspected recurrence of colorectal cancer, (6) preoperative evaluation of patients being considered for surgical resection of hepatic or lung metastases from colorectal cancer, (7) detection of metastatic disease potentially respectable in patients with melanoma, (8) evaluation of medically refractory epilepsy who are being considered for surgery, (9) assessment of viable myocardium that may respond to reperfu‐ sion in patients with ischemic hearth disease being considered for coronary revasculariza‐ tion. However the availability of PET is still quite limited, as evidenced by low numbers of scanners in each country.

In this book, divided into three sections, authors review some of the recent developments in PET, concentrating on factors influencing instrumentation development and the acceptance of PET as a research and clinical tool.

In the first section of the book authors review the technical basic design and performance characteristics of PET scanning emphasing on data acquisition, processing and image recon‐ struction. In particular authors present an historical review of Time-Of-Flight (TOF) sys‐ tems, discuss their main advantages and describe requirements on the scintillation crystals and detectors suitable for TOF-PET design. Authors review recent development in acquisi‐ tion, processing and archiving of PET-CT raw data and image data in clinical PET-CT envi‐ ronment primarily centred on oncology and neurology and illustrate key points of basic PET imaging processing and data analyses, using data and images from several neurolegands.

In the second section authors expose examples of use of PET imaging for human research purposes such as (1) study of cognitive function in normal subject, (2) study of cerebral me‐ tabolism in patients with cognitive decline related to cerebrovascular or degenerative dis‐ eases, (3) study of nicotine acetylcholine receptors in tobacco smoking, (3) imaging of dopamine release in response to alcohol consumption, (4) imaging of serotoninergic system in neuropsychiatric disorders such as temporal lobe epilepsy, depression, schizophrenia, (5) imaging of dopaminergic system in emotional, motivational, stress responses as in patholog‐ ical gambling.

The third section of the book is centred around PET imaging techniques and assessment of response to oncologic treatment. In particular authors discuss assessment of response with early and late post-radiotherapy PET imaging for head and neck cancer, non-small cell lung cancer, lymphoma and gastrointestinal malignancies such as oesophageal cancer and anal cancer. The authors also expose how PET could be useful to predict tumour response, indi‐ vidualizing treatments, to avoid ineffective chemotherapies in particular in the management of chemotherapy in breast cancer.

> **Dr. Sandro Misciagna** Don Gnocchi Foundation Rome, Italy

**Section 1**

**PET Instrumentation and Imaging Processing**

**PET Instrumentation and Imaging Processing**

On current clinical practice the disease areas covered by PET are: (1) differentiation of be‐ nign from malignant lesions in the case of isolated lung nodules, (2) preoperative staging of non-small cell lung cancer, (3) guiding biopsy to the highest area in primary brain tumours, (4) diagnosis of radiation necrosis, residual or recurrent mass in patients treated with radio‐ therapy for malignant glioma, (5) diagnosis of suspected recurrence of colorectal cancer, (6) preoperative evaluation of patients being considered for surgical resection of hepatic or lung metastases from colorectal cancer, (7) detection of metastatic disease potentially respectable in patients with melanoma, (8) evaluation of medically refractory epilepsy who are being considered for surgery, (9) assessment of viable myocardium that may respond to reperfu‐ sion in patients with ischemic hearth disease being considered for coronary revasculariza‐ tion. However the availability of PET is still quite limited, as evidenced by low numbers of

In this book, divided into three sections, authors review some of the recent developments in PET, concentrating on factors influencing instrumentation development and the acceptance

In the first section of the book authors review the technical basic design and performance characteristics of PET scanning emphasing on data acquisition, processing and image recon‐ struction. In particular authors present an historical review of Time-Of-Flight (TOF) sys‐ tems, discuss their main advantages and describe requirements on the scintillation crystals and detectors suitable for TOF-PET design. Authors review recent development in acquisi‐ tion, processing and archiving of PET-CT raw data and image data in clinical PET-CT envi‐ ronment primarily centred on oncology and neurology and illustrate key points of basic PET imaging processing and data analyses, using data and images from several neurolegands. In the second section authors expose examples of use of PET imaging for human research purposes such as (1) study of cognitive function in normal subject, (2) study of cerebral me‐ tabolism in patients with cognitive decline related to cerebrovascular or degenerative dis‐ eases, (3) study of nicotine acetylcholine receptors in tobacco smoking, (3) imaging of dopamine release in response to alcohol consumption, (4) imaging of serotoninergic system in neuropsychiatric disorders such as temporal lobe epilepsy, depression, schizophrenia, (5) imaging of dopaminergic system in emotional, motivational, stress responses as in patholog‐

The third section of the book is centred around PET imaging techniques and assessment of response to oncologic treatment. In particular authors discuss assessment of response with early and late post-radiotherapy PET imaging for head and neck cancer, non-small cell lung cancer, lymphoma and gastrointestinal malignancies such as oesophageal cancer and anal cancer. The authors also expose how PET could be useful to predict tumour response, indi‐ vidualizing treatments, to avoid ineffective chemotherapies in particular in the management

> **Dr. Sandro Misciagna** Don Gnocchi Foundation

> > Rome, Italy

scanners in each country.

VIII Preface

ical gambling.

of chemotherapy in breast cancer.

of PET as a research and clinical tool.

**Chapter 1**

**Implementation of TOF-PET Systems on Advanced**

The ability to resolve the Time-Of-Flight (TOF) of the gamma particles resulting after the positron annihilation until their absorption by the detector material has a strong impact on the performance of the Positron Emission Tomography (PET) systems. This occurs because, by reducing the noise level, it becomes possible to also reduce the total amount of data required to reconstruct the medical image to a given quality degree. This furthermore translates into a reduction of the time required for the image acquisition or into a reduction of the radioactive dose employed. Additionally, the capability to resolve the TOF is critical for image recon‐ struction in situations where the detectors cannot be completely deployed around the point of

In Figure 1 it is shown the improvement on the image quality as a function of the TOF resolution and the solid angle covered by the detectors. As it can be seen from the figure, the importance of the TOF-PET measurement is greater as the solid angle covered by the detectors becomes smaller. According to this, the TOF capability is essential to any PET system that cannot completely surround the patient, like it could be the case of specific-application PET systems developed for particular applications, as for instance the approach for nuclear cardiology

Current PET scanners are built around analog subsystems implemented with discrete circuits. The electronic advances have allowed replacing the analog circuits by digital equivalents. Some of the reasons are that digital circuits present higher throughput; digital circuits also increase self-test and diagnostic capability; they present higher reliability and they also present

> © 2013 Torres et al.; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Reconfigurable Logic Devices**

J. Torres, R. García, A. Aguilar, J. Soret, J. Martos,

A.J. González, F. Sánchez, J.M. Benlloch and

Additional information is available at the end of the chapter

M.J. Rodríguez

**1. Introduction**

interest [1].

depicted on Figure 2.

http://dx.doi.org/10.5772/57123

### **Implementation of TOF-PET Systems on Advanced Reconfigurable Logic Devices**

J. Torres, R. García, A. Aguilar, J. Soret, J. Martos, A.J. González, F. Sánchez, J.M. Benlloch and M.J. Rodríguez

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57123

#### **1. Introduction**

The ability to resolve the Time-Of-Flight (TOF) of the gamma particles resulting after the positron annihilation until their absorption by the detector material has a strong impact on the performance of the Positron Emission Tomography (PET) systems. This occurs because, by reducing the noise level, it becomes possible to also reduce the total amount of data required to reconstruct the medical image to a given quality degree. This furthermore translates into a reduction of the time required for the image acquisition or into a reduction of the radioactive dose employed. Additionally, the capability to resolve the TOF is critical for image recon‐ struction in situations where the detectors cannot be completely deployed around the point of interest [1].

In Figure 1 it is shown the improvement on the image quality as a function of the TOF resolution and the solid angle covered by the detectors. As it can be seen from the figure, the importance of the TOF-PET measurement is greater as the solid angle covered by the detectors becomes smaller. According to this, the TOF capability is essential to any PET system that cannot completely surround the patient, like it could be the case of specific-application PET systems developed for particular applications, as for instance the approach for nuclear cardiology depicted on Figure 2.

Current PET scanners are built around analog subsystems implemented with discrete circuits. The electronic advances have allowed replacing the analog circuits by digital equivalents. Some of the reasons are that digital circuits present higher throughput; digital circuits also increase self-test and diagnostic capability; they present higher reliability and they also present

© 2013 Torres et al.; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PET systems contain trigger units responsible to identify true coincidences. These units are typically based on Complex Programmable Logic Device (CPLD) or Application Specific

Implementation of TOF-PET Systems on Advanced Reconfigurable Logic Devices

On one hand, DSPs are designed to support high-performance, repetitive and numerically complex sequential tasks. They are specialized on execution of repetitive algorithms, which involve multiplication and accumulation operations. The execution of several operations with one instruction are the features that accelerate the performance in state of the art DSPs [3]. Such a performance strongly relies on pipelining, which increases the number of instructions that can be executed in a time unit. However, parallelism in DSP is not very extensive; DSP is limited in performance by the clock rate and the number of useful operations that can be performed at each clock cycle. For instance, the TMS320C6202 processor, a well-known DSP, has two

On the other hand, CPLDs are very simple reconfigurable logic devices, with a few tens of input channels and quite small logic units for data processing. They have gradually been replaced for more complex devices with higher amount of resources. For instance, ASICs present a better optimization of logic size and power management. For many high-volume designs the cost-per-gate for a given performance level is lower than that of high speed CPLDs or DSPs. However, the inherently fixed nature of ASICs limits their flexibility, and the long design cycle may not justify the cost for low-volume or prototype implementation, unless the design would be sufficiently general to adapt to many different applications. Moreover, the development of very high performance reconfigurable logic devices, as Field Programmable Gate Arrays (FPGAs), has allowed its successful application in a wide number of areas.

First FPGAs lacked the gate capacity to implement demanding DSP algorithms and did not have specific tools well enough for implementing DSP tasks. They were also perceived as being expensive and with a relatively poor power management. But these limitations are being overcome with the introduction of new DSP-oriented products from Altera and Xilinx, the two leading companies for FPGAs. High throughput and design flexibility have positioned FPGAs as a solid silicon solution over traditional DSP devices in high-performance signal processing applications. FPGAs can provide more raw data processing power than traditional DSP

Since FPGAs can be hardware reconfigured, they offer a complete customization while implementing various DSP applications. All these features are, nowadays, easy to implement by means of a new generation of specific tools. FPGAs also have features that are critical to DSP applications, such as embedded memory, DSP blocks and embedded processors. Current FPGAs provide more than 96 embedded DSP blocks, delivering at least 384 multipliers operating at 420 MHz. This results on over 160 billion multiplications per second, a perform‐ ance improvement of over 30 times what is provided by the fastest DSPs. This configuration leaves the programmable logic elements on the FPGAs available to implement additional signal processing functions and a system logic, including interfaces to high-speed chips and external memory interfaces such as DDR2 controllers. Using high bandwidth embedded

memory, FPGAs can in certain cases suppress the need for external memory.

multiplications per second,

http://dx.doi.org/10.5772/57123

5

Integrated Circuit (ASIC) devices combined with Digital Signal Processors (DSPs).

multipliers and a 200 MHz clock, so it can achieve at most 400 106

processors by using massive parallelism.

which is much less than a programmable logic device counterpart.

**Figure 1.** Improvement on image quality provided for TOF-PET scanners as a function of time resolution and covered solid angle [1]

**Figure 2.** Example of a TOF-PET system setup for cardiology applications.

higher security of intellectual proprieties. In contrast to these advantages, uncertainties on the time determination appear due to the discretization and the rounding effect of the digital systems. Moreover, the complexity of the design tools is considerably higher [2].

PET systems contain trigger units responsible to identify true coincidences. These units are typically based on Complex Programmable Logic Device (CPLD) or Application Specific Integrated Circuit (ASIC) devices combined with Digital Signal Processors (DSPs).

On one hand, DSPs are designed to support high-performance, repetitive and numerically complex sequential tasks. They are specialized on execution of repetitive algorithms, which involve multiplication and accumulation operations. The execution of several operations with one instruction are the features that accelerate the performance in state of the art DSPs [3]. Such a performance strongly relies on pipelining, which increases the number of instructions that can be executed in a time unit. However, parallelism in DSP is not very extensive; DSP is limited in performance by the clock rate and the number of useful operations that can be performed at each clock cycle. For instance, the TMS320C6202 processor, a well-known DSP, has two multipliers and a 200 MHz clock, so it can achieve at most 400 106 multiplications per second, which is much less than a programmable logic device counterpart.

On the other hand, CPLDs are very simple reconfigurable logic devices, with a few tens of input channels and quite small logic units for data processing. They have gradually been replaced for more complex devices with higher amount of resources. For instance, ASICs present a better optimization of logic size and power management. For many high-volume designs the cost-per-gate for a given performance level is lower than that of high speed CPLDs or DSPs. However, the inherently fixed nature of ASICs limits their flexibility, and the long design cycle may not justify the cost for low-volume or prototype implementation, unless the design would be sufficiently general to adapt to many different applications. Moreover, the development of very high performance reconfigurable logic devices, as Field Programmable Gate Arrays (FPGAs), has allowed its successful application in a wide number of areas.

First FPGAs lacked the gate capacity to implement demanding DSP algorithms and did not have specific tools well enough for implementing DSP tasks. They were also perceived as being expensive and with a relatively poor power management. But these limitations are being overcome with the introduction of new DSP-oriented products from Altera and Xilinx, the two leading companies for FPGAs. High throughput and design flexibility have positioned FPGAs as a solid silicon solution over traditional DSP devices in high-performance signal processing applications. FPGAs can provide more raw data processing power than traditional DSP processors by using massive parallelism.

Since FPGAs can be hardware reconfigured, they offer a complete customization while implementing various DSP applications. All these features are, nowadays, easy to implement by means of a new generation of specific tools. FPGAs also have features that are critical to DSP applications, such as embedded memory, DSP blocks and embedded processors. Current FPGAs provide more than 96 embedded DSP blocks, delivering at least 384 multipliers operating at 420 MHz. This results on over 160 billion multiplications per second, a perform‐ ance improvement of over 30 times what is provided by the fastest DSPs. This configuration leaves the programmable logic elements on the FPGAs available to implement additional signal processing functions and a system logic, including interfaces to high-speed chips and external memory interfaces such as DDR2 controllers. Using high bandwidth embedded memory, FPGAs can in certain cases suppress the need for external memory.

higher security of intellectual proprieties. In contrast to these advantages, uncertainties on the time determination appear due to the discretization and the rounding effect of the digital

**Figure 1.** Improvement on image quality provided for TOF-PET scanners as a function of time resolution and covered

4 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

solid angle [1]

systems. Moreover, the complexity of the design tools is considerably higher [2].

**Figure 2.** Example of a TOF-PET system setup for cardiology applications.

Summarizing, FPGAs present a high speed data transfer; fast data processing capabilities; the ability to handle simultaneously a huge number of electronic signals; and the possibility to reconfigure itself to adapt to the very wide range of applications without the need of modifying the hardware design. They additionally include hardware (Xilinx PowerPC) or software (Xilinx MicroBlaze) processor cores, depending on the model; they offer a huge storage capacity with dedicated RAM blocks and look-up table memories; and large logic capacity with tens of millions of system gates. All these features make FPGAs to be great candidates to replace CPLD or ASIC devices on PET trigger units.

it hardly suitable for TOF-PET systems. It is also remarkable in 1980s that is the time span in which two major companies (i.e., General Electric and Computer Technology Imagery) entered into the PET industry and gave credence to the clinical application of PET, because prior to this time (the late 1980s) most PET applications had been research applications [17,18].

Implementation of TOF-PET Systems on Advanced Reconfigurable Logic Devices

http://dx.doi.org/10.5772/57123

7

The development improvement of TOF-PET systems was stopped until the discovery in 1990s of new scintillators based on Cerium-doped Lutetium Orthosilicate (Lu2SiO5 or LSO). LSO quickly revolutionized PET imaging systems because it excelled in three fundamen‐ tal detector material parameters: high density, high effective *Z* and a relatively high light yield with a short decay time of around 40 ns, allowing very narrow coincidence win‐ dows. The short decay time (LSO decays 7.5 times faster than BGO) permitted to de‐ creased patient scan times and, thus, supposed an improvement that made patients more comfortable during the procedure and from a clinical standpoint increased patient throughput. The increase in patient throughput made the procedure accessible to more patients and subsequently increased the testing revenue for hospitals and PET imaging centers. The short decay time also lowered the level of random noise in these scans [5]. In terms of resolution, systems based on LSO scintillators permitted a new generation of TOF-PET scanners with timing resolutions as small as 300 ps [19]. The decade of the 1990s, thus, is known as the decade in which the extended use of PET progressed and made strong in the clinical sector. As more and more members of the medical community became acquainted with the utility of PET and its present and future benefits, PET imaging became increasingly popular and was available in more hospitals, diagnostic clinics, mobile systems,

Recently, the discovery of new materials as Cerium-doped Lanthanum Bromide (LaBr3) with shorter decay time (16 ns) and excellent energy resolution has led to the develop‐ ment of TOF-PET systems also reaching time resolutions of 420 ps, and it is expected to reduce this resolution to 315-330 ps [20]. LaBr3 present the drawback of being hygroscop‐

Finally, from a commercial point of view, only two TOF-PET scanners have been introduced in the market by Philips and Siemens. The Gemini TF PET-CT is commercialized by Philips since 2006, it uses LYSO scintillator crystals (similar to LSO but with slightly lower density) and achieves a time resolution of 585 ps [21]. Recently, there has been presented results for the

Currently, in parallel with advances in scintillator materials, new fast and cost-effective photosensors are being developed. Silicon Photomultipliers (SiPMs) are at the forefront of this development. They are almost unaffected by magnetic fields [23], are very fast and have high gain. SiPMs aim to improve TOF resolution due to their fast timing [24]. Single-photo-electro timing resolutions close to 50 ps root-mean-square have been reported [25]. It is expected that a new generation of TOF-PET scanners based on fast scintillators and SiPMs would be able to

For additional information about the historical development of TOF-PET systems, excellent

Siemens TOF-PET scanner, called mMR, showing a time resolution of 550 ps [22].

ic and, thus, requiring a tedious manipulation and montage.

reviews can be found in the literature, for instance in [26-28].

achieve unprecedented time resolutions.

and physician practices.

Besides the advantages of PET systems based on FPGAs, recent advances in digital electronic design allows to use FPGAs for TOF determination with very high accuracy, less than 100 ps [4, 5]. This timing resolution opens the door to the development of trigger units for PETs systems with TOF capabilities built on them at a very competitive cost. Moreover, the recon‐ figuration characteristics of these devices allow to easily modify the PET setup (number of channels, detector coincidence map, etc) and to adapt it to different environments or physical requirements. In this chapter the main considerations for the design of TOF-PET systems based on advanced reconfigurable logic devices will be presented.

In the first section, the main advantages of TOF-PET systems will be highlighted and a historical review of these systems will be presented. In the second section, the requirements on the scintillation crystals and detectors suitable for TOF-PET designs will be described. Details of the electronic TOF implementation on FPGAs will be provided in the third section. In the fourth section, the impact of the TOF information on the reconstruction algorithms will be discussed and, finally, the conclussions will be pointed out in the fifth section.

#### **2. Historical perspective**

In this section, a brief description of the evolution of TOF-PET scanners from its origin to nowadays is presented.

The idea of TOF information for PET was already suggested by Anger [6] and Brownell [7] in the 1960s. However, it was rejected since the available scintillators crystals, photo-sensors and electronics were not fast enough. It was considered again when the type of crystals like CsF or BaF2 appeared in early 1980s. Several TOF-PET scanners were built at that time by leading groups as by CEA-LETI in Grenoble [8, 9], by Ter-Pogossian's group at Washington University [10,11] and by Wong's group at University of Texas [12, 13]. This first generation of TOF-PET devices achieved time resolutions ranging from 470 to 750 ps [14-16]. The decay time of these scintillator materials (CsF and BaF2) was very short (see Table 1 below), but their low density, low photoelectric fraction and low light output resulted on a poor spatial resolution and sensitivity.

At the same time, Bismuth Germanate (Bi4Ge3O12 or BGO) began to also be used for PET designs. This scintillator has much better characteristics for PET systems, as high detector efficiency due to its increase effective atomic number (*Z)*. However, its long decay time made it hardly suitable for TOF-PET systems. It is also remarkable in 1980s that is the time span in which two major companies (i.e., General Electric and Computer Technology Imagery) entered into the PET industry and gave credence to the clinical application of PET, because prior to this time (the late 1980s) most PET applications had been research applications [17,18].

Summarizing, FPGAs present a high speed data transfer; fast data processing capabilities; the ability to handle simultaneously a huge number of electronic signals; and the possibility to reconfigure itself to adapt to the very wide range of applications without the need of modifying the hardware design. They additionally include hardware (Xilinx PowerPC) or software (Xilinx MicroBlaze) processor cores, depending on the model; they offer a huge storage capacity with dedicated RAM blocks and look-up table memories; and large logic capacity with tens of millions of system gates. All these features make FPGAs to be great candidates to

6 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Besides the advantages of PET systems based on FPGAs, recent advances in digital electronic design allows to use FPGAs for TOF determination with very high accuracy, less than 100 ps [4, 5]. This timing resolution opens the door to the development of trigger units for PETs systems with TOF capabilities built on them at a very competitive cost. Moreover, the recon‐ figuration characteristics of these devices allow to easily modify the PET setup (number of channels, detector coincidence map, etc) and to adapt it to different environments or physical requirements. In this chapter the main considerations for the design of TOF-PET systems based

In the first section, the main advantages of TOF-PET systems will be highlighted and a historical review of these systems will be presented. In the second section, the requirements on the scintillation crystals and detectors suitable for TOF-PET designs will be described. Details of the electronic TOF implementation on FPGAs will be provided in the third section. In the fourth section, the impact of the TOF information on the reconstruction algorithms will

In this section, a brief description of the evolution of TOF-PET scanners from its origin to

The idea of TOF information for PET was already suggested by Anger [6] and Brownell [7] in the 1960s. However, it was rejected since the available scintillators crystals, photo-sensors and electronics were not fast enough. It was considered again when the type of crystals like CsF or BaF2 appeared in early 1980s. Several TOF-PET scanners were built at that time by leading groups as by CEA-LETI in Grenoble [8, 9], by Ter-Pogossian's group at Washington University [10,11] and by Wong's group at University of Texas [12, 13]. This first generation of TOF-PET devices achieved time resolutions ranging from 470 to 750 ps [14-16]. The decay time of these scintillator materials (CsF and BaF2) was very short (see Table 1 below), but their low density, low photoelectric fraction and low light output resulted on a poor spatial resolution and

At the same time, Bismuth Germanate (Bi4Ge3O12 or BGO) began to also be used for PET designs. This scintillator has much better characteristics for PET systems, as high detector efficiency due to its increase effective atomic number (*Z)*. However, its long decay time made

be discussed and, finally, the conclussions will be pointed out in the fifth section.

replace CPLD or ASIC devices on PET trigger units.

on advanced reconfigurable logic devices will be presented.

**2. Historical perspective**

nowadays is presented.

sensitivity.

The development improvement of TOF-PET systems was stopped until the discovery in 1990s of new scintillators based on Cerium-doped Lutetium Orthosilicate (Lu2SiO5 or LSO). LSO quickly revolutionized PET imaging systems because it excelled in three fundamen‐ tal detector material parameters: high density, high effective *Z* and a relatively high light yield with a short decay time of around 40 ns, allowing very narrow coincidence win‐ dows. The short decay time (LSO decays 7.5 times faster than BGO) permitted to de‐ creased patient scan times and, thus, supposed an improvement that made patients more comfortable during the procedure and from a clinical standpoint increased patient throughput. The increase in patient throughput made the procedure accessible to more patients and subsequently increased the testing revenue for hospitals and PET imaging centers. The short decay time also lowered the level of random noise in these scans [5]. In terms of resolution, systems based on LSO scintillators permitted a new generation of TOF-PET scanners with timing resolutions as small as 300 ps [19]. The decade of the 1990s, thus, is known as the decade in which the extended use of PET progressed and made strong in the clinical sector. As more and more members of the medical community became acquainted with the utility of PET and its present and future benefits, PET imaging became increasingly popular and was available in more hospitals, diagnostic clinics, mobile systems, and physician practices.

Recently, the discovery of new materials as Cerium-doped Lanthanum Bromide (LaBr3) with shorter decay time (16 ns) and excellent energy resolution has led to the develop‐ ment of TOF-PET systems also reaching time resolutions of 420 ps, and it is expected to reduce this resolution to 315-330 ps [20]. LaBr3 present the drawback of being hygroscop‐ ic and, thus, requiring a tedious manipulation and montage.

Finally, from a commercial point of view, only two TOF-PET scanners have been introduced in the market by Philips and Siemens. The Gemini TF PET-CT is commercialized by Philips since 2006, it uses LYSO scintillator crystals (similar to LSO but with slightly lower density) and achieves a time resolution of 585 ps [21]. Recently, there has been presented results for the Siemens TOF-PET scanner, called mMR, showing a time resolution of 550 ps [22].

Currently, in parallel with advances in scintillator materials, new fast and cost-effective photosensors are being developed. Silicon Photomultipliers (SiPMs) are at the forefront of this development. They are almost unaffected by magnetic fields [23], are very fast and have high gain. SiPMs aim to improve TOF resolution due to their fast timing [24]. Single-photo-electro timing resolutions close to 50 ps root-mean-square have been reported [25]. It is expected that a new generation of TOF-PET scanners based on fast scintillators and SiPMs would be able to achieve unprecedented time resolutions.

For additional information about the historical development of TOF-PET systems, excellent reviews can be found in the literature, for instance in [26-28].

#### **3. Crystals and detectors for TOF-PET scanners**

The capability of PET systems to return highly accurate TOF performances strongly depends on the read-out electronics but also on the detector block itself. In this section, the main considerations about this block namely the type of crystal and the photosensor, will be presented paying special attention to its timing properties.

light outputs reduce, i.e. improve, the time resolution. The shortest the decay time the lower the sensor dead time to process more events. The high initial rate suggests that LSO should

**Density (gr/cm**<sup>3</sup>**)** 3*.*67 7*.*1 6*.*7 7*.*4 7*.*1 1/μ **a** 511 **keV (mm)** 29*.*1 10*.*4 14*.*1 11*.*4 12*.*0 **Zeff** 51 75 59 66 64*,*5 **Light yield (γ /MeV)** 41000 9000 8000 31000 32000

**Time constant (ns)** 230 300 30 − 60 40 − 47 40 − 48 **Refraction index** 1*.*85 2*.*15 1*.*85 1*.*82 1*.*81 **Emission peak (nm)** 410 480 430 420 420 **Naturally radioactive** No No No Yes Yes **Hygroscopic** Yes No No No No

However, the timing properties of a scintillator depend on both the energy deposited in the

**Initial rate (γ/ns/MeV)** 37 232 676

**NaI BGO GSO LSO LYSO**

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return excellent timing properties.

**Table 1.** Scintillation crystals for TOF-PET systems.

**Figure 3.** Scintillation signal and decay time (τ).

crystal and the geometry of the scintillation crystal.

#### **3.1. Crystals for TOF-PET systems**

PET devices containing scintillators crystals must be as denser as possible since they have to stop the photons of 511 keV energy produced in the positron-electron annihilation. Such crystals need to generate high amounts of scintillation light to be detected with the photosen‐ sors. The crystal light yield is very important since it directly relates with the energy resolution of the system but also with the spatial resolution and later with the timing performance. To increase the photon emission probability in the visible range during the relaxation process, most of the crystals are doped with small quantities of impurities which generate intermediate states of energy.

In order to obtain fast output signals from the scintillation light, it is also important to account for a decay time of such light as short as possible. Moreover, the emission light wavelength should match the sensitivity of the photo-sensor utilized for electronic conversion.

NaI(Tl) has been one of the first types of crystals used for PET design. It generates significant amounts of scintillation light providing a high energy resolution and, thus, allowing to distinguish for instance photons of similar energies. One of the drawbacks when using this material has been its hygroscopic property, which requires using it in dry environments. In contrast to NaI, as stayed before, BGO crystal have been the most used scintillation crystal for PET applications, especially due to its high density, but with the lack of a good light yield and, therefore, time response.

GSO (Gadolinium-orthosilicate) has also been considered for PET designs although the light yield is also low compared to others. In this ranking, LSO (Lutetium oxyorthosilicate) appears to be good positioned offering a similar stopping power than BGO but also generating a high light yield compared to NaI. Nowadays, a LSO variant, commercially named LYSO is being widely used since its performances are very similar to LSO but at lower prices.

We will focus now in the decay time of the scintillation light since it is the dominant property in order to accurately achieve a TOF determination. As shortly introduced above, the scintil‐ lation light is described by a fast increase of the intensity followed by an exponential decrease of this emission. Here, it is called scintillation decay time to the one reached after the light pulse intensity reduces to 1/e of its maximum.

The time resolution is conditioned by the rise time, decay time and absolute light output. The rise time is negligible compared to the decay time, only the decay time and light output determine the intrinsic limits of the time resolution. In particular, faster decay times and higher light outputs reduce, i.e. improve, the time resolution. The shortest the decay time the lower the sensor dead time to process more events. The high initial rate suggests that LSO should return excellent timing properties.


**Table 1.** Scintillation crystals for TOF-PET systems.

**3. Crystals and detectors for TOF-PET scanners**

presented paying special attention to its timing properties.

**3.1. Crystals for TOF-PET systems**

states of energy.

therefore, time response.

pulse intensity reduces to 1/e of its maximum.

The capability of PET systems to return highly accurate TOF performances strongly depends on the read-out electronics but also on the detector block itself. In this section, the main considerations about this block namely the type of crystal and the photosensor, will be

8 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

PET devices containing scintillators crystals must be as denser as possible since they have to stop the photons of 511 keV energy produced in the positron-electron annihilation. Such crystals need to generate high amounts of scintillation light to be detected with the photosen‐ sors. The crystal light yield is very important since it directly relates with the energy resolution of the system but also with the spatial resolution and later with the timing performance. To increase the photon emission probability in the visible range during the relaxation process, most of the crystals are doped with small quantities of impurities which generate intermediate

In order to obtain fast output signals from the scintillation light, it is also important to account for a decay time of such light as short as possible. Moreover, the emission light wavelength

NaI(Tl) has been one of the first types of crystals used for PET design. It generates significant amounts of scintillation light providing a high energy resolution and, thus, allowing to distinguish for instance photons of similar energies. One of the drawbacks when using this material has been its hygroscopic property, which requires using it in dry environments. In contrast to NaI, as stayed before, BGO crystal have been the most used scintillation crystal for PET applications, especially due to its high density, but with the lack of a good light yield and,

GSO (Gadolinium-orthosilicate) has also been considered for PET designs although the light yield is also low compared to others. In this ranking, LSO (Lutetium oxyorthosilicate) appears to be good positioned offering a similar stopping power than BGO but also generating a high light yield compared to NaI. Nowadays, a LSO variant, commercially named LYSO is being

We will focus now in the decay time of the scintillation light since it is the dominant property in order to accurately achieve a TOF determination. As shortly introduced above, the scintil‐ lation light is described by a fast increase of the intensity followed by an exponential decrease of this emission. Here, it is called scintillation decay time to the one reached after the light

The time resolution is conditioned by the rise time, decay time and absolute light output. The rise time is negligible compared to the decay time, only the decay time and light output determine the intrinsic limits of the time resolution. In particular, faster decay times and higher

widely used since its performances are very similar to LSO but at lower prices.

should match the sensitivity of the photo-sensor utilized for electronic conversion.

**Figure 3.** Scintillation signal and decay time (τ).

However, the timing properties of a scintillator depend on both the energy deposited in the crystal and the geometry of the scintillation crystal.

#### **3.2. Photosensor, detectors capable of TOF and signal types**

The photosensors are the next part of the puzzle in order to reach high time resolutions. Two main groups of photosensors are currently under use in PET technology namely Photomulti‐ plier Tubes (PMT) and solid state photo-diodes.

Semiconductor detectors and, in particular, Avalanche Photodiodes (APDs) have proven to be suitable photosensors for PET detectors since the mid-1990s. These compact and reliable silicon-based devices have successfully been used to replace bulky photomultiplier tubes in high-resolution PET systems. Since arrays of small dimensions crystals are most commonly used as the scintillation block, these crystal pixels may be used individually coupled to single small area APDs. These sensors are very thin and, because of the high internal electric field and the short transit distances of the charge carriers, they are quite immune to magnetic fields. This characteristic allows them to be placed inside a magnet and to operate quite normally. APDs have been tested in high magnetic fields of up to 7 or 9.4 T without showing any

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Although APDs are compact and insensitive to magnetic fields, they present limitations for optimal PET performance. In particular, they can be hardly used for TOF measurements due to their slow response time. They also show low gains in the order of a few hundreds, and therefore, require sophisticated preamplifiers. These drawbacks seem to be overcome by the so-called Silicon Photomultipliers (SiPMs). Note that they are differently named depending

A SiPM consists of multiple tiny (currently up to about 20 microns side length) avalanche photo-diodes (so-called microcells) connected to a common electrode structure. When a reverse bias is applied to the SiPM at a voltage higher than the breakdown, each microcell operates in Geiger mode providing single photon counting capability. However, one photoelectron saturates the microcell limiting the linear response of the device as a function of the quantity of photoelectrons to about half the number of microcells. Similarly to APDs, they are compact, exhibit good photon detection efficiency (PDE) and do not need high voltage power supply. In advantage to APDs, they require simpler electronics and provide a high gain

Due to their excellent timing resolution (hundreds of picoseconds), SiPMs are currently considered as the best choice for future TOF-PET applications. Their insensitivity to magnetic fields makes them ideal for the development of hybrid PET-MRI scanners. Moreover, their costs are expected to diminish rapidly in the near future due to increasing competition (there

**4. Design and implementation of a TOF-PET system based on a FPGA**

In this section, several electronic techniques for TOF measurement will be described, also introducing the concept of FPGAs. The main features of this technology will be identified and their impact on the total system performance will be discussed. Once the use of FPGAs has been justified, the multiple implementation techniques, advantages and benefits for TOF

There exist several techniques for electronically measuring the photons TOF. In a first ap‐ proach, TOF systems were based on analog circuits, using extremely uniform current sources

is no patent for the main invention) and automated massive production.

performance degradation [29].

measurements will be exposed.

**4.1. Electronic techniques enabling TOF calculation**

on the manufacturer.

(105 -106 ).

PMTs use the external photo-electric effect. The scintillation photon enters the PMT through the crystal window, deposits its energy in the photocathode, and excites the electrons in the photocathode coating. The photoelectrons are accelerated and focused to the first anode with the help of an electric field. The photoelectrons are multiplied after impacting the first dynode, and this structure is sequentially repeated. A typical PMT gain is of about 106 from anode to last dynode. It is possible to increase the gain with the high voltage difference and the number of stages or dynode sequence.

Most scintillators emit in the 400 nm range, allowing the use of Borosilicate glass-windowed PMTs. Many of the PMTs that are used in commercial PET cameras have transit times that vary significantly across the face of the PMT. Such a time corresponds to the interval between the light pulse striking the photocathode and the pulse signal at the anode. The transit time inversely depends with the square root of the supplied voltage. However, concerning the time resolution of the PMTs, this is better defined as the mean transit time. TOF measurements with PET scanners based on PMTs require a transit time variation very small among the different PMTs used in the design but also across the different PADs (anodes) of each individual device.

The coupling of PMTs and scintillation crystals permit to recover the photon impact position. In the case of multi-anode PMTs it is somehow easier to derive such an incidence position. The location of the interaction is achieved by measuring the light detected on each anode. This is referred as Anger-logic. In the following table, the characteristics of typical signals of a PMT are shown, together with the specifications of those for Silicon Photomultipliers.


**Table 2.** PMT and SiPM comparison.

Semiconductor detectors and, in particular, Avalanche Photodiodes (APDs) have proven to be suitable photosensors for PET detectors since the mid-1990s. These compact and reliable silicon-based devices have successfully been used to replace bulky photomultiplier tubes in high-resolution PET systems. Since arrays of small dimensions crystals are most commonly used as the scintillation block, these crystal pixels may be used individually coupled to single small area APDs. These sensors are very thin and, because of the high internal electric field and the short transit distances of the charge carriers, they are quite immune to magnetic fields. This characteristic allows them to be placed inside a magnet and to operate quite normally. APDs have been tested in high magnetic fields of up to 7 or 9.4 T without showing any performance degradation [29].

**3.2. Photosensor, detectors capable of TOF and signal types**

plier Tubes (PMT) and solid state photo-diodes.

of stages or dynode sequence.

**Table 2.** PMT and SiPM comparison.

The photosensors are the next part of the puzzle in order to reach high time resolutions. Two main groups of photosensors are currently under use in PET technology namely Photomulti‐

10 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

PMTs use the external photo-electric effect. The scintillation photon enters the PMT through the crystal window, deposits its energy in the photocathode, and excites the electrons in the photocathode coating. The photoelectrons are accelerated and focused to the first anode with the help of an electric field. The photoelectrons are multiplied after impacting the first dynode, and this structure is sequentially repeated. A typical PMT gain is of about 106 from anode to last dynode. It is possible to increase the gain with the high voltage difference and the number

Most scintillators emit in the 400 nm range, allowing the use of Borosilicate glass-windowed PMTs. Many of the PMTs that are used in commercial PET cameras have transit times that vary significantly across the face of the PMT. Such a time corresponds to the interval between the light pulse striking the photocathode and the pulse signal at the anode. The transit time inversely depends with the square root of the supplied voltage. However, concerning the time resolution of the PMTs, this is better defined as the mean transit time. TOF measurements with PET scanners based on PMTs require a transit time variation very small among the different PMTs used in the design but also across the different PADs (anodes) of each individual device.

The coupling of PMTs and scintillation crystals permit to recover the photon impact position. In the case of multi-anode PMTs it is somehow easier to derive such an incidence position. The location of the interaction is achieved by measuring the light detected on each anode. This is referred as Anger-logic. In the following table, the characteristics of typical signals of a PMT

are shown, together with the specifications of those for Silicon Photomultipliers.

**H8500 Hamamatsu**

**Anode pixels** 64 (8 x 8) 20 x 20 (50 x 50 um each)

**SiPM**

**S10362-11-050 Hamamatsu**

**PMT**

**Spectral response** 300 to 650 nm 320 to 900 nm **Typical peak wavelength** 420 nm 420 nm **Window (material, thickness)** Borosilicate glass, 1.5 mm Epoxy, 300 μm

**Active area** 49 x 49 mm 1 x 1 mm **Supply voltage** -1100 V 70 V **Quantum efficiency** 24% 50 % **Gain** 1.5x106 7.5x105

**Time (rise, transit, transit spread)** 0.8 ns, 6 ns, 0.4 ns NA, NA, < 0.3 ns **Anode dark current** 0.1 nA 400 kcps

Although APDs are compact and insensitive to magnetic fields, they present limitations for optimal PET performance. In particular, they can be hardly used for TOF measurements due to their slow response time. They also show low gains in the order of a few hundreds, and therefore, require sophisticated preamplifiers. These drawbacks seem to be overcome by the so-called Silicon Photomultipliers (SiPMs). Note that they are differently named depending on the manufacturer.

A SiPM consists of multiple tiny (currently up to about 20 microns side length) avalanche photo-diodes (so-called microcells) connected to a common electrode structure. When a reverse bias is applied to the SiPM at a voltage higher than the breakdown, each microcell operates in Geiger mode providing single photon counting capability. However, one photoelectron saturates the microcell limiting the linear response of the device as a function of the quantity of photoelectrons to about half the number of microcells. Similarly to APDs, they are compact, exhibit good photon detection efficiency (PDE) and do not need high voltage power supply. In advantage to APDs, they require simpler electronics and provide a high gain (105 -106 ).

Due to their excellent timing resolution (hundreds of picoseconds), SiPMs are currently considered as the best choice for future TOF-PET applications. Their insensitivity to magnetic fields makes them ideal for the development of hybrid PET-MRI scanners. Moreover, their costs are expected to diminish rapidly in the near future due to increasing competition (there is no patent for the main invention) and automated massive production.

#### **4. Design and implementation of a TOF-PET system based on a FPGA**

In this section, several electronic techniques for TOF measurement will be described, also introducing the concept of FPGAs. The main features of this technology will be identified and their impact on the total system performance will be discussed. Once the use of FPGAs has been justified, the multiple implementation techniques, advantages and benefits for TOF measurements will be exposed.

#### **4.1. Electronic techniques enabling TOF calculation**

There exist several techniques for electronically measuring the photons TOF. In a first ap‐ proach, TOF systems were based on analog circuits, using extremely uniform current sources and converting the electrical charge accumulated by a capacitor into voltage values, propor‐ tional to the charging time, that later were digitalized [30], as illustrated in Figure 4.

**4.2. FPGAs overview**

instance:

change the internal logic of the device.

FPGAs are pre-fabricated silicon devices that can be electrically programmed to carry out multiple digital functions. Unlike Microprocessors or Computers in which programming means change the incoming instructions to the device, programming an FPGA consist of

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Historically, their strongest competitors in the market were the ASICs. They are designed for specific application using CAD (Computer-Aided Design) tools. Developing an ASIC takes much time but they have a great advantage in terms of recurring costs as very little material is wasted due to the fixed number of basic elements in the design. With an FPGA, a certain number of basic elements are always wasted, as these packages are standard. This means that the cost of an FPGA is often higher than that of a comparable ASIC. Although the recurring cost of an ASIC is quite low, its non-recurring cost is relatively high and often reaching into the millions. Since it is non-recurring though, its value per IC (Integrated Circuit) decreases with increased volume. If the cost of production in relation to the volume is analyzed, it will be find that going lower in production numbers, using FPGA actually becomes cheaper than

using ASICs [34]. Furthermore, it is hardly possible to correct errors after fabrication.

Figure 5 shows the design flow of the two mentioned devices.

because is carried out by the manufacturer.

In contrast to ASICs, FPGAs are configured after fabrication allowing the user for further reconfigurations. This is done with a hardware description language (HDL), which is compiled to a bit stream and downloaded to the FPGA. The disadvantages of FPGAs are that the same application needs more space on chip and the application runs faster on the ASIC counterpart. Due to the size reduction of the basic components, FPGAs were getting more powerful over the years. Herein, the development of ASICs was decreasing and becoming more expensive.

From Figure 6 it is easy to observe the highest complexity involved in an ASIC design as for

**•** Design for Testability (DFT) Insertion. This technique is used to check whether the manu‐ facturing process has added defects to the chip. DFT insertion means incorporating an

**•** Hand-off to foundry. The process takes several months due to the "personalized" design.

**•** Equivalency checking. A system design flow requires comparison between a Transaction Level Model (TLM) and its corresponding Resistor-Transistor Logic (RTL) specification.

**•** Verification of 2nd and 3rd order effects. This stage is not included in the FPGA design flow

An FPGA design flow eliminates the complex and time-consuming floorplanning (design and interconnection of the internal blocks), place and route, timing analysis, and other stages of the ASIC design project since the design logic is already synthesized to be placed onto an already verified, characterized FPGA device. However, when needed, manufacturers provide the advanced floorplanning, hierarchical design, and timing tools to allow users to maximize the performance for the most demanding designs. Furthermore, FPGA technologies are

additional logic to improve the testability of the internal nodes of the design.

**Figure 4.** Analog TDC based on current integration and analog-to-digital conversion.

This technique presents several drawbacks, mainly related with scalability, design complexity and static power dissipation. Nowadays, most of TOF measurement devices are based on digital circuits using delay lines in different configurations. These devices use the propagation delay across the individual digital blocks to measure TOF [31-33], so they are able to measure it with a resolution lower than the system clock period. Figure 5 represents a digital delay line used to measure TOF.

**Figure 5.** Digital delay line for TOF calculation.

The digital TDCs (Time to Digital Converters) overcome the inconvenient of the analog approach and, if properly designed, they can even compensate the effect of temperature and/ or power supply fluctuations. However, most of them are built on ASICs, so they are expensive, have a reduced number of available channels, and their functionality is limited. Here, the development in recent years of very sophisticated reconfigurable logic devices opens the possibility to integrate digital TDCs on high performance FPGA.

#### **4.2. FPGAs overview**

and converting the electrical charge accumulated by a capacitor into voltage values, propor‐

tional to the charging time, that later were digitalized [30], as illustrated in Figure 4.

12 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

ADC 
 Time 

<sup>C</sup> Csh <sup>c</sup> Iop

**Figure 4.** Analog TDC based on current integration and analog-to-digital conversion.

Sample 
 & 
 Hold

This technique presents several drawbacks, mainly related with scalability, design complexity and static power dissipation. Nowadays, most of TOF measurement devices are based on digital circuits using delay lines in different configurations. These devices use the propagation delay across the individual digital blocks to measure TOF [31-33], so they are able to measure it with a resolution lower than the system clock period. Figure 5 represents a digital delay line

The digital TDCs (Time to Digital Converters) overcome the inconvenient of the analog approach and, if properly designed, they can even compensate the effect of temperature and/ or power supply fluctuations. However, most of them are built on ASICs, so they are expensive, have a reduced number of available channels, and their functionality is limited. Here, the development in recent years of very sophisticated reconfigurable logic devices opens the

possibility to integrate digital TDCs on high performance FPGA.

…… 

Time 
 Words

Interval Logic 

Up 

Iop

Vdda

Down 

Start

Stop 

used to measure TOF.

**Figure 5.** Digital delay line for TOF calculation.

FPGAs are pre-fabricated silicon devices that can be electrically programmed to carry out multiple digital functions. Unlike Microprocessors or Computers in which programming means change the incoming instructions to the device, programming an FPGA consist of change the internal logic of the device.

Historically, their strongest competitors in the market were the ASICs. They are designed for specific application using CAD (Computer-Aided Design) tools. Developing an ASIC takes much time but they have a great advantage in terms of recurring costs as very little material is wasted due to the fixed number of basic elements in the design. With an FPGA, a certain number of basic elements are always wasted, as these packages are standard. This means that the cost of an FPGA is often higher than that of a comparable ASIC. Although the recurring cost of an ASIC is quite low, its non-recurring cost is relatively high and often reaching into the millions. Since it is non-recurring though, its value per IC (Integrated Circuit) decreases with increased volume. If the cost of production in relation to the volume is analyzed, it will be find that going lower in production numbers, using FPGA actually becomes cheaper than using ASICs [34]. Furthermore, it is hardly possible to correct errors after fabrication.

In contrast to ASICs, FPGAs are configured after fabrication allowing the user for further reconfigurations. This is done with a hardware description language (HDL), which is compiled to a bit stream and downloaded to the FPGA. The disadvantages of FPGAs are that the same application needs more space on chip and the application runs faster on the ASIC counterpart. Due to the size reduction of the basic components, FPGAs were getting more powerful over the years. Herein, the development of ASICs was decreasing and becoming more expensive. Figure 5 shows the design flow of the two mentioned devices.

From Figure 6 it is easy to observe the highest complexity involved in an ASIC design as for instance:


An FPGA design flow eliminates the complex and time-consuming floorplanning (design and interconnection of the internal blocks), place and route, timing analysis, and other stages of the ASIC design project since the design logic is already synthesized to be placed onto an already verified, characterized FPGA device. However, when needed, manufacturers provide the advanced floorplanning, hierarchical design, and timing tools to allow users to maximize the performance for the most demanding designs. Furthermore, FPGA technologies are

**•** IOBs. They are used to connect the FPGA to other systems of the whole application.

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**•** Programmable Interconnect. Enables the communication between CLBs and IOBs.

**•** Clock blocks that are intended to additional clock signal generation for using either in

**•** Distributed memory blocks that store the user-programmed configuration.

**•** Other blocks that manage the proper coexistence of all the resources.

**Figure 7.** FPGA internal blocks (left) and typical example of an ASIC internal structure (right).

Figure 7 (left) shows the internal block distribution of a conventional FPGA. It is easy to appreciate how the blocks are uniformly placed in order to make possible multiple applica‐ tions. Green blocks represent the IOBs, located on the boundary of the device to facilitate the interaction off-chip. Blue blocks represent the CLBs, centered with respect to the device and close to each other. They are connected through an Interconnection Matrix (not showed) which path would go over the white spaces between CLBs. Figure 6 (right) represents the internal part of an ASIC. Unlike Figure 7 (left), in this case there are not blocks uniformly distributed but different specific blocks placed optimizing the speed and space. These two figures highlight the mentioned features. The following table summarizes the commented character‐

**Speed Integration density Reconfiguration capability Time until cost-effective**

**ASIC** High High Hardly High **CPLD** Medium Low Yes Low **FPGA** Medium Medium Yes Low

Additionally to these basic blocks, FPGAs incorporate:

internal blocks or external purposes.

istics of the three technologies.

**Table 3.** Programmable logic devices comparison.

**Figure 6.** Design flow comparison: FPGA and ASIC.

considered very competitive due to the wide specification ranges. Each manufacturer provides FPGAs with different capabilities that adapt to the desired application. There are families for high performance applications, for high volume of production and even radiation tolerant families.

CPLDs are, in some cases, a good alternative to FPGA. They have a similar internal architecture to the FPGAs, as shown in the Figure 6. CPLDs are composed of digital blocks, which imple‐ ment digital functions, analogous to the FPGA, IOBs (Input Output Block) and Interconnection Matrices. In general terms, CPLDs have less internal resources than FPGAs but they are able to achieve better speeds. However, when a considerable number of resources such as memory blocks and multipliers are required, FPGAs are still the best choice. In fact most of the current FPGAs incorporate Digital System Processing blocks, which have internal Multipliers. FPGAs have become more popular and, thus, CLPDs have experienced a noticeable decrease in its production, which gives FPGAs more guarantee of continuity. Therefore, FPGAs are increas‐ ingly applied to high performance embedded systems.

#### **4.3. FPGA internal architecture**

In the following, a basic description of the internal blocks of an FPGA is presented. Its basic structure is composed of three main blocks:

**•** CLBs (Configurable Logic Blocks). Generic blocks, which contain digital logic for imple‐ menting specific functions.


Additionally to these basic blocks, FPGAs incorporate:


**Figure 7.** FPGA internal blocks (left) and typical example of an ASIC internal structure (right).

Figure 7 (left) shows the internal block distribution of a conventional FPGA. It is easy to appreciate how the blocks are uniformly placed in order to make possible multiple applica‐ tions. Green blocks represent the IOBs, located on the boundary of the device to facilitate the interaction off-chip. Blue blocks represent the CLBs, centered with respect to the device and close to each other. They are connected through an Interconnection Matrix (not showed) which path would go over the white spaces between CLBs. Figure 6 (right) represents the internal part of an ASIC. Unlike Figure 7 (left), in this case there are not blocks uniformly distributed but different specific blocks placed optimizing the speed and space. These two figures highlight the mentioned features. The following table summarizes the commented character‐ istics of the three technologies.


**Table 3.** Programmable logic devices comparison.

considered very competitive due to the wide specification ranges. Each manufacturer provides FPGAs with different capabilities that adapt to the desired application. There are families for high performance applications, for high volume of production and even radiation tolerant

14 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

CPLDs are, in some cases, a good alternative to FPGA. They have a similar internal architecture to the FPGAs, as shown in the Figure 6. CPLDs are composed of digital blocks, which imple‐ ment digital functions, analogous to the FPGA, IOBs (Input Output Block) and Interconnection Matrices. In general terms, CPLDs have less internal resources than FPGAs but they are able to achieve better speeds. However, when a considerable number of resources such as memory blocks and multipliers are required, FPGAs are still the best choice. In fact most of the current FPGAs incorporate Digital System Processing blocks, which have internal Multipliers. FPGAs have become more popular and, thus, CLPDs have experienced a noticeable decrease in its production, which gives FPGAs more guarantee of continuity. Therefore, FPGAs are increas‐

In the following, a basic description of the internal blocks of an FPGA is presented. Its basic

**•** CLBs (Configurable Logic Blocks). Generic blocks, which contain digital logic for imple‐

ingly applied to high performance embedded systems.

**4.3. FPGA internal architecture**

menting specific functions.

structure is composed of three main blocks:

**Figure 6.** Design flow comparison: FPGA and ASIC.

families.

#### **4.4. FPGA design for TOF measurement**

As commented above, there are several alternatives for implementing the TOF determination, many of them based on ASICs, that are expensive, hardly reconfigurable, and they need to be produced in high volumes to be cost-effective. However, reconfiguration capabilities of FPGAs and their low cost compared to other solutions have made them the ideal candidates for the development of complex electronic equipment, as PET systems [35]. Additionally, it is technically possible to use FPGAs to measure TOF with a very high time resolution [36], much better than the resolution of current commercial PET systems whose resolution is around 600 ps. Thus, the electronic device responsible for the TOF measurement must be able to distin‐ guish events between time periods in the order of few-tens hundreds of picoseconds to be competitive enough in the market. In this subsection, the main considerations for TOF calculation using an FPGA will be presented.

#### *4.4.1. Time to digital converter*

TDC is a well-known technique traditionally used for TOF determination [37]. The TDC goal is to recognize events and to provide a digital representation of the time they occurred. There are many TDC implementation possibilities. Focusing in digital TDCs and leaving aside the analog TDC, the simplest is a high-frequency counter, which value is incremented at each clock cycle. When an event occurs, the accumulated amount of clock periods are stored and presented. The drawback of this approach is that the stored counter is a number of integer clock cycles and, therefore, the resolution is restricted to the clock system. Thus, in order to get accurate resolution, the use of a faster clock is required. Thus, the larger the frequency the more the signal integrity problems, translating into a complex system design. Moreover, the stability of the clock system becomes critical.

**•** A calibration signal is initially selected for the system calibration. This is a necessary task to determine the individual delay of the elements from which the delay line is composed by.

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**•** Each raw time element previously booked into the histogram memory is converted into a

**•** The system is ready to receive an event through the "signal" connection, which is selected

**•** When the time event is greater than the clock period, a number of entire clock cycles must

**•** Then, when an event occurs the "signal" is bypassed into the delay line. The encoder counts the number of elements reached by the signal and provides this number to the LUT, which convert this number to time and, after this value is combined with the coarse counter value,

TDCs may incorporate more than one channel. In the block diagram previously described, a multiple channel TDC is referred. In this case, the proposed TDC channels will share the histogram memory block and coarse counter block. At the time to get the final timestamp, the coarse counter block will store each coarse time associated to each channel number. Analo‐ gously, the histogram memory block will store, after the initial calibration, the time delay of

The importance of channels lays in the possibility of group in one single device the TOF measurement of a complete PET system [35]. The outputs of the detectors placed on the PET ring system have to be fed into a trigger unit, which will be the responsible of data processing. When a signal coming from one detector is received, the system waits certain time with the

The raw counter (not yet in terms of time) is stored into the histogram memory.

real time value and booked again into a look up table (LUT).

be stored, performed by the coarse counter block.

by the "select" signal.

**Figure 8.** Digital TDC basic scheme.

*4.4.2. System architecture*

each tap for each channel.

a final timestamp is generated.

Interpolation circuits emerged as a necessity to measure events below the clock period. These circuits measure the time between a clock event and the event being measured. One of the problems is the TDC time required to perform a measurement, blocking new measurements for a certain period of time. One of the most implemented structures based on interpolating circuits is the Vernier Delay line.

Until recently, TDCs were ASIC implemented either by companies which launched the product to the market or by owners who wanted a specific design. Nowadays, the use of FPGAs aimed at this purpose is getting more popular [36-38]. Low cost, fast development cycle and commercial availability are some of the motivations of this fact. Other trade-offs of using FPGAs compared to ASICs have been amply discussed in previous sections. Sometimes a TDC is completely included within an FPGA but, depending on the application, some parts may be outside FPGA. Beyond the delay line, current TDCs contain many other elements. An example of a TDC block diagram is depicted in Figure 8.

Figure 8 represents a basic scheme of a modern TDC. The most complex block corresponds to the delay line, which will be deeply discussed below. A simplified description of a TDC follows:

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**Figure 8.** Digital TDC basic scheme.

**4.4. FPGA design for TOF measurement**

calculation using an FPGA will be presented.

stability of the clock system becomes critical.

of a TDC block diagram is depicted in Figure 8.

circuits is the Vernier Delay line.

follows:

*4.4.1. Time to digital converter*

As commented above, there are several alternatives for implementing the TOF determination, many of them based on ASICs, that are expensive, hardly reconfigurable, and they need to be produced in high volumes to be cost-effective. However, reconfiguration capabilities of FPGAs and their low cost compared to other solutions have made them the ideal candidates for the development of complex electronic equipment, as PET systems [35]. Additionally, it is technically possible to use FPGAs to measure TOF with a very high time resolution [36], much better than the resolution of current commercial PET systems whose resolution is around 600 ps. Thus, the electronic device responsible for the TOF measurement must be able to distin‐ guish events between time periods in the order of few-tens hundreds of picoseconds to be competitive enough in the market. In this subsection, the main considerations for TOF

16 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

TDC is a well-known technique traditionally used for TOF determination [37]. The TDC goal is to recognize events and to provide a digital representation of the time they occurred. There are many TDC implementation possibilities. Focusing in digital TDCs and leaving aside the analog TDC, the simplest is a high-frequency counter, which value is incremented at each clock cycle. When an event occurs, the accumulated amount of clock periods are stored and presented. The drawback of this approach is that the stored counter is a number of integer clock cycles and, therefore, the resolution is restricted to the clock system. Thus, in order to get accurate resolution, the use of a faster clock is required. Thus, the larger the frequency the more the signal integrity problems, translating into a complex system design. Moreover, the

Interpolation circuits emerged as a necessity to measure events below the clock period. These circuits measure the time between a clock event and the event being measured. One of the problems is the TDC time required to perform a measurement, blocking new measurements for a certain period of time. One of the most implemented structures based on interpolating

Until recently, TDCs were ASIC implemented either by companies which launched the product to the market or by owners who wanted a specific design. Nowadays, the use of FPGAs aimed at this purpose is getting more popular [36-38]. Low cost, fast development cycle and commercial availability are some of the motivations of this fact. Other trade-offs of using FPGAs compared to ASICs have been amply discussed in previous sections. Sometimes a TDC is completely included within an FPGA but, depending on the application, some parts may be outside FPGA. Beyond the delay line, current TDCs contain many other elements. An example

Figure 8 represents a basic scheme of a modern TDC. The most complex block corresponds to the delay line, which will be deeply discussed below. A simplified description of a TDC


#### *4.4.2. System architecture*

TDCs may incorporate more than one channel. In the block diagram previously described, a multiple channel TDC is referred. In this case, the proposed TDC channels will share the histogram memory block and coarse counter block. At the time to get the final timestamp, the coarse counter block will store each coarse time associated to each channel number. Analo‐ gously, the histogram memory block will store, after the initial calibration, the time delay of each tap for each channel.

The importance of channels lays in the possibility of group in one single device the TOF measurement of a complete PET system [35]. The outputs of the detectors placed on the PET ring system have to be fed into a trigger unit, which will be the responsible of data processing. When a signal coming from one detector is received, the system waits certain time with the purpose of receiving another signal coming from an opposite detector (or a defined set of them). The block CFD (Constraint Fraction Discriminator) is in charge to adapt the voltage values of the signals from the detector to those required by the FPGA, without disturbing the timing information. A TDC measures the time difference between the events coming from the two detectors in order to estimate the TOF. Data will be transferred to the co-processor unit (see below) to be further sent to the acquisition control unit. Figure 9 represents the mentioned architecture.

delay line path (path which join the bins) becomes critical. There are three major issues that

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The propagation features of the delay elements are temperature and voltage dependent. This means that the variation of the temperature inside the device and the variations of the supplied voltage have to be controlled. In ASIC-based TDCs is possible compensating the delay variation through analog method, more exactly, generating a control voltage internal circuit ad-hoc. In FPGAs, analog calibration is not suitable and a digital compensation is adopted [39].

**•** *Double registration*. In this approach the total delay time of the delay line is designed to be longer than the system clock period. After a random time, the incoming signal is stored twice in order to take the average time value. This solution presents a fast time response but the drawback of this configuration is that does not provide a calibration of every bin

**•** *Statistical*. In this other approach the calibration process provides a compensated delay to each bin. The calibration process is, in many cases, automatically designed through a specific feedback. For instance, a certain component, which is also affected by PVT (Process Voltage and Temperature induced variations), is implemented and placed close to the delay line in order to resemble the temperature and voltage variations. This component might be, for example, a ring oscillator whose oscillator frequency is temperature and voltage dependent. Initially, the ring oscillator frequency is measured and stored as well as the initial time delay of each tap. Then, once the system has been calibrated, it remains continuously checking if the ring oscillator frequency has changed. If it has, the time values of each tap are interpo‐

A design tool often places delay elements of TDC automatically, what sometimes triggers imbalanced delays [37]. FPGAs dispose of repetitive structures commonly known as chain structures. FPGA designers place these sorted structures for general-purpose applications. The benefit is the short path connection between them what makes their use appropriate for TDC delay line implementation. Some of the different kinds of chain structures that the vendors include in many FPGAs are carry chain structures, sum-of-products chain, cascade chains, etc.

Figure 10 shows an internal view of a commercial FPGA. Red blocks corresponds to the delay line, which in this case if composed of carry logic structures. This is one possible placement of many. Depending on the length of the delay line, it is possible to locate the carry chain in multiples areas as long as the region contains carry elements (they are not present in all FPGA blocks). In this case, the carry chain occupancy is almost 400 slices. Often it occurs that there is not space enough to accommodate all the carry chains in a single column and additional columns are required. This fact will make the delay line less uniform. Therefore, in some

independently since the average is taken when the bins have different width.

The two more popular approaches already proposed are:

lated according to the ring oscillator frequency differences.

designs a possible placement restriction must be taken into account.

Figure 10 depicts a deployed carry chain structure.

threaten them [37, 38]:

**b. Delay line placement.**

**a. PVT**

**Figure 9.** TOF-PET architecture.

The selected FPGA must account for enough resources to accommodate the required channels. Key resources that have to be considered are those that are going to be part of the delay line. Depending on the total amount of channels needed by the application, it will be mandatory focusing on the resources, which delay elements will be placed, and a proper FPGA selection.

Concerning the channel implementation in FPGA compared to other devices, FPGAs offer flexibility at the time of providing high number of channel inputs. These channels can be dynamically defined by software and enable/disable some of them if required. This means that those resources that are now free can be used for other purposes.

#### *4.4.3. Delay line*

Basically, a delay line is a set of interconnected elements whereby a signal is passed through. It is normally used to count the time between two or more events. Each delay element (also referred as tap or bins) has a propagation delay (τ) and a storage block (see Figure 5). At certain time instant, the incoming signal is stopped and the total amount of reached taps is counted. Since the propagation delay of each element was previously measured, the time interval from the input signal arriving to the delay line until the signal is halted, can be determined.

It is very important to be taken into account that the total delay of the delay chain must be equal or greater than the clock period. Additionally, when high accuracy in TOF measurements is required (below 100 ps), any change on the propagation feature of the delay elements or the delay line path (path which join the bins) becomes critical. There are three major issues that threaten them [37, 38]:

#### **a. PVT**

purpose of receiving another signal coming from an opposite detector (or a defined set of them). The block CFD (Constraint Fraction Discriminator) is in charge to adapt the voltage values of the signals from the detector to those required by the FPGA, without disturbing the timing information. A TDC measures the time difference between the events coming from the two detectors in order to estimate the TOF. Data will be transferred to the co-processor unit (see below) to be further sent to the acquisition control unit. Figure 9 represents the mentioned

18 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

The selected FPGA must account for enough resources to accommodate the required channels. Key resources that have to be considered are those that are going to be part of the delay line. Depending on the total amount of channels needed by the application, it will be mandatory focusing on the resources, which delay elements will be placed, and a proper FPGA selection. Concerning the channel implementation in FPGA compared to other devices, FPGAs offer flexibility at the time of providing high number of channel inputs. These channels can be dynamically defined by software and enable/disable some of them if required. This means that

Basically, a delay line is a set of interconnected elements whereby a signal is passed through. It is normally used to count the time between two or more events. Each delay element (also referred as tap or bins) has a propagation delay (τ) and a storage block (see Figure 5). At certain time instant, the incoming signal is stopped and the total amount of reached taps is counted. Since the propagation delay of each element was previously measured, the time interval from the input signal arriving to the delay line until the signal is halted, can be determined.

It is very important to be taken into account that the total delay of the delay chain must be equal or greater than the clock period. Additionally, when high accuracy in TOF measurements is required (below 100 ps), any change on the propagation feature of the delay elements or the

those resources that are now free can be used for other purposes.

architecture.

**Figure 9.** TOF-PET architecture.

*4.4.3. Delay line*

The propagation features of the delay elements are temperature and voltage dependent. This means that the variation of the temperature inside the device and the variations of the supplied voltage have to be controlled. In ASIC-based TDCs is possible compensating the delay variation through analog method, more exactly, generating a control voltage internal circuit ad-hoc. In FPGAs, analog calibration is not suitable and a digital compensation is adopted [39]. The two more popular approaches already proposed are:


#### **b. Delay line placement.**

A design tool often places delay elements of TDC automatically, what sometimes triggers imbalanced delays [37]. FPGAs dispose of repetitive structures commonly known as chain structures. FPGA designers place these sorted structures for general-purpose applications. The benefit is the short path connection between them what makes their use appropriate for TDC delay line implementation. Some of the different kinds of chain structures that the vendors include in many FPGAs are carry chain structures, sum-of-products chain, cascade chains, etc. Figure 10 depicts a deployed carry chain structure.

Figure 10 shows an internal view of a commercial FPGA. Red blocks corresponds to the delay line, which in this case if composed of carry logic structures. This is one possible placement of many. Depending on the length of the delay line, it is possible to locate the carry chain in multiples areas as long as the region contains carry elements (they are not present in all FPGA blocks). In this case, the carry chain occupancy is almost 400 slices. Often it occurs that there is not space enough to accommodate all the carry chains in a single column and additional columns are required. This fact will make the delay line less uniform. Therefore, in some designs a possible placement restriction must be taken into account.

Figure 11 plots an FPGA delay line time distribution. The delay line is composed of 456 taps. A calibration process determines the delay of each tap. The maximum delay is about 70 ps and the minimum delay is about 2 ps, what exhibits a big discordance between the tap uniformity. It is easy to appreciate the DNL (Differential Non Linearity of the delay bins) effect. This effect deteriorates the time resolution of the TOF measurement system but, fortunately, there exist

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An important part of the system intended to measure the TOF is the co-processor. The goal of this component is to manage the information coming from the TDC and to provide with a timestamp to the next part of the system. Traditionally, it is not included in the trigger system

Trigger systems have currently become more complex, integrating more sub-systems in it. With the advent of modern devices, co-processors have been integrated into the main part of this trigger system, namely, FPGAs or ASICs. Either in ASIC or last decade in FPGAs, the coprocessor was hardware integrated, what meant that certain resources were already used and there were no chance to make user-defined architecture. However, new generation FPGAs provide software-defined co-processors, which are liable to be dimensioned according to the application requirements. This relatively new feature has given FPGAs even more advantages

To finalize this chapter, we will it will be described how the algorithms currently used for

Conventional PET (or non TOF-PET) reconstruction uses TOF only to determine if two detected photons are in the same time coincidence Δt and therefore belong to the same positron annihilation event. Here, a positron annihilation event would be registered along the line at which the event occurred, but it is unable to identify which voxel is the source of the event, thus all the voxels along the path are suggested to have the same probability of emission.

However, in TOF-PETs, the faster detectors are able to measure the difference in the arrival time of the two gamma rays, providing better localization of the annihilation event along the line formed by each detector pair. In fact, the position is blurred by a time measurement uncertainty named "time resolution", the time resolution of a detector is defined as the minimum time interval between two subsequent photon events in order for these to be recorded as separate events and depends on several instrumental factors. The smaller time resolution Δt, the smaller error on the localization of the source Δx. In fact the FWHM of the probability function is the localization uncertainty Δx (FWHM) = cΔt/2. This results in an overall improvement in signal to noise ratio (SNR) of the reconstructed image. In particular, the SNR in an image including TOF information improves with decreasing time resolution Δt (or the corresponding spatial uncertainty Δx). Therefore, such an uncertainty is larger for

some techniques to reduce this negative effect if required [38].

and, thus, more relevance when it deals with TOF calculation systems.

**5. Impact of TOF information on reconstruction algorithms**

image reconstruction are affected by the TOF information.

*4.4.4. Co-processor*

but it as an extra module.

**Figure 10.** Carry chain structure.

#### **c. Differential non linearity (DNL).**

The problem of the non-uniformity of tap delays is the greatest disadvantage of the FPGA delay line implementation. Its origins come from the internal way whereby the delay taps are connected, which in some cases is made by a CAD tool. Moreover, the discordances relate to the special features of some FPGAs. More specifically when the input signal passes across Logic Array Block boundaries and extra delays added cause ultra-wide bins [38]. An example of this effect is depicted in Figure 11.

Figure 11 plots an FPGA delay line time distribution. The delay line is composed of 456 taps. A calibration process determines the delay of each tap. The maximum delay is about 70 ps and the minimum delay is about 2 ps, what exhibits a big discordance between the tap uniformity. It is easy to appreciate the DNL (Differential Non Linearity of the delay bins) effect. This effect deteriorates the time resolution of the TOF measurement system but, fortunately, there exist some techniques to reduce this negative effect if required [38].

#### *4.4.4. Co-processor*

**c. Differential non linearity (DNL).**

**Figure 11.** Time delay of each delay element.

**Figure 10.** Carry chain structure.

of this effect is depicted in Figure 11.

The problem of the non-uniformity of tap delays is the greatest disadvantage of the FPGA delay line implementation. Its origins come from the internal way whereby the delay taps are connected, which in some cases is made by a CAD tool. Moreover, the discordances relate to the special features of some FPGAs. More specifically when the input signal passes across Logic Array Block boundaries and extra delays added cause ultra-wide bins [38]. An example

20 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

An important part of the system intended to measure the TOF is the co-processor. The goal of this component is to manage the information coming from the TDC and to provide with a timestamp to the next part of the system. Traditionally, it is not included in the trigger system but it as an extra module.

Trigger systems have currently become more complex, integrating more sub-systems in it. With the advent of modern devices, co-processors have been integrated into the main part of this trigger system, namely, FPGAs or ASICs. Either in ASIC or last decade in FPGAs, the coprocessor was hardware integrated, what meant that certain resources were already used and there were no chance to make user-defined architecture. However, new generation FPGAs provide software-defined co-processors, which are liable to be dimensioned according to the application requirements. This relatively new feature has given FPGAs even more advantages and, thus, more relevance when it deals with TOF calculation systems.

#### **5. Impact of TOF information on reconstruction algorithms**

To finalize this chapter, we will it will be described how the algorithms currently used for image reconstruction are affected by the TOF information.

Conventional PET (or non TOF-PET) reconstruction uses TOF only to determine if two detected photons are in the same time coincidence Δt and therefore belong to the same positron annihilation event. Here, a positron annihilation event would be registered along the line at which the event occurred, but it is unable to identify which voxel is the source of the event, thus all the voxels along the path are suggested to have the same probability of emission.

However, in TOF-PETs, the faster detectors are able to measure the difference in the arrival time of the two gamma rays, providing better localization of the annihilation event along the line formed by each detector pair. In fact, the position is blurred by a time measurement uncertainty named "time resolution", the time resolution of a detector is defined as the minimum time interval between two subsequent photon events in order for these to be recorded as separate events and depends on several instrumental factors. The smaller time resolution Δt, the smaller error on the localization of the source Δx. In fact the FWHM of the probability function is the localization uncertainty Δx (FWHM) = cΔt/2. This results in an overall improvement in signal to noise ratio (SNR) of the reconstructed image. In particular, the SNR in an image including TOF information improves with decreasing time resolution Δt (or the corresponding spatial uncertainty Δx). Therefore, such an uncertainty is larger for bigger patients (being related to the effective diameter D). The TOF SNR is proportional to the non-TOF SNR, through the following relationship:

whatever the tomography technique is considered (computed tomography, Single Photon

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Analytical (*i.e.* Filtered Back Projection, FBP) reconstruction methods were the only recon‐ struction methods available at the beginning of TOF-PET development and were originally described in the 1980s for 2D data [41, 42]. In an analytical TOF-PET approach, the image is reconstructed by using a one dimensional time-of-flight weight along the time-of-flight line [43]. In this reconstruction, the TOF response kernel *k(l)* is usually taken to be a Gaussian where

whose spatial FWHM, Δx=(2σ2(4ln2))1/2, is related to the FWHM time resolution Δt as described above. The convolution of the function describing the "unknown" emitter distribu‐ tion e(r) with the kernel function *k(l)* is directly related to the TOF projection data d(θ,r) as:

where *û* is the unit vector in the projection direction at angle *θ*. It can be demonstrated [44] that the function describing the emitter in the frequency domain, E(ν), can be obtained from:

with *K(ν û)* the FT of the TOF kernel *k(l)*. The function *W(û, ν)* is the filtering function, which is normally used if we consider FBP-like approaches. Distinct reconstruction filters normally differ only in the way they propagate noise or artifacts. Different TOF reconstruction filters can be considered (*i.e.* Most Likely Position, Confidence Weighting, Transverse Ramp, Convolved Ramp and Gaussian, Convolved Ramp and Gaussian With Confidence Weighting) being the Confidence Weighting (CW) the most widely used. In this case the filtering function is chosen as *W(û, ν)=K(ν, û)*. The CW reconstruction TOF filter has been shown to be optimal in terms of minimizing image noise variance when working with Poisson data from an infinite uniform source distribution [43], but could not be optimal in other situations. In the above discussion we have considered the 2D tomography problem and the continuous domain. These expressions can be discretized for practical implementation on real TOF-PET data. The 2D approach has been also extended to 3D data. Axial single-slice and Fourier rebinning ap‐ proaches followed by 2D reconstruction have been described [45-47]. Moreover, techniques

based on rebinning the TOF data into non-TOF arrays have been also developed [48].

where *D(θ,ν)* is the Fourier Transform (FT) of the projection data at angle *θ*, and

Emission Computed Tomography (SPECT), and PET).

**Analytical methods**

*l* is a scalar variable [44]:

exp(<sup>−</sup> *<sup>l</sup>* <sup>2</sup>

<sup>2</sup>*<sup>σ</sup>* <sup>2</sup> ),

^)*<sup>k</sup>*(*l*) *dl*,

^, *<sup>ν</sup>*)*D*(*θ*, *<sup>ν</sup>*) *<sup>d</sup>θ*,

^, *<sup>ν</sup>*)

^) *<sup>d</sup><sup>θ</sup>*

^, *<sup>ν</sup>*)*K*(*<sup>ν</sup>* <sup>⋅</sup>*<sup>u</sup>*

2*πσ*

−*∞*

^, *<sup>ν</sup>*)= *<sup>W</sup>* (*<sup>u</sup>*

*∫W* (*u*

*e*(*r* + *lu*

+*∞*

*<sup>k</sup>*(*l*)= <sup>1</sup>

*d*(*θ*, *r*)= *∫*

*E*(*ν*)=*∫H* (*u*

*H* (*u*

$$SNR\_{TOF} = \sqrt{\frac{D}{\Delta x}} SNR\_{\text{non-TOF}}$$

Nowadays, the image reconstruction problem for fully 3D TOF-PET is challenging because of the large data sizes involved. Thus, it produces a high degree of redundancy in 3D TOF-PET data which can be exploited in multiple ways as reducing data storage and thereby accelerating image reconstruction, or to reject missing or inconsistent data. These unmeasured data samples can be caused either by defective detectors, or incomplete angular coverage of the patient due to special PET scanner architectures like it could be the case of a dedicated ring PET with an aperture aiming to allow for biopsy procedures.

Mathematically, redundancy is expressed by consistency conditions which can be visualized in terms of the 3D Fourier Transform and employed for compensation of missing data, using Fourier rebinning of PET data from TOF to non TOF. Thus, TOF-PET systems require less data to provide higher quality images, so the doses to the patient could be reduced. Moreover, redundancy of information can be used to overcome missing data either from defective detectors or to special scanner architectures.

Current TOF-PETs timing resolutions of about 550-600 ps do not directly lead to an improve‐ ment in the spatial resolution of the reconstructed image. It actually reduces noise propagation by localizing events along segments of each Line of Response (LOR) rather than spreading statistical noise across the full length of each LOR. At the ultimate limit, TOF-PET could potentially localize annihilation events to within a single image voxel, effectively measuring the activity distribution directly and eliminating the need for tomographic reconstruction. However, this would require a timing-resolution of approximately 10 ps to isolate events to within a 3-mm voxel. With the current TOF-PET devices, inclusion of TOF information provides a degree of improvement similar to that obtained with the Point Spread Function (PSF) model. Moreover, TOF information can lead to an artifact-free image reconstruction when the number of angular samplings is reduced. This fact is important if PET devices with limited angle coverage are considered. Partial ring PET devices can have advantages over full ring geometries in future dedicated PET systems designed for imaging specific organs. However, partial ring design leads to an incomplete sampling of the polar angles, producing artifacts in image reconstruction. Nevertheless, the number of angular views necessary for an artifact-free image reconstruction is reduced as TOF-PET timing resolution improves (*i.e.* the additional TOF information can recover some of the missing information and reduce or eliminate the artifacts). In this sense, with TOF information, the angular sampling require‐ ments are reduced. [40]

TOF-PET approaches put challenges in the field of image reconstruction algorithms. The first challenge is to make the reconstruction time clinically viable, as TOF-PET implies a nonnegligible increase on the image reconstruction computational cost. A variety of reconstruction methods already exist for TOF-PET data. These image reconstruction procedures can be divided in two groups: analytical and iterative algorithms. This division is normally made whatever the tomography technique is considered (computed tomography, Single Photon Emission Computed Tomography (SPECT), and PET).

#### **Analytical methods**

bigger patients (being related to the effective diameter D). The TOF SNR is proportional to the

22 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Nowadays, the image reconstruction problem for fully 3D TOF-PET is challenging because of the large data sizes involved. Thus, it produces a high degree of redundancy in 3D TOF-PET data which can be exploited in multiple ways as reducing data storage and thereby accelerating image reconstruction, or to reject missing or inconsistent data. These unmeasured data samples can be caused either by defective detectors, or incomplete angular coverage of the patient due to special PET scanner architectures like it could be the case of a dedicated ring PET with an

Mathematically, redundancy is expressed by consistency conditions which can be visualized in terms of the 3D Fourier Transform and employed for compensation of missing data, using Fourier rebinning of PET data from TOF to non TOF. Thus, TOF-PET systems require less data to provide higher quality images, so the doses to the patient could be reduced. Moreover, redundancy of information can be used to overcome missing data either from defective

Current TOF-PETs timing resolutions of about 550-600 ps do not directly lead to an improve‐ ment in the spatial resolution of the reconstructed image. It actually reduces noise propagation by localizing events along segments of each Line of Response (LOR) rather than spreading statistical noise across the full length of each LOR. At the ultimate limit, TOF-PET could potentially localize annihilation events to within a single image voxel, effectively measuring the activity distribution directly and eliminating the need for tomographic reconstruction. However, this would require a timing-resolution of approximately 10 ps to isolate events to within a 3-mm voxel. With the current TOF-PET devices, inclusion of TOF information provides a degree of improvement similar to that obtained with the Point Spread Function (PSF) model. Moreover, TOF information can lead to an artifact-free image reconstruction when the number of angular samplings is reduced. This fact is important if PET devices with limited angle coverage are considered. Partial ring PET devices can have advantages over full ring geometries in future dedicated PET systems designed for imaging specific organs. However, partial ring design leads to an incomplete sampling of the polar angles, producing artifacts in image reconstruction. Nevertheless, the number of angular views necessary for an artifact-free image reconstruction is reduced as TOF-PET timing resolution improves (*i.e.* the additional TOF information can recover some of the missing information and reduce or eliminate the artifacts). In this sense, with TOF information, the angular sampling require‐

TOF-PET approaches put challenges in the field of image reconstruction algorithms. The first challenge is to make the reconstruction time clinically viable, as TOF-PET implies a nonnegligible increase on the image reconstruction computational cost. A variety of reconstruction methods already exist for TOF-PET data. These image reconstruction procedures can be divided in two groups: analytical and iterative algorithms. This division is normally made

non-TOF SNR, through the following relationship:

aperture aiming to allow for biopsy procedures.

detectors or to special scanner architectures.

*SN Rnon*−*TOF*

*SN RTOF* <sup>=</sup> *<sup>D</sup>*

*Δx*

ments are reduced. [40]

Analytical (*i.e.* Filtered Back Projection, FBP) reconstruction methods were the only recon‐ struction methods available at the beginning of TOF-PET development and were originally described in the 1980s for 2D data [41, 42]. In an analytical TOF-PET approach, the image is reconstructed by using a one dimensional time-of-flight weight along the time-of-flight line [43]. In this reconstruction, the TOF response kernel *k(l)* is usually taken to be a Gaussian where *l* is a scalar variable [44]:

$$k(l) = \frac{1}{\sqrt{2\pi}\sigma} \exp(-\frac{l^2}{2\sigma^2}),$$

whose spatial FWHM, Δx=(2σ2(4ln2))1/2, is related to the FWHM time resolution Δt as described above. The convolution of the function describing the "unknown" emitter distribu‐ tion e(r) with the kernel function *k(l)* is directly related to the TOF projection data d(θ,r) as:

$$d\left(\Theta\_{\prime},r\right) = \bigcap\_{\omega\_{\ast}}^{\star\ast} e(r+l\stackrel{\wedge}{\omega})k\left(l\right)dl\left(\omega\right)$$

where *û* is the unit vector in the projection direction at angle *θ*. It can be demonstrated [44] that the function describing the emitter in the frequency domain, E(ν), can be obtained from:

$$E\left(\nu\right) = \left[H\left(\stackrel{\bigwedge}{\mu}, \nu\right)D(\theta, \,\nu)\,d\theta\right]$$

where *D(θ,ν)* is the Fourier Transform (FT) of the projection data at angle *θ*, and

$$H(\stackrel{\bigwedge}{\stackrel{\wedge}{\mu}},\nu) = \frac{W(\stackrel{\bigwedge}{\stackrel{\wedge}{\mu}},\nu)}{\int W(\stackrel{\bigwedge}{\stackrel{\wedge}{\mu}},\nu)K(\nu\cdot\stackrel{\wedge}{\mu})d\theta}$$

with *K(ν û)* the FT of the TOF kernel *k(l)*. The function *W(û, ν)* is the filtering function, which is normally used if we consider FBP-like approaches. Distinct reconstruction filters normally differ only in the way they propagate noise or artifacts. Different TOF reconstruction filters can be considered (*i.e.* Most Likely Position, Confidence Weighting, Transverse Ramp, Convolved Ramp and Gaussian, Convolved Ramp and Gaussian With Confidence Weighting) being the Confidence Weighting (CW) the most widely used. In this case the filtering function is chosen as *W(û, ν)=K(ν, û)*. The CW reconstruction TOF filter has been shown to be optimal in terms of minimizing image noise variance when working with Poisson data from an infinite uniform source distribution [43], but could not be optimal in other situations. In the above discussion we have considered the 2D tomography problem and the continuous domain. These expressions can be discretized for practical implementation on real TOF-PET data. The 2D approach has been also extended to 3D data. Axial single-slice and Fourier rebinning ap‐ proaches followed by 2D reconstruction have been described [45-47]. Moreover, techniques based on rebinning the TOF data into non-TOF arrays have been also developed [48].

Data corrections concerning randoms, attenuation and possibly also normalization for TOF-PET devices seem not to have a TOF structure. Thus, the current approach is to apply con‐ ventional non-TOF corrections to the new TOF data. However, scatter correction is clearly identified as the component that definitely has a TOF structure and requires an appropriate

Implementation of TOF-PET Systems on Advanced Reconfigurable Logic Devices

http://dx.doi.org/10.5772/57123

25

Finally, it should be pointed out that TOF reconstruction is much less sensitive to errors and improper approximations. The redundant information present in TOF data naturally corrects the data inconsistencies during the reconstruction. It has been observed that TOF reconstruc‐ tion reduces artifacts due to incorrect normalization, approximated scatter correction, trun‐

In this chapter a complete review of the main design characteristics of TOF-PET systems based on reconfigurable logic devices has been performed. These systems have been presented from a historical perspective, and the main advantages of recovery timing information have been discussed. The goodness of the application of reconfigurable logic devices for TOF-PET systems have been described as well as digital electronics designs that would allow to accurate measure the timing information. Finally, the impact of timing information on image recon‐

As a conclusion, the implementation of the electronic hardware of PET systems on reconfig‐ urable devices, including the TOF measurement capability, seems to offer several advantages over conventional approaches based on ASICs or CPLDs, mainly in terms of cost-effectiveness, time-to-market and re-configurability. Modern programmable logic devices present the necessary features to compete with the traditional used devices in terms of TOF calculation as technology of fabrication reaches high speeds and smaller sizes. For the time being, time resolutions in FPGAs are limited by the propagation time of the digital gates that conform the digital internal blocks of the device. But, due to the fast advances in fabrication processes, it is

, J. Martos1

1 Communications and Digital Systems Design Group, Department of Electronic Engineer‐

, A.J. González2

, F. Sánchez2

,

envisaged that these limitations will be overcome in the near future.

, J. Soret1

2 Institute for Instrumentation in Molecular Imaging, UPV-CSIC, Valencia, Spain

, A. Aguilar1

and M.J. Rodríguez2

ing, University of Valencia, Valencia, Spain

TOF computation [58].

**6. Conclusion**

**Author details**

, R. García1

J. Torres1

J.M. Benlloch2

cated attenuation map, to name but a few [59].

struction algorithms has also been discussed.

#### **Iterative Methods**

Although analytical reconstruction methods are generally faster than the iterative ones, these last generate higher quality images, in terms of spatial resolution and image noise [49]. Iterative reconstruction methods such as the Ordered Subsets Expectation Maximization (OSEM) algorithm have to be modified in order to take into account TOF information. This is done by including a PSF along the LOR in the projector, with a width directly related to the time resolution of the scanner. Despite of the high computational cost of the iterative algorithms with respect to the analytical ones, current iterative reconstruction methods are the standard in clinical PET, and also appear to be the natural choice for TOF-PET in both present and future clinical TOF scanners [50]. Moreover, TOF-PET adds complexity to data organization and computation time to the reconstruction algorithm. If the reconstruction is sinogram based, TOF information adds a "4th" dimension to the 3D sinogram representation, changing data storage and dynamic memory requirements. In contrast to these drawbacks, if the reconstruction is list-mode based, the data are stored as a list of detected events [51]. However, 3D list-mode iterative TOF reconstruction allows for the modeling of all physical effects of the scanner system, thus retaining the resolutions of the data in the spatial and temporal domains without any binning approximation. In this sense, this approach is much more flexible and powerful than the sinogram approach at the cost of a computationally effort, being slower, since backand forward- projections are independently executed for each event of the list. In this case, the reconstruction time depends not only on the length of the list, *i.e.* the number of detected events, but also on the sizes of the spatial and TOF kernels. Fully 3D implementations of the TOF-OSEM algorithm from list-mode data have been described in [52, 53].

In order to get image reconstruction times compatible with the daily clinic routine, 3D listmode TOF-OSEM algorithms use multiple (10–20) processors and non-optimized reconstruc‐ tion parameter choices (*e.g.*, stopping criteria determined by the reconstruction time rather than convergence and use of a truncated TOF kernel to speed up the forward- and backprojection steps) [54]. However, great effort has been put in optimizing timing requirements for TOF-PET iterative reconstruction algorithms. In reference [55] a new formulation for computing line projection operations on graphics processing units (GPUs) using the compute unified device architecture (CUDA) framework, is described. When applied to 3D list-mode TOF-OSEM image reconstruction this procedure is >300 times faster than the single-threaded reference CPU implementation[51].

Recently [56], a new TOF-PET list-mode based algorithm has been developed (DIRECT, direct image reconstruction for TOF) to speed up TOF-PET reconstruction that takes advantage of the reduced angular sampling requirement of TOF data by grouping list-mode data into a small number of azimuthal views and co-polar tilts. In terms of computing time, the total processing and reconstruction time for the DIRECT approach seems to be about 25%–30% that of list-mode 3D TOF-OSEM for comparable image quality. In addition, the total processing and reconstruction time is roughly constant with DIRECT, regardless of the sizes of the TOF and LOR resolution kernels, while the times for list-mode TOF-OSEM strongly depend on these kernel sizes. The reconstruction time per iteration for DIRECT is also independent of the number of events, while the per-iteration time for list-mode TOF-OSEM is almost linear with the number of counts [57].

Data corrections concerning randoms, attenuation and possibly also normalization for TOF-PET devices seem not to have a TOF structure. Thus, the current approach is to apply con‐ ventional non-TOF corrections to the new TOF data. However, scatter correction is clearly identified as the component that definitely has a TOF structure and requires an appropriate TOF computation [58].

Finally, it should be pointed out that TOF reconstruction is much less sensitive to errors and improper approximations. The redundant information present in TOF data naturally corrects the data inconsistencies during the reconstruction. It has been observed that TOF reconstruc‐ tion reduces artifacts due to incorrect normalization, approximated scatter correction, trun‐ cated attenuation map, to name but a few [59].

#### **6. Conclusion**

**Iterative Methods**

Although analytical reconstruction methods are generally faster than the iterative ones, these last generate higher quality images, in terms of spatial resolution and image noise [49]. Iterative reconstruction methods such as the Ordered Subsets Expectation Maximization (OSEM) algorithm have to be modified in order to take into account TOF information. This is done by including a PSF along the LOR in the projector, with a width directly related to the time resolution of the scanner. Despite of the high computational cost of the iterative algorithms with respect to the analytical ones, current iterative reconstruction methods are the standard in clinical PET, and also appear to be the natural choice for TOF-PET in both present and future clinical TOF scanners [50]. Moreover, TOF-PET adds complexity to data organization and computation time to the reconstruction algorithm. If the reconstruction is sinogram based, TOF information adds a "4th" dimension to the 3D sinogram representation, changing data storage and dynamic memory requirements. In contrast to these drawbacks, if the reconstruction is list-mode based, the data are stored as a list of detected events [51]. However, 3D list-mode iterative TOF reconstruction allows for the modeling of all physical effects of the scanner system, thus retaining the resolutions of the data in the spatial and temporal domains without any binning approximation. In this sense, this approach is much more flexible and powerful than the sinogram approach at the cost of a computationally effort, being slower, since backand forward- projections are independently executed for each event of the list. In this case, the reconstruction time depends not only on the length of the list, *i.e.* the number of detected events, but also on the sizes of the spatial and TOF kernels. Fully 3D implementations of the

24 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

TOF-OSEM algorithm from list-mode data have been described in [52, 53].

reference CPU implementation[51].

the number of counts [57].

In order to get image reconstruction times compatible with the daily clinic routine, 3D listmode TOF-OSEM algorithms use multiple (10–20) processors and non-optimized reconstruc‐ tion parameter choices (*e.g.*, stopping criteria determined by the reconstruction time rather than convergence and use of a truncated TOF kernel to speed up the forward- and backprojection steps) [54]. However, great effort has been put in optimizing timing requirements for TOF-PET iterative reconstruction algorithms. In reference [55] a new formulation for computing line projection operations on graphics processing units (GPUs) using the compute unified device architecture (CUDA) framework, is described. When applied to 3D list-mode TOF-OSEM image reconstruction this procedure is >300 times faster than the single-threaded

Recently [56], a new TOF-PET list-mode based algorithm has been developed (DIRECT, direct image reconstruction for TOF) to speed up TOF-PET reconstruction that takes advantage of the reduced angular sampling requirement of TOF data by grouping list-mode data into a small number of azimuthal views and co-polar tilts. In terms of computing time, the total processing and reconstruction time for the DIRECT approach seems to be about 25%–30% that of list-mode 3D TOF-OSEM for comparable image quality. In addition, the total processing and reconstruction time is roughly constant with DIRECT, regardless of the sizes of the TOF and LOR resolution kernels, while the times for list-mode TOF-OSEM strongly depend on these kernel sizes. The reconstruction time per iteration for DIRECT is also independent of the number of events, while the per-iteration time for list-mode TOF-OSEM is almost linear with

In this chapter a complete review of the main design characteristics of TOF-PET systems based on reconfigurable logic devices has been performed. These systems have been presented from a historical perspective, and the main advantages of recovery timing information have been discussed. The goodness of the application of reconfigurable logic devices for TOF-PET systems have been described as well as digital electronics designs that would allow to accurate measure the timing information. Finally, the impact of timing information on image recon‐ struction algorithms has also been discussed.

As a conclusion, the implementation of the electronic hardware of PET systems on reconfig‐ urable devices, including the TOF measurement capability, seems to offer several advantages over conventional approaches based on ASICs or CPLDs, mainly in terms of cost-effectiveness, time-to-market and re-configurability. Modern programmable logic devices present the necessary features to compete with the traditional used devices in terms of TOF calculation as technology of fabrication reaches high speeds and smaller sizes. For the time being, time resolutions in FPGAs are limited by the propagation time of the digital gates that conform the digital internal blocks of the device. But, due to the fast advances in fabrication processes, it is envisaged that these limitations will be overcome in the near future.

#### **Author details**

J. Torres1 , R. García1 , A. Aguilar1 , J. Soret1 , J. Martos1 , A.J. González2 , F. Sánchez2 , J.M. Benlloch2 and M.J. Rodríguez2

1 Communications and Digital Systems Design Group, Department of Electronic Engineer‐ ing, University of Valencia, Valencia, Spain

2 Institute for Instrumentation in Molecular Imaging, UPV-CSIC, Valencia, Spain

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[40] S. Surti, J.S. Karp, " Design considerations for a limited angle, dedicated breast, TOF

[41] D. L. Snyder, L. J. Thomas, and M. M. Ter-Pogossian, "A mathematical model for positron-emission tomography systems having time-of-flight measurements," IEEE

[42] E. A. Philippe, N. A. Mullani, W.H. Wong, and R. Hartz, "Real-time image recon‐ struction for time-of-flight positron emission tomography (TOFPET)," IEEE Trans.

[43] T. Tomitani, "Image reconstruction and noise evaluation in photon time-of-flight as‐ sisted positron emission tomography," IEEE Trans. Nucl. Sci., vol. NS-28, no. 6, pp.

[44] C.C. Watson, "An Evaluation of Image Noise Variance for Time-of-Flight PET," IEEE

[45] M. Defrise, M. E. Casey, C. Michel, and M. Conti, "Fourier rebinning of time-of-flight

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[59] M. E. Daube-Witherspoon, S. Surti, A. Perkins, C. C. M Kyba, R. Wiener, M. EWern‐ er, R. Kulp, and J. S. Karp, "The imaging performance of a LaBr3-based PET scan‐ ner", Phys. Med. Biol., vol. 55, pp. 45-64, 2010.

**Chapter 2**

**Positron Emission Tomography-Computed Tomography**

Combined and optimized Positron Emission Tomography and Computed Tomography (PET-CT) exams are among the more complex of the radiographic modalities utilized in both body oncology and neurology settings. A distinct and targeted workflow is essential to successful data acquisition, processing, and related image management and reporting [1, 2]. This chapter will review the primary considerations involved in acquisition, processing, and archiving of PET-CT raw data and image data in a clinical PET-CT environment primarily centered on

The method utilized for the creation of PET images is steeped in proprietary acquisition techniques available from a very limited number of PET-CT scanner manufacturers. Regard‐ less of the manufacturer, successful PET-CT acquisition depends on a consistent quality assurance and quality control program as well as an attentive technologist staff and supportive physicist. Routine and careful quality control at daily intervals is at the center of any high performing PET-CT department. The pinnacle of PET quality control is the acquisition and evaluation of PET sinograms that comprise the raw data. PET-CT raw data consists of gigabyte sinogram data sets that are used to generate image sets consisting of transverse slices. Each transverse slice maps to a sine wave frequency. These frequencies on the sinogram can be practically visualized as displacements or rows on the x axis and an angle on the y-axis which represent a projection through the object being imaged. At the smallest level, each pixel in the sinogram corresponds to specific line-of-response (LOR) based on the byproducts of a positron

> © 2013 Faasse; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Data Acquisition and Image Management**

Additional information is available at the end of the chapter

Todd Faasse

**1. Introduction**

oncology and neurology.

**2. Raw data acquisition**

http://dx.doi.org/10.5772/57119

### **Positron Emission Tomography-Computed Tomography Data Acquisition and Image Management**

Todd Faasse

[59] M. E. Daube-Witherspoon, S. Surti, A. Perkins, C. C. M Kyba, R. Wiener, M. EWern‐ er, R. Kulp, and J. S. Karp, "The imaging performance of a LaBr3-based PET scan‐

30 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

ner", Phys. Med. Biol., vol. 55, pp. 45-64, 2010.

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57119

#### **1. Introduction**

Combined and optimized Positron Emission Tomography and Computed Tomography (PET-CT) exams are among the more complex of the radiographic modalities utilized in both body oncology and neurology settings. A distinct and targeted workflow is essential to successful data acquisition, processing, and related image management and reporting [1, 2]. This chapter will review the primary considerations involved in acquisition, processing, and archiving of PET-CT raw data and image data in a clinical PET-CT environment primarily centered on oncology and neurology.

#### **2. Raw data acquisition**

The method utilized for the creation of PET images is steeped in proprietary acquisition techniques available from a very limited number of PET-CT scanner manufacturers. Regard‐ less of the manufacturer, successful PET-CT acquisition depends on a consistent quality assurance and quality control program as well as an attentive technologist staff and supportive physicist. Routine and careful quality control at daily intervals is at the center of any high performing PET-CT department. The pinnacle of PET quality control is the acquisition and evaluation of PET sinograms that comprise the raw data. PET-CT raw data consists of gigabyte sinogram data sets that are used to generate image sets consisting of transverse slices. Each transverse slice maps to a sine wave frequency. These frequencies on the sinogram can be practically visualized as displacements or rows on the x axis and an angle on the y-axis which represent a projection through the object being imaged. At the smallest level, each pixel in the sinogram corresponds to specific line-of-response (LOR) based on the byproducts of a positron

© 2013 Faasse; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

annihilation event detected in the scanner PET crystals. The resulting pixel rendering is considered image data. Additional or revised reconstructions of different slice thickness or overlap can only be rendered from *raw* data. Image data slice thickness cannot be changed once rendered. Figure 1 illustrates a sinogram rendered from daily quality control procedures.

downtime. Figure 3 demonstrates a typical positron emission tomography acquisition

Positron Emission Tomography-Computed Tomography Data Acquisition and Image Management

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33

Once an appropriate sinogram data set has been acquired and confirmed as meeting the manufacturer and site-specific quality control requirements, reconstruction of slices from the data can be commenced. Common and clinically useful reconstructions include filtered back projection corrected and uncorrected images as well as iterative reconstructions. With iterative reconstructions, manufacturers are also bringing to bear time of flight capabilities made possible as a result of the very latest and most progressive reconstruction algorithms. Regard‐ less of the vendor or reconstruction methodology employed, any actions necessary to correct

Two dimensional (2D) versus three dimensional (3D)acquisitions continue to play a role in image reconstruction management with 3D gaining primacy and near routine usage for all PET reconstructions [3]. In the earlier days of PET, 2D imaging was the most desirable and feasible means of imaging. This was true because, too many events would be detected within the PET crystal array with excessive dead time and image degradation in adjacent PET detector rings. This was overcome by placing septa comprised of tungsten or lead in between the detector rings. Along with these septa, the scanner electronics were configured to only detect

for random events, scatter, decay, normalization, and dead time will be applied.

**3. Raw data reconstruction into processed image data**

**Figure 2.** PET sinogram with failed block ("stripes" with no activity)

interface.

**Figure 1.** Normal PET sinogram

The PET sinogram will reveal excessive and non-uniform fluctuations occurring in the gantry crystal detector architecture. Any significant change in the detector crystals will be manifest as a "stripe" of non-uniformity. In most cases, this stripe indicates a detector block failure. The presence of a failed detector block will require a repeat of the quality control to attempt to verify scanner malfunction. Block failure is a serious malfunction that in most cases requires the intervention of a PET service engineer. The block will either need to have the corresponding electronics tuned or the block will require replacement in order to continue with scanning. Figure 2 depicts a PET sinogram with a failed block artifact.

PET scintillation crystals are especially susceptible to failure due to environmental conditions such as dramatic alterations in ambient temperature, humidity, or cooling infrastructure. As a result, the technologist should intermittently but frequently review a gantry interface that provides a continuous report of gantry status and conditions. In particular, the technologist should be mindful of alterations in gantry temperature or dew point as well as substantial changes in the voltage of the detector electronics. Maintaining vigilance in monitoring gantry conditions can be an important part of early troubleshooting to minimize delays and eventual

Positron Emission Tomography-Computed Tomography Data Acquisition and Image Management http://dx.doi.org/10.5772/57119 33

**Figure 2.** PET sinogram with failed block ("stripes" with no activity)

annihilation event detected in the scanner PET crystals. The resulting pixel rendering is considered image data. Additional or revised reconstructions of different slice thickness or overlap can only be rendered from *raw* data. Image data slice thickness cannot be changed once rendered. Figure 1 illustrates a sinogram rendered from daily quality control procedures.

32 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

The PET sinogram will reveal excessive and non-uniform fluctuations occurring in the gantry crystal detector architecture. Any significant change in the detector crystals will be manifest as a "stripe" of non-uniformity. In most cases, this stripe indicates a detector block failure. The presence of a failed detector block will require a repeat of the quality control to attempt to verify scanner malfunction. Block failure is a serious malfunction that in most cases requires the intervention of a PET service engineer. The block will either need to have the corresponding electronics tuned or the block will require replacement in order to continue with scanning.

PET scintillation crystals are especially susceptible to failure due to environmental conditions such as dramatic alterations in ambient temperature, humidity, or cooling infrastructure. As a result, the technologist should intermittently but frequently review a gantry interface that provides a continuous report of gantry status and conditions. In particular, the technologist should be mindful of alterations in gantry temperature or dew point as well as substantial changes in the voltage of the detector electronics. Maintaining vigilance in monitoring gantry conditions can be an important part of early troubleshooting to minimize delays and eventual

Figure 2 depicts a PET sinogram with a failed block artifact.

**Figure 1.** Normal PET sinogram

downtime. Figure 3 demonstrates a typical positron emission tomography acquisition interface.

#### **3. Raw data reconstruction into processed image data**

Once an appropriate sinogram data set has been acquired and confirmed as meeting the manufacturer and site-specific quality control requirements, reconstruction of slices from the data can be commenced. Common and clinically useful reconstructions include filtered back projection corrected and uncorrected images as well as iterative reconstructions. With iterative reconstructions, manufacturers are also bringing to bear time of flight capabilities made possible as a result of the very latest and most progressive reconstruction algorithms. Regard‐ less of the vendor or reconstruction methodology employed, any actions necessary to correct for random events, scatter, decay, normalization, and dead time will be applied.

Two dimensional (2D) versus three dimensional (3D)acquisitions continue to play a role in image reconstruction management with 3D gaining primacy and near routine usage for all PET reconstructions [3]. In the earlier days of PET, 2D imaging was the most desirable and feasible means of imaging. This was true because, too many events would be detected within the PET crystal array with excessive dead time and image degradation in adjacent PET detector rings. This was overcome by placing septa comprised of tungsten or lead in between the detector rings. Along with these septa, the scanner electronics were configured to only detect

cially available and integrated with PET-CT. CT detector architecture utilizing upwards of 128 rows can now be found on commercially available PET-CT scanners [4]. In the earlier days of PET, Ge-68 or Cs-137 rod sources were used to generate a transmission scan through each slice of the patient's body resulting in a measurement of attenuation correction for each pixel. Typically, the rod source was maintained within a shielded portion of the gantry. Upon the issuing of a transmission command from the scanner operating software, the shielded rod would be extended and rotated about the patient for a predefined time per bed position, usually 3-4 minutes per bed. This was a lengthy process that commonly took upwards of 30 minutes to complete. Modern PET scanners no longer utilize transmission rod sources and PET scanners containing CT infrastructure are the norm due to the dramatically increased speed of acquisition and resulting attenuation correction map [5]. Figure 5 depicts transmission

Positron Emission Tomography-Computed Tomography Data Acquisition and Image Management

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35

**Figure 5.** PET rod transmission source scan: Contemporary PET scanners no longer make use of rod-based transmis‐

sion because CT has become the sole source of transmission-based attenuation correction.

scan created with a rotating radioactive rod source assembly.

**Figure 4.** PET detection modes

**Figure 3.** PET acquisition interface. In addition to critical benchmarks such as gantry temperature and dew point, the technologist may also view PET prompt information such as random, true, and single events.

coincidence events from within a limited plane to exclude non-collinear events. This also reduced the sensitivity of coincidence detection and corresponding image resolution. With improvements in crystal technology and detector electronics, it became possible to remove the septa that separated PET rings and detect collinear events in the adjacent PET rings. This could occur without concomitant dead time affects and allowed for a nearly quadruple increase in sensitivity. Figure 4 depicts 2D mode imaging (left) and 3D mode (right):

Attenuation corrections methods must also be implemented routinely or the PET axial images will have a muted or dim appearance for those structures that are more towards the center and deeper aspects of the patient's anatomy. The most simple attenuation correction method is that of filtered back projection whereby the body is assumed to be an ellipse of relatively uniform density. This "Chang technique" works well in uniformly dense anatomic structures but is woefully slow and inadequate in portions of the anatomy that contains variable density structures. Therefore, for both speed and accuracy, measured attenuation is preferable via the use a of a CT source. The historical arc of PET-CT attenuation projection has progressed from usage of an external transmission rod source to "modern" CT scanners that are now commer‐

**Figure 4.** PET detection modes

coincidence events from within a limited plane to exclude non-collinear events. This also reduced the sensitivity of coincidence detection and corresponding image resolution. With improvements in crystal technology and detector electronics, it became possible to remove the septa that separated PET rings and detect collinear events in the adjacent PET rings. This could occur without concomitant dead time affects and allowed for a nearly quadruple increase in

**Figure 3.** PET acquisition interface. In addition to critical benchmarks such as gantry temperature and dew point, the

34 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Attenuation corrections methods must also be implemented routinely or the PET axial images will have a muted or dim appearance for those structures that are more towards the center and deeper aspects of the patient's anatomy. The most simple attenuation correction method is that of filtered back projection whereby the body is assumed to be an ellipse of relatively uniform density. This "Chang technique" works well in uniformly dense anatomic structures but is woefully slow and inadequate in portions of the anatomy that contains variable density structures. Therefore, for both speed and accuracy, measured attenuation is preferable via the use a of a CT source. The historical arc of PET-CT attenuation projection has progressed from usage of an external transmission rod source to "modern" CT scanners that are now commer‐

sensitivity. Figure 4 depicts 2D mode imaging (left) and 3D mode (right):

technologist may also view PET prompt information such as random, true, and single events.

cially available and integrated with PET-CT. CT detector architecture utilizing upwards of 128 rows can now be found on commercially available PET-CT scanners [4]. In the earlier days of PET, Ge-68 or Cs-137 rod sources were used to generate a transmission scan through each slice of the patient's body resulting in a measurement of attenuation correction for each pixel. Typically, the rod source was maintained within a shielded portion of the gantry. Upon the issuing of a transmission command from the scanner operating software, the shielded rod would be extended and rotated about the patient for a predefined time per bed position, usually 3-4 minutes per bed. This was a lengthy process that commonly took upwards of 30 minutes to complete. Modern PET scanners no longer utilize transmission rod sources and PET scanners containing CT infrastructure are the norm due to the dramatically increased speed of acquisition and resulting attenuation correction map [5]. Figure 5 depicts transmission scan created with a rotating radioactive rod source assembly.

**Figure 5.** PET rod transmission source scan: Contemporary PET scanners no longer make use of rod-based transmis‐ sion because CT has become the sole source of transmission-based attenuation correction.

The advantage of the traditional transmission rod source was that the patient received much less radiation dose with a transmission rod source compared to modern CT transmission methods [6]. Additionally, the transmission data were acquired in the native 511 keV energy obviating the need for segmentation that is required for CT. Segmentation involves smoothing the transaxial CT images to approximate the spatial resolution of the PET scanner. This segmentation is necessary because the energy settings of 80-140 keV inherent to CT are much lower than the 511 keV energies common to PET. The pixel values of these regions are altered and replaced with the known linear attenuation coefficient for the imaged tissue or other internal materials such as a prosthetic (joint replacement, pacemaker etc.). The process of replacing the pixel values eliminates a considerable amount of noise inherent in the "raw" image. The segmented CT attenuation map is scaled to the 511 keV and applied as attenuation correction to the PET images.

**Figure 6.** PET low (128 matrix) PET high (400 matrix)

contrast phases and rendered in multiple kernels and windows

CT raw data requires substantially more space, with modern 64-row scanner used in PET-CT generating upwards of 70 MB of projection data per second. As a result, the typical whole torso PET-CT examination can readily require in excess of 2 gigabytes (GB) of hard drive storage space for the raw data alone when there is a single CT acquisition created for the entire torso axial coverage (Table 1). With the addition of other CT acquisitions which may include lung breath hold, multiple contrast phases or longer axial coverage, the raw data space consumed increases accordingly to 4 GB and greater. The reconstructed images consume considerably less hard drive space; an entire image set, including different PET and CT image reconstruc‐ tions occupy less than 500 MB. Common PET image reconstructions include attenuation corrected iterative and non-attenuation corrected filtered back projection. Figure 7 depicts the

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37

**Figure 7.** Typical transaxial PET-CT image reconstructions. Note CT was acquired with both arterial and equilibrium

In a very active practice in which 10 or more patients are imaged per scanner, several GB of hard drive space can be easily filled in the course of a day [1]. If the PET-CT technologist does

transaxial PET reconstructions commonly used in body oncology imaging.

As mentioned previously, the PET-CT scanning acquisition results in the creation of raw projection data. This raw projection data is processed and rendered into reconstructed image sets. It is common practice at most clinical imaging institutions to retain the CT raw projection data for a limited number of days. This permits sufficient time to elapse such that the corre‐ sponding reconstructed images can be reviewed by the interpreting physician. It is particularly important to retain the raw data for those limited but important circumstances that the interpreting physician requests an additional reconstruction for better elucidation of a particular abnormality prior to generating the final scan interpretation. Reconstructed axial images may also be utilized to create additional projections including coronal and sagittal image sets. If the images are to be used outside of the oncology realm that PET-CT has principally been concerned with, the image data will be rendered into vertical and horizontal long axis images to accompany the usual transverse/transaxial image sets. However, certain institutions due to internal protocols or to adhere to specific research protocols must retain the raw data indefinitely. In this case, a reliable and timely means of archiving of all of the raw data generated by a scan will be necessary. There are myriad options available for archiving of said data. Reliable and timely archiving and retrievabililty will figure prominently in deciding which type of archiving solution is appropriate. Despite the increasing availability of robust and inexpensive computer memory, these data sets quickly deplete available hard drive space and create a pressing need for removal. This is because the CT raw data sets are much larger when compared to a corresponding PET acquisition of the same axial coverage. Archival and retrieval methods and strategies will be covered later in this chapter.

The amount of raw image data space required for each PET-CT examination depends on both the particular scanner configuration as well as the scan protocols in general usage by a facility. Each PET bed will require fewer than 10 megabytes (MB) of storage for lower matrix acquis‐ itions. Lower matrices are usually those that are lower than 256. A lower matrix would be commonly used for axial coverage necessary for torso-based oncology such as breast, color‐ ectal, and lymphoma staging and restaging. Higher matrices, such as those used for head & neck oncology or neurology imaging on the very latest and modern PET-CT scanners, are as high as 512. These high, fine matrices will require in excess of 70 MB for a single PET bed position. Figure 6 shows lower and higher matrix image examples.

**Figure 6.** PET low (128 matrix) PET high (400 matrix)

The advantage of the traditional transmission rod source was that the patient received much less radiation dose with a transmission rod source compared to modern CT transmission methods [6]. Additionally, the transmission data were acquired in the native 511 keV energy obviating the need for segmentation that is required for CT. Segmentation involves smoothing the transaxial CT images to approximate the spatial resolution of the PET scanner. This segmentation is necessary because the energy settings of 80-140 keV inherent to CT are much lower than the 511 keV energies common to PET. The pixel values of these regions are altered and replaced with the known linear attenuation coefficient for the imaged tissue or other internal materials such as a prosthetic (joint replacement, pacemaker etc.). The process of replacing the pixel values eliminates a considerable amount of noise inherent in the "raw" image. The segmented CT attenuation map is scaled to the 511 keV and applied as attenuation

36 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

As mentioned previously, the PET-CT scanning acquisition results in the creation of raw projection data. This raw projection data is processed and rendered into reconstructed image sets. It is common practice at most clinical imaging institutions to retain the CT raw projection data for a limited number of days. This permits sufficient time to elapse such that the corre‐ sponding reconstructed images can be reviewed by the interpreting physician. It is particularly important to retain the raw data for those limited but important circumstances that the interpreting physician requests an additional reconstruction for better elucidation of a particular abnormality prior to generating the final scan interpretation. Reconstructed axial images may also be utilized to create additional projections including coronal and sagittal image sets. If the images are to be used outside of the oncology realm that PET-CT has principally been concerned with, the image data will be rendered into vertical and horizontal long axis images to accompany the usual transverse/transaxial image sets. However, certain institutions due to internal protocols or to adhere to specific research protocols must retain the raw data indefinitely. In this case, a reliable and timely means of archiving of all of the raw data generated by a scan will be necessary. There are myriad options available for archiving of said data. Reliable and timely archiving and retrievabililty will figure prominently in deciding which type of archiving solution is appropriate. Despite the increasing availability of robust and inexpensive computer memory, these data sets quickly deplete available hard drive space and create a pressing need for removal. This is because the CT raw data sets are much larger when compared to a corresponding PET acquisition of the same axial coverage.

Archival and retrieval methods and strategies will be covered later in this chapter.

position. Figure 6 shows lower and higher matrix image examples.

The amount of raw image data space required for each PET-CT examination depends on both the particular scanner configuration as well as the scan protocols in general usage by a facility. Each PET bed will require fewer than 10 megabytes (MB) of storage for lower matrix acquis‐ itions. Lower matrices are usually those that are lower than 256. A lower matrix would be commonly used for axial coverage necessary for torso-based oncology such as breast, color‐ ectal, and lymphoma staging and restaging. Higher matrices, such as those used for head & neck oncology or neurology imaging on the very latest and modern PET-CT scanners, are as high as 512. These high, fine matrices will require in excess of 70 MB for a single PET bed

correction to the PET images.

CT raw data requires substantially more space, with modern 64-row scanner used in PET-CT generating upwards of 70 MB of projection data per second. As a result, the typical whole torso PET-CT examination can readily require in excess of 2 gigabytes (GB) of hard drive storage space for the raw data alone when there is a single CT acquisition created for the entire torso axial coverage (Table 1). With the addition of other CT acquisitions which may include lung breath hold, multiple contrast phases or longer axial coverage, the raw data space consumed increases accordingly to 4 GB and greater. The reconstructed images consume considerably less hard drive space; an entire image set, including different PET and CT image reconstruc‐ tions occupy less than 500 MB. Common PET image reconstructions include attenuation corrected iterative and non-attenuation corrected filtered back projection. Figure 7 depicts the transaxial PET reconstructions commonly used in body oncology imaging.

**Figure 7.** Typical transaxial PET-CT image reconstructions. Note CT was acquired with both arterial and equilibrium contrast phases and rendered in multiple kernels and windows

In a very active practice in which 10 or more patients are imaged per scanner, several GB of hard drive space can be easily filled in the course of a day [1]. If the PET-CT technologist does not routinely transfer raw data sets and reconstructed image sets to other storage sites or delete them from the hard drive space on a routine basis, system functionality can be severely hampered. In some cases, intensive hard drive utilization may cause database corruption resulting in significant interruptions and possibly downtime. Table 1 depicts a comparison of both PET and CT raw and reconstructed file sizes.

technology has been the primary strategy targeted at improving image resolution and acquisition speed [8, 9]. The concept of time of flight dates back many years and was utilized for limited applications employing very fast and expensive crystal arrays [8, 9]. The economics of crystal manufacture combined with more affordable and rapid computer processors and memory have made ToF feasible to deploy among virtually all of the mainstream PET-CT manufacturers. The crystal standard for many years in PET technology was the bismuth germinate crystal. It had the advantage of having good 511 keV stopping power, universal availability and was well-tested within PET gantry design. However, it lacked the fast scintillation capabilities that are essential to ToF PET. Lutetium oxyorthosilicate (LSO) or cerium-doped lutetium yttrium orthosilicate (LYSO) have emerged as the industry standard

Positron Emission Tomography-Computed Tomography Data Acquisition and Image Management

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39

The principle advantage of ToF is the ability to dramatically improve the positioning of annihilation events that occur outside of the line of response (LOR). This is accomplished by locating the annihilation photon energy deposition on the opposing sides of the ring of crystals

It is important to understand that ToF allows for better lesion detectability not because of improvement in resolution but as a result of improved signal-to-noise definition inherent in improved timing resolution. For this to occur in contemporary PET scanners, the coincidence timing window must be configured to be very short (4-6 nanoseconds) to improve the fraction

**5. Quantitative PET imaging: Considerations for optimizing and rendering**

Provided accurate attenuation correction is performed, PET scanners provide the opportunity to generate semi-quantitative measurements of tumor metabolism. These measurements, known as standardized uptake values (SUVs) continue to be the primary and most universally accepted method for generating semi-quantitative measurements that depict tumor metabo‐ lism [11]. The default unit of measurement in all PET scanners is kilobecuerels per milliliter. This unit of measurement together with the quantity of injected radioactivity, patient weight, and decay time is used to compute the SUV. Considerable error inherent to all of the afore‐ mentioned criteria can result in badly flawed measurements and ultimately, false tumor metabolism quantification. In order to reduce the likelihood of introducing error in SUVs, at a minimum, the following must be evaluated and effectively implemented in the SUV

**•** Scanner cross-calibration: procedure performed to ensure that dose calibrator dose assays

**•** Measurement of residual syringe activity: This occurs immediately subsequent to admin‐ istering the dose to the patient. The residual syringe activity is subtracted and the total

in the PET gantry and determining the difference in arrival times of those events.

capable of the rapid scintillation times necessary to support ToF [10].

of randoms detected and resultant improvement in image contrast.

**the standardized uptake value (SUV)**

match the radioactivity measured by the PET scanner.

calculation [11]:


File size assumptions: A PET bed occupying approximately 10 cm of axial coverage requires 70 MB. A CT of the corresponding PET axial coverage is 3 times as large or ~ 210 MB. \*The typical PET-CT would be of the torso ("skull base to thighs") and would be approximately 5-6 bed positions. Depending on the axial field of view, wholebody (skull vertex to toes) imaging may require as many as 15 or more bed positions to provide sufficient axial coverage.

**Table 1.** Comparison of both PET and CT raw and reconstructed file sizes

Common and scalable raw and image data archiving strategies and solutions will be discussed later in this chapter.

#### **4. Time-of-flight PET**

The PET scanner crystals remain the primary limiting factor in both image resolution and speed of acquisition capabilities [7]. The development and implementation of Time-of-Flight (ToF) technology has been the primary strategy targeted at improving image resolution and acquisition speed [8, 9]. The concept of time of flight dates back many years and was utilized for limited applications employing very fast and expensive crystal arrays [8, 9]. The economics of crystal manufacture combined with more affordable and rapid computer processors and memory have made ToF feasible to deploy among virtually all of the mainstream PET-CT manufacturers. The crystal standard for many years in PET technology was the bismuth germinate crystal. It had the advantage of having good 511 keV stopping power, universal availability and was well-tested within PET gantry design. However, it lacked the fast scintillation capabilities that are essential to ToF PET. Lutetium oxyorthosilicate (LSO) or cerium-doped lutetium yttrium orthosilicate (LYSO) have emerged as the industry standard capable of the rapid scintillation times necessary to support ToF [10].

not routinely transfer raw data sets and reconstructed image sets to other storage sites or delete them from the hard drive space on a routine basis, system functionality can be severely hampered. In some cases, intensive hard drive utilization may cause database corruption resulting in significant interruptions and possibly downtime. Table 1 depicts a comparison of

38 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**PET raw data set size in MB**

 3 70 210 280 6 140 420 560 9 210 630 840 12 280 840 1120 15 350 1050 1400 **\*6 18 420 1260 1680** 21 490 1470 1960 24 560 1680 2240 27 630 1890 2520 30 700 2100 2800 33 770 2310 3080 36 840 2520 3360 39 910 2730 3640 42 980 2940 3920 45 1050 3150 4200 File size assumptions: A PET bed occupying approximately 10 cm of axial coverage requires 70 MB. A CT of the corresponding PET axial coverage is 3 times as large or ~ 210 MB. \*The typical PET-CT would be of the torso ("skull base to thighs") and would be approximately 5-6 bed positions. Depending on the axial field of view, wholebody (skull vertex to toes) imaging may require as many as 15 or more bed positions to provide sufficient axial coverage.

Common and scalable raw and image data archiving strategies and solutions will be discussed

The PET scanner crystals remain the primary limiting factor in both image resolution and speed of acquisition capabilities [7]. The development and implementation of Time-of-Flight (ToF)

**CT raw data set size in MB**

**Total PET-CT file size in MB**

both PET and CT raw and reconstructed file sizes.

**Table 1.** Comparison of both PET and CT raw and reconstructed file sizes

later in this chapter.

**4. Time-of-flight PET**

**in seconds**

**# of PET beds CT scanning time**

The principle advantage of ToF is the ability to dramatically improve the positioning of annihilation events that occur outside of the line of response (LOR). This is accomplished by locating the annihilation photon energy deposition on the opposing sides of the ring of crystals in the PET gantry and determining the difference in arrival times of those events.

It is important to understand that ToF allows for better lesion detectability not because of improvement in resolution but as a result of improved signal-to-noise definition inherent in improved timing resolution. For this to occur in contemporary PET scanners, the coincidence timing window must be configured to be very short (4-6 nanoseconds) to improve the fraction of randoms detected and resultant improvement in image contrast.

### **5. Quantitative PET imaging: Considerations for optimizing and rendering the standardized uptake value (SUV)**

Provided accurate attenuation correction is performed, PET scanners provide the opportunity to generate semi-quantitative measurements of tumor metabolism. These measurements, known as standardized uptake values (SUVs) continue to be the primary and most universally accepted method for generating semi-quantitative measurements that depict tumor metabo‐ lism [11]. The default unit of measurement in all PET scanners is kilobecuerels per milliliter. This unit of measurement together with the quantity of injected radioactivity, patient weight, and decay time is used to compute the SUV. Considerable error inherent to all of the afore‐ mentioned criteria can result in badly flawed measurements and ultimately, false tumor metabolism quantification. In order to reduce the likelihood of introducing error in SUVs, at a minimum, the following must be evaluated and effectively implemented in the SUV calculation [11]:


quantity administered is recorded in the radiopharmaceutical administration record. This same resulting quantity is used for all SUV calculations.

PET images. More specifically, it was proposed that the intravenous contrast or oral barium sulfate attenuation correction artifacts diminished the readability of the PET [14, 15]. While there are limited examples of attenuation correction artifacts from oral or intravenous contrast, experienced PET-CT readers have learned to utilize filtered back projection uncorrected images to differentiate artifacts versus clinically relevant findings [16]. The emergence of routinely used dual syringe intravenous contrast injectors that permit the injection of a normal saline "chaser" after the initial intravenous contrast have virtually eliminated intravenous

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There are substantial requirements and preparations necessary to incorporating optimized CT into PET-CT practice [2]. The most ideal approach has been to have truly-dually trained and boarded radiologists and technologists working together to produce the PET-CT images. Regrettably, this situation is rarely achievable given the time investment necessary to garner nuclear medicine physician and radiologist credentials or for similar circumstances to be available to nuclear medicine technologists. Nevertheless, it is possible to routinely incorporate optimized CT into the PET-CT practice provided there can be collaboration between nuclear

Critical considerations for optimizing CT acquired along with PET include configuring scanner parameters for the best quality image while dosing the patient safely. Technologist staff should become knowledgeable regarding basic CT principles such as pitch and slice overlap, CT dose index (mGy and mAs or mA), slice thickness and noise inter-relationship, and x-ray penetra‐ tion characteristics (keV setting). Intravenous contrast administration requires careful screen‐ ing of each patient both at the time the patient's appointment is scheduled as well as during the actual appointment. Internal protocols should be developed to optimize the patient's ingestion of oral contrast, administration of intravenous contrast for optimized bolus timing, as well as persistent awareness of the potential for contrast reactions. Figure 8 illustrates a

contrast artifacts on the attenuation corrected images [17].

medicine and CT departments.

**Figure 8.** Optimized CT-PET protocol

protocol for PET-CT incorporating optimized CT:


The equation for SUV calculation is as follows:

#### **SUV= Region of interest of radiopharmaceutical concentration**

#### **(Tracer dose/patient weight)**

Because radiopharmaceutical dose and patient weight are in the denominator, these are among the 2 most important values to optimize to reduce the magnitude of error inherent to the calculation.

#### **6. Computed Tomography acquisitions considerations for PET-CT**

Prior to 1998 and the prototype development of the PET-CT at the University of Pittsburgh, PET-only systems had primacy given that those systems were the only offering available [3]. The genesis of PET combined with CT derived from the suggestion of a Swiss oncology surgeon. During the development of the PET-CT, the oncologist opined that a CT scanner in the voids between the banks of the PET detectors might provide useful anatomical information familiar to oncology surgeons. This suggestion was a catalyst to the advent of the modern-day PET-CT. Dr. David Townsend and Ron Nutt began creating a prototype PET-CT in 1991 but it would not be a viable device for use clinically until 1998 [3].

Since that time, the practice of PET-**CT** could be considered more largely to be PET-**ct** in which the CT portion of the scan is used primarily for attenuation correction and anatomic localiza‐ tion. However, the original intent of Townsend and colleagues was to generate *clinical* CT and *clinical* PET scans in the course of a single scanning session using a single machine. Moreover, the desired purpose of the CT was to provide clinical patient information rather than only attenuation correction and anatomic localization. Indeed, CT for attenuation correction was a secondary to the main purpose of developing a clinical PET-CT scanner [3]. High-quality, optimized CT was possible routinely even on 2 row CT units that were commonly available and interfaced with the PET gantry at that time [3].

There has been considerable divergence over the routine integration of optimized, contrast enhanced CT with PET. However, over the course of the past decade, the literature has repeatedly borne out the superior quality and efficacy of optimized CT used in conjunction with PET [12, 13]. The most strident objection to performing optimized, contrast-enhanced CT with PET is that the oral and/or intravenous contrasts utilized on the CT creates artifacts in the PET images. More specifically, it was proposed that the intravenous contrast or oral barium sulfate attenuation correction artifacts diminished the readability of the PET [14, 15]. While there are limited examples of attenuation correction artifacts from oral or intravenous contrast, experienced PET-CT readers have learned to utilize filtered back projection uncorrected images to differentiate artifacts versus clinically relevant findings [16]. The emergence of routinely used dual syringe intravenous contrast injectors that permit the injection of a normal saline "chaser" after the initial intravenous contrast have virtually eliminated intravenous contrast artifacts on the attenuation corrected images [17].

There are substantial requirements and preparations necessary to incorporating optimized CT into PET-CT practice [2]. The most ideal approach has been to have truly-dually trained and boarded radiologists and technologists working together to produce the PET-CT images. Regrettably, this situation is rarely achievable given the time investment necessary to garner nuclear medicine physician and radiologist credentials or for similar circumstances to be available to nuclear medicine technologists. Nevertheless, it is possible to routinely incorporate optimized CT into the PET-CT practice provided there can be collaboration between nuclear medicine and CT departments.

Critical considerations for optimizing CT acquired along with PET include configuring scanner parameters for the best quality image while dosing the patient safely. Technologist staff should become knowledgeable regarding basic CT principles such as pitch and slice overlap, CT dose index (mGy and mAs or mA), slice thickness and noise inter-relationship, and x-ray penetra‐ tion characteristics (keV setting). Intravenous contrast administration requires careful screen‐ ing of each patient both at the time the patient's appointment is scheduled as well as during the actual appointment. Internal protocols should be developed to optimize the patient's ingestion of oral contrast, administration of intravenous contrast for optimized bolus timing, as well as persistent awareness of the potential for contrast reactions. Figure 8 illustrates a protocol for PET-CT incorporating optimized CT:

**Figure 8.** Optimized CT-PET protocol

quantity administered is recorded in the radiopharmaceutical administration record. This

40 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Because radiopharmaceutical dose and patient weight are in the denominator, these are among the 2 most important values to optimize to reduce the magnitude of error inherent to the

Prior to 1998 and the prototype development of the PET-CT at the University of Pittsburgh, PET-only systems had primacy given that those systems were the only offering available [3]. The genesis of PET combined with CT derived from the suggestion of a Swiss oncology surgeon. During the development of the PET-CT, the oncologist opined that a CT scanner in the voids between the banks of the PET detectors might provide useful anatomical information familiar to oncology surgeons. This suggestion was a catalyst to the advent of the modern-day PET-CT. Dr. David Townsend and Ron Nutt began creating a prototype PET-CT in 1991 but

Since that time, the practice of PET-**CT** could be considered more largely to be PET-**ct** in which the CT portion of the scan is used primarily for attenuation correction and anatomic localiza‐ tion. However, the original intent of Townsend and colleagues was to generate *clinical* CT and *clinical* PET scans in the course of a single scanning session using a single machine. Moreover, the desired purpose of the CT was to provide clinical patient information rather than only attenuation correction and anatomic localization. Indeed, CT for attenuation correction was a secondary to the main purpose of developing a clinical PET-CT scanner [3]. High-quality, optimized CT was possible routinely even on 2 row CT units that were commonly available

There has been considerable divergence over the routine integration of optimized, contrast enhanced CT with PET. However, over the course of the past decade, the literature has repeatedly borne out the superior quality and efficacy of optimized CT used in conjunction with PET [12, 13]. The most strident objection to performing optimized, contrast-enhanced CT with PET is that the oral and/or intravenous contrasts utilized on the CT creates artifacts in the

**6. Computed Tomography acquisitions considerations for PET-CT**

same resulting quantity is used for all SUV calculations.

**•** Accurate patient weight

**(Tracer dose/patient weight)**

calculation.

The equation for SUV calculation is as follows:

**•** Accurate patient dose

**•** Synchronization of all clocks utilized in reporting injection time

**SUV= Region of interest of radiopharmaceutical concentration**

it would not be a viable device for use clinically until 1998 [3].

and interfaced with the PET gantry at that time [3].

**•** Assurance of proper infusion of radiopharmaceutical (no dose extravasation)

A final consideration for performing optimized CT is patient safety given clinically significant findings. In the course of performing optimized CT, it is not uncommon to encounter a large pleural effusion (fluid in the lungs) or a pneumothorax (collapsed region of lung) or similar life-threatening circumstance. PET-CT technologists must be vigilant and trained to routinely evaluate the CT images for obvious significant findings and report these findings to a radiol‐ ogist for appropriate follow up. Figure 9a illustrates a pleural effusion and Figure 9b shows a pneumothorax:

On rare occasions, pulmonary emboli are also encountered and must be reported but these findings are often extremely subtle even to the experienced imager.

Along with noticing clinically significant findings during and subsequent to the scan, it is vital that the technologist provide the utmost in safety while administering intravenous contrast. The threat of intravenous contrast extravasation, allergic reactions, or renal compromise are the foremost dangers for the patient. It has been well-documented that intravenous contrast extravasations of 100 milliliters or greater almost always require a plastic surgery consult as localized tissue necrosis may occur [18]. This is because the osmolality of commonly used nonionic intravenous contrast (~650 mOsm/kg) is often vastly different from osmolality of blood (~285 mOsm/kg) creating conditions for unfavorable osmotic gradients to occur [19]. The majority of intravenous contrast extravasations can be avoided entirely by verifying venous patency prior to and during the administration of contrast [1]. Figure 10 demonstrates a graphical depiction of the venous patency both *before* (10a) and *during* (10b) contrast admin‐ istration. Figure 10c reveals an example of a steeply sloped, worrisome curve that may indicate an extravasation event will occur.

Additionally, though uncommon, allergic reactions to intravenous contrast range from localized mild urticaria to anaphylactic shock [20]. Also, patients at risk for renal insufficiency such as those who have diabetes, hypertension, solitary kidney, or any combination of the aforementioned are at substantial risk for developing contrast induced nephropathy (CIN) [21]. Therefore, *all* patients must be carefully screened prior to receiving contrast. This will include a thorough review of the patient's medical history as well as assessment of creatinine and estimated glomerular filtration rate ideally within 30 days of administering intravenous contrast [22].

#### **7. Image fusion**

Prior to the introduction and routine utilization of modern PET-CT scanners, the technologist or similar staff used third party programs in post-processing attempts targeted at aligning PET and CT or PET and MR image sets that had been acquired on different scanners. In addition, the radiologist was also tasked with customary mental alignment of image metabolism structures, so called "mental fusion" [23]. The fully integrated and combined PET-CT has allowed for practical and real-time image fusion that is considered commonplace in contem‐ porary imaging [24]. Unfortunately, this has not obviated the need for third party image fusion systems because fusion of IR, MR or other modality fusion is now considered standard-of-care.

This is increasingly becoming the case in multidisciplinary oncology environments as well as neurology subspecialty environments that include an epileptologist as part of a multidiscipli‐ nary epilepsy team. Until recently, rigid fusion was the only possible fusion option. Rigid fusion involves image landmark matching to achieve the closest best fit among anatomic structures and metabolic activity. This is achievable by using software to co-register multiple image volumes against a reference volume. However, due to myriad alterations in patient

**Figure 9.** (a.) Bilateral pleural effusions encountered during viewing of CT images; (b.) Pneumothorax. Note that this clinically-significant finding is *only fully revealed* upon application of a CT kernel and appropriate windowing.

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A final consideration for performing optimized CT is patient safety given clinically significant findings. In the course of performing optimized CT, it is not uncommon to encounter a large pleural effusion (fluid in the lungs) or a pneumothorax (collapsed region of lung) or similar life-threatening circumstance. PET-CT technologists must be vigilant and trained to routinely evaluate the CT images for obvious significant findings and report these findings to a radiol‐ ogist for appropriate follow up. Figure 9a illustrates a pleural effusion and Figure 9b shows a

42 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

On rare occasions, pulmonary emboli are also encountered and must be reported but these

Along with noticing clinically significant findings during and subsequent to the scan, it is vital that the technologist provide the utmost in safety while administering intravenous contrast. The threat of intravenous contrast extravasation, allergic reactions, or renal compromise are the foremost dangers for the patient. It has been well-documented that intravenous contrast extravasations of 100 milliliters or greater almost always require a plastic surgery consult as localized tissue necrosis may occur [18]. This is because the osmolality of commonly used nonionic intravenous contrast (~650 mOsm/kg) is often vastly different from osmolality of blood (~285 mOsm/kg) creating conditions for unfavorable osmotic gradients to occur [19]. The majority of intravenous contrast extravasations can be avoided entirely by verifying venous patency prior to and during the administration of contrast [1]. Figure 10 demonstrates a graphical depiction of the venous patency both *before* (10a) and *during* (10b) contrast admin‐ istration. Figure 10c reveals an example of a steeply sloped, worrisome curve that may indicate

Additionally, though uncommon, allergic reactions to intravenous contrast range from localized mild urticaria to anaphylactic shock [20]. Also, patients at risk for renal insufficiency such as those who have diabetes, hypertension, solitary kidney, or any combination of the aforementioned are at substantial risk for developing contrast induced nephropathy (CIN) [21]. Therefore, *all* patients must be carefully screened prior to receiving contrast. This will include a thorough review of the patient's medical history as well as assessment of creatinine and estimated glomerular filtration rate ideally within 30 days of administering intravenous

Prior to the introduction and routine utilization of modern PET-CT scanners, the technologist or similar staff used third party programs in post-processing attempts targeted at aligning PET and CT or PET and MR image sets that had been acquired on different scanners. In addition, the radiologist was also tasked with customary mental alignment of image metabolism structures, so called "mental fusion" [23]. The fully integrated and combined PET-CT has allowed for practical and real-time image fusion that is considered commonplace in contem‐ porary imaging [24]. Unfortunately, this has not obviated the need for third party image fusion systems because fusion of IR, MR or other modality fusion is now considered standard-of-care.

findings are often extremely subtle even to the experienced imager.

pneumothorax:

an extravasation event will occur.

contrast [22].

**7. Image fusion**

**Figure 9.** (a.) Bilateral pleural effusions encountered during viewing of CT images; (b.) Pneumothorax. Note that this clinically-significant finding is *only fully revealed* upon application of a CT kernel and appropriate windowing.

This is increasingly becoming the case in multidisciplinary oncology environments as well as neurology subspecialty environments that include an epileptologist as part of a multidiscipli‐ nary epilepsy team. Until recently, rigid fusion was the only possible fusion option. Rigid fusion involves image landmark matching to achieve the closest best fit among anatomic structures and metabolic activity. This is achievable by using software to co-register multiple image volumes against a reference volume. However, due to myriad alterations in patient

position between scanners, patient weight changes, and surgical variants rigid fusion fre‐ quently reveals undesirable matches between image sets. In contrast, deformable fusion has emerged and permits more favorable metabolic and structural alignment by incorporating virtual stretch algorithms. This involves mutual information algorithms that function at the

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Figure 11 demonstrates a post-processed PET-CT fusion image while Figure 12 illustrates a

**Figure 11.** PET-CT fusion images: Images were acquired during co-registered acquisition and fused during post-proc‐

Provided the processed image matrices are similar, deformable fusion is routinely achievable and permits for favorable and clinically useful alignment of morphological and metabolic

image sets across multiple cross-sectional modalities [26].

pixel and/or voxel level to "warp" the image data [25].

post-processed PET-MR deformably fused image.

essing

**Figure 10.** a. Saline test bolus phase, b. Intravenous contrast bolus phase, c. Non-patent I.V.: Administering intrave‐ nous contrast when the test bolus has a rapidly increasing slope that does not level off is an imminent indicator of extravasation Venous patency tracing viewed both during test bolus of saline (a), injection of intravenous contrast (b) and non-patent IV (c). For maximum safety, the technologist should actually palpate the injection site during an initial bolus of normal saline while also reviewing the time versus pressure tracing.

position between scanners, patient weight changes, and surgical variants rigid fusion fre‐ quently reveals undesirable matches between image sets. In contrast, deformable fusion has emerged and permits more favorable metabolic and structural alignment by incorporating virtual stretch algorithms. This involves mutual information algorithms that function at the pixel and/or voxel level to "warp" the image data [25].

Figure 11 demonstrates a post-processed PET-CT fusion image while Figure 12 illustrates a post-processed PET-MR deformably fused image.

**Figure 11.** PET-CT fusion images: Images were acquired during co-registered acquisition and fused during post-proc‐ essing

**Figure 10.** a. Saline test bolus phase, b. Intravenous contrast bolus phase, c. Non-patent I.V.: Administering intrave‐ nous contrast when the test bolus has a rapidly increasing slope that does not level off is an imminent indicator of extravasation Venous patency tracing viewed both during test bolus of saline (a), injection of intravenous contrast (b) and non-patent IV (c). For maximum safety, the technologist should actually palpate the injection site during an initial

44 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

bolus of normal saline while also reviewing the time versus pressure tracing.

Provided the processed image matrices are similar, deformable fusion is routinely achievable and permits for favorable and clinically useful alignment of morphological and metabolic image sets across multiple cross-sectional modalities [26].

institutions as well as the number of patients with healthcare insurance who could afford to have PET-CTs. What emerged was a new paradigm of very efficient, higher volume imaging workflows in PET-CT in both public and private hospital industry. Institutions with targeted and efficient workflows have been able to weather the continued acrimonious economic conditions as funds for both full time equivalents (FTEs) and capital infrastructures such as scanners continues to diminish. PET-CT has continued to grow although the percentage increase has tended to decrease each year since 2005 [30]. This environment is indeed the new

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**9. Specialized acquisition circumstances: Pediatrics, radiation therapy**

Pediatric PET-CT acquisition requires all of the same precautions as those that accompany adult PET-CT *plus* specific considerations for PET emission times, matrix, and minimization of movement artifacts. Despite the fact that pediatric patients tend to be shorter and have much lower body mass than adult patients, acquisition paradoxically takes longer. This is because ideally, a higher and finer matrix will be used to image the smaller bodies of pediatric patients. As a general guideline, if the matrix size is doubled there should be concomitant quadrupling of acquisition time in order to achieve appropriate imaging statistics and image quality. Given these considerations, achieving high-quality, motion-free images may require coordination of sedation services, immobilization devices and/or considerable psychosocial support from the PET-CT staff as well as accompanying patient guardian(s) [31]. Within a conventional scheduling paradigm, high quality pediatric scanning invariably requires more planning and imaging time. These needs cannot be underestimated and should be an integral part of the

In any pediatric PET-CT imaging environment, there should be age and weight-specific criteria for dosing the patient with radiopharmaceuticals. One method that can be used is to stand‐ ardize the pediatric dose to the "standard man" of 70 kilograms while also setting absolute low and high dose limits. As an example, an institution might designate 74 MBq (2 mCi) as the minimum dose and 370 MBq (10 mCi) as the maximum dose. The dose would then be

It is helpful to use any number of commercially available spreadsheet programs to extrapolate

Pediatric PET-CT will also require careful consideration of radiation dose delivered in the CT portion of the exam. This is of the utmost importance if the institution has incorporated optimized or diagnostic CT parameters because dose from CT will be nearly twice the radiation dose from the 511 keV emitting radiopharmaceutical such as fluorine-18 2-deoxy-2-fluoro-D-

all values of radiopharmaceutical dosing based on this equation for ease of reference.

**Pediatric radiopharmaceutical dose=370 MBq x child's weight in kg/150 kg**

normal and will likely persist for several years to come.

**planning, and inpatients**

pediatric PET-CT scheduling process.

computed with the following equation:

**9.1. Pediatrics**

**Figure 12.** PET-MR fusion images-the PET and MR were acquired separately and fused utilizing deformable fusion post-process application software.

#### **8. Workflow and the optimized PET-CT acquisition: The United States perspective**

If PET-CT experienced a "golden age" it was immediately following more widespread adoption of PET-CT in the early 2000s. Numerous PET-CT facilities had business models based upon as few as 3 patients per day due to robust reimbursement that prevailed up until 2005. This was an ephemeral but important time of prosperity, growth, and development for PET-CT. At that time, the per scan fee provided by the Centers for Medicare and Medicaid Services (CMS) was at an all time high. This period was destined for an eventual phase out but was hastened by the implementation and enforcement of the Deficit Reduction Act (DRA) [26, 27, 28, 29].The DRA of 2005 (signed into law February of 2006) was implemented as part of a broader strategy targeted at limiting the unnecessary expenditure of funds thought to be redundant in patients' care [26]. The ultimate result of this policy was that reimbursement for PET-CT was reduced by nearly one half in the non-hospital, free-standing imaging environ‐ ment [26]. Many independent imaging centers that once prospered by only performing 3 or 4 patients per day no longer could achieve a margin to sustain a solvent business model. In the ensuing aftermath of full phase in of DRA policy, many of these facilities were either assimi‐ lated by larger institutions or simply became insolvent and bankrupt.

In addition to the DRA of 2005, a second blow to PET-CT arrived in the form of the major economic downturn and crisis of 2008. This dramatically reduced the borrowing power of institutions as well as the number of patients with healthcare insurance who could afford to have PET-CTs. What emerged was a new paradigm of very efficient, higher volume imaging workflows in PET-CT in both public and private hospital industry. Institutions with targeted and efficient workflows have been able to weather the continued acrimonious economic conditions as funds for both full time equivalents (FTEs) and capital infrastructures such as scanners continues to diminish. PET-CT has continued to grow although the percentage increase has tended to decrease each year since 2005 [30]. This environment is indeed the new normal and will likely persist for several years to come.

### **9. Specialized acquisition circumstances: Pediatrics, radiation therapy planning, and inpatients**

#### **9.1. Pediatrics**

**8. Workflow and the optimized PET-CT acquisition: The United States**

46 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**Figure 12.** PET-MR fusion images-the PET and MR were acquired separately and fused utilizing deformable fusion

If PET-CT experienced a "golden age" it was immediately following more widespread adoption of PET-CT in the early 2000s. Numerous PET-CT facilities had business models based upon as few as 3 patients per day due to robust reimbursement that prevailed up until 2005. This was an ephemeral but important time of prosperity, growth, and development for PET-CT. At that time, the per scan fee provided by the Centers for Medicare and Medicaid Services (CMS) was at an all time high. This period was destined for an eventual phase out but was hastened by the implementation and enforcement of the Deficit Reduction Act (DRA) [26, 27, 28, 29].The DRA of 2005 (signed into law February of 2006) was implemented as part of a broader strategy targeted at limiting the unnecessary expenditure of funds thought to be redundant in patients' care [26]. The ultimate result of this policy was that reimbursement for PET-CT was reduced by nearly one half in the non-hospital, free-standing imaging environ‐ ment [26]. Many independent imaging centers that once prospered by only performing 3 or 4 patients per day no longer could achieve a margin to sustain a solvent business model. In the ensuing aftermath of full phase in of DRA policy, many of these facilities were either assimi‐

In addition to the DRA of 2005, a second blow to PET-CT arrived in the form of the major economic downturn and crisis of 2008. This dramatically reduced the borrowing power of

lated by larger institutions or simply became insolvent and bankrupt.

**perspective**

post-process application software.

Pediatric PET-CT acquisition requires all of the same precautions as those that accompany adult PET-CT *plus* specific considerations for PET emission times, matrix, and minimization of movement artifacts. Despite the fact that pediatric patients tend to be shorter and have much lower body mass than adult patients, acquisition paradoxically takes longer. This is because ideally, a higher and finer matrix will be used to image the smaller bodies of pediatric patients. As a general guideline, if the matrix size is doubled there should be concomitant quadrupling of acquisition time in order to achieve appropriate imaging statistics and image quality. Given these considerations, achieving high-quality, motion-free images may require coordination of sedation services, immobilization devices and/or considerable psychosocial support from the PET-CT staff as well as accompanying patient guardian(s) [31]. Within a conventional scheduling paradigm, high quality pediatric scanning invariably requires more planning and imaging time. These needs cannot be underestimated and should be an integral part of the pediatric PET-CT scheduling process.

In any pediatric PET-CT imaging environment, there should be age and weight-specific criteria for dosing the patient with radiopharmaceuticals. One method that can be used is to stand‐ ardize the pediatric dose to the "standard man" of 70 kilograms while also setting absolute low and high dose limits. As an example, an institution might designate 74 MBq (2 mCi) as the minimum dose and 370 MBq (10 mCi) as the maximum dose. The dose would then be computed with the following equation:

#### **Pediatric radiopharmaceutical dose=370 MBq x child's weight in kg/150 kg**

It is helpful to use any number of commercially available spreadsheet programs to extrapolate all values of radiopharmaceutical dosing based on this equation for ease of reference.

Pediatric PET-CT will also require careful consideration of radiation dose delivered in the CT portion of the exam. This is of the utmost importance if the institution has incorporated optimized or diagnostic CT parameters because dose from CT will be nearly twice the radiation dose from the 511 keV emitting radiopharmaceutical such as fluorine-18 2-deoxy-2-fluoro-D- glucose (18FDG) [32]. There are now well-established "Image Gently" protocols available from the American College of Radiology that can assist any facility in creating protocols that provide age-appropriate CT dosing. In recent years, these protocols have become increasingly common in many pediatric-based radiology departments although the adoption of optimized or diagnostic CT parameters in PET-CT has been slower to emerge [33]. Integrated applications to reduce CT dose should be routinely incorporated into the imaging of pediatric patients to maintain their dose as low as reasonably achievable (ALARA). Low dose pediatric CT is generally accepted to be 5 mSv or below for the typical torso axial coverage [34]. This is easily achievable in younger and smaller pediatric patients who possess a lower body mass index (BMI) but becomes considerably more difficult in imaging older and higher BMI pediatric patients. An ongoing and continuing dialogue with a health physicist and radiologist is essential to providing safe and lower dose CT in the pediatric PET-CT environment [35].

#### **9.2. Radiation therapy planning**

Similar to pediatric PET-CT, radiation therapy (RT) planning may be a very small portion of image volume but requires considerable additional time and attention to execute properly. PET-CT has been playing an increasingly important role in the radiation therapy process, especially in multidisciplinary oncology centers [36, 38]. One of the essential advantages that PET-CT offers over CT alone is the detection of smaller lymph nodes that would not likely be considered positive on CT by size criteria [36]. Additionally, there is now ample evidence that PET-CT consistently locates unsuspected distant metastatic disease that is not visible on CT alone [36]. There are several possible approaches to incorporating radiation therapy planning into the PET-CT environment but 2 primary methods have emerged in more routine PET-CT clinical practice. The simplest method is to complete the PET-CT on a flat RT therapy planning pallet with the patient positioned in a manner approximating the positioning established or anticipated in the patient's RT planning [36-39]. Figure 13 depicts a PET-CT scanner equipped with the RT pallet.

and used by the radiation oncologist and dosmetrist for the patient's radiation therapy sessions. The advantage of this approach is that the PET-CT images acquired are the *actual* simulation or planning images and PET with respect to a simulation CT will contain no error [36]. The disadvantage is that the additional time required to perform a full PET-CT simulation of this type can be upwards of 30 minutes. Moreover, the radiation exposure the dosimetrist and technologist receive while setting the patient up can be significant and unacceptable if performed routinely. Additionally, scanner time is expensive and in a busy institution, the additional time necessary for true PET-CT RT may create significant scheduling backlogs or patient scanning delays. For this approach to be practical, the PET-CT scanner may even be

**Figure 13.** PET-CT equipped with RT pallet. Note radiation therapy planning laser adjacent to scanner (left) that will

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A final but important consideration for PET-CT acquisition is the additional maneuvers required for inpatient scanning. Inpatients will almost always require more time to ambulate, transition, and position in the PET-CT scanner. A corresponding increase in staff time must be planned for given the higher level of acuity inherent to inpatient scanning. A variety of imaging workflows and paradigms exist for incorporating inpatients into a busy imaging practice. One approach is to have an inpatient-only scanner dedicated exclusively to performing inpatient requests. This approach is more readily integrated in a large academic institution that has the resources for multiple scanners allocated for specific purposes. It is not well-suited to the typical, smaller imaging environment that relies on higher volume and more closely sequenced outpatients. Nevertheless, as the result of diminishing funds and resources, it has become increasingly common to perform inpatient studies in the outpatient setting. In any case, many institutions have found that a radiology RN is vital link in the preparation necessary to create

sited in the RT department.

be used in aligning patient.

**9.3. Inpatients in the PET-CT environment**

This approach requires no additional preparation other than the PET-CT staff receiving notification in advance to place the patient on the RT pallet. A more complex method is to position the patient in the same RT apparatus as created for the patient's original simulation. In this case, the patient is instructed to bring their simulation position device with them to their PET-CT appointment.

The primary limiting factor for this approach is usually the bore of the PET-CT gantry [36, 40]. Most manufacturers now offer RT-sized PET-CT gantries because of the emerging complementary nature of RT and PET-CT [36]. This approach permits the most accurate but also most complex and time-intensive approach with the simulation and PET-CT occurring all in one session. In this environment, the dosimetrist or radiation therapist will position the patient in their custom radiation therapy body cradle, thermoplastic mask, or similar radiation therapy simulation apparatus [36-38]. Figure 13 a and b depict a patient who has been fitted with the same thermoplastic mask as used in the patient's actual radiation therapy. Figure 14 shows the fiducials together with RT planning "B pillar" viewed on the reconstructed images. The PET-CT image sets are then migrated to the radiation therapy planning software Positron Emission Tomography-Computed Tomography Data Acquisition and Image Management http://dx.doi.org/10.5772/57119 49

**Figure 13.** PET-CT equipped with RT pallet. Note radiation therapy planning laser adjacent to scanner (left) that will be used in aligning patient.

and used by the radiation oncologist and dosmetrist for the patient's radiation therapy sessions. The advantage of this approach is that the PET-CT images acquired are the *actual* simulation or planning images and PET with respect to a simulation CT will contain no error [36]. The disadvantage is that the additional time required to perform a full PET-CT simulation of this type can be upwards of 30 minutes. Moreover, the radiation exposure the dosimetrist and technologist receive while setting the patient up can be significant and unacceptable if performed routinely. Additionally, scanner time is expensive and in a busy institution, the additional time necessary for true PET-CT RT may create significant scheduling backlogs or patient scanning delays. For this approach to be practical, the PET-CT scanner may even be sited in the RT department.

#### **9.3. Inpatients in the PET-CT environment**

glucose (18FDG) [32]. There are now well-established "Image Gently" protocols available from the American College of Radiology that can assist any facility in creating protocols that provide age-appropriate CT dosing. In recent years, these protocols have become increasingly common in many pediatric-based radiology departments although the adoption of optimized or diagnostic CT parameters in PET-CT has been slower to emerge [33]. Integrated applications to reduce CT dose should be routinely incorporated into the imaging of pediatric patients to maintain their dose as low as reasonably achievable (ALARA). Low dose pediatric CT is generally accepted to be 5 mSv or below for the typical torso axial coverage [34]. This is easily achievable in younger and smaller pediatric patients who possess a lower body mass index (BMI) but becomes considerably more difficult in imaging older and higher BMI pediatric patients. An ongoing and continuing dialogue with a health physicist and radiologist is essential to providing safe and lower dose CT in the pediatric PET-CT environment [35].

48 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Similar to pediatric PET-CT, radiation therapy (RT) planning may be a very small portion of image volume but requires considerable additional time and attention to execute properly. PET-CT has been playing an increasingly important role in the radiation therapy process, especially in multidisciplinary oncology centers [36, 38]. One of the essential advantages that PET-CT offers over CT alone is the detection of smaller lymph nodes that would not likely be considered positive on CT by size criteria [36]. Additionally, there is now ample evidence that PET-CT consistently locates unsuspected distant metastatic disease that is not visible on CT alone [36]. There are several possible approaches to incorporating radiation therapy planning into the PET-CT environment but 2 primary methods have emerged in more routine PET-CT clinical practice. The simplest method is to complete the PET-CT on a flat RT therapy planning pallet with the patient positioned in a manner approximating the positioning established or anticipated in the patient's RT planning [36-39]. Figure 13 depicts a PET-CT scanner equipped

This approach requires no additional preparation other than the PET-CT staff receiving notification in advance to place the patient on the RT pallet. A more complex method is to position the patient in the same RT apparatus as created for the patient's original simulation. In this case, the patient is instructed to bring their simulation position device with them to

The primary limiting factor for this approach is usually the bore of the PET-CT gantry [36, 40]. Most manufacturers now offer RT-sized PET-CT gantries because of the emerging complementary nature of RT and PET-CT [36]. This approach permits the most accurate but also most complex and time-intensive approach with the simulation and PET-CT occurring all in one session. In this environment, the dosimetrist or radiation therapist will position the patient in their custom radiation therapy body cradle, thermoplastic mask, or similar radiation therapy simulation apparatus [36-38]. Figure 13 a and b depict a patient who has been fitted with the same thermoplastic mask as used in the patient's actual radiation therapy. Figure 14 shows the fiducials together with RT planning "B pillar" viewed on the reconstructed images. The PET-CT image sets are then migrated to the radiation therapy planning software

**9.2. Radiation therapy planning**

with the RT pallet.

their PET-CT appointment.

A final but important consideration for PET-CT acquisition is the additional maneuvers required for inpatient scanning. Inpatients will almost always require more time to ambulate, transition, and position in the PET-CT scanner. A corresponding increase in staff time must be planned for given the higher level of acuity inherent to inpatient scanning. A variety of imaging workflows and paradigms exist for incorporating inpatients into a busy imaging practice. One approach is to have an inpatient-only scanner dedicated exclusively to performing inpatient requests. This approach is more readily integrated in a large academic institution that has the resources for multiple scanners allocated for specific purposes. It is not well-suited to the typical, smaller imaging environment that relies on higher volume and more closely sequenced outpatients. Nevertheless, as the result of diminishing funds and resources, it has become increasingly common to perform inpatient studies in the outpatient setting. In any case, many institutions have found that a radiology RN is vital link in the preparation necessary to create

patient can be transported and maintained in the PET-CT department safely. Primary consid‐

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**Ambulation and falls:** Minimizing falls is at the center of patient safety in any clinical service and becomes especially important when caring for inpatients. The public health and hospital safety literature have repeatedly reported the poor outcomes and compromised care that falls cause in the hospital setting [41-43]. The prevention of falls has arisen to such a level that it has garnered the attention of the Joint Commission as a National Patient Safety Goal [44]. Pre‐ venting falls for inpatients undergoing PET-CT will require a peer-to-peer RN interaction whenever possible to reduce the likelihood of the patient falling upon transition to the PET-

**Diabetes:** In an oncology setting, diabetes can be the single most challenging inpatient management regimen as the patient's medication schedule and diet must be carefully con‐ trolled to achieve a euglycemic state compatible with high quality 18FDG PET-CT imaging. If blood glucose levels exceed 200 mg/dL, the PET imaging cannot be undertaken [45]. This is true because image quality will be suboptimal as endogenous glucose competes with the same

**Medications:** Many inpatients receive intravenous medications in an excipient such as dextrose that will make the PET-CT impossible to perform due to glucose receptor saturation. There are also numerous medications that create difficult circumstances for blood sugar control and achieving the desired serum glucose level prior to the PET-CT. These include but are not

**Telemetry:** Contemporary higher acuity inpatient practice has incorporated routine usage of telemetry as a proactive means of discovering and treating cardiac events. In the peer-to-peer interaction, a plan must be formulated either for safely and temporarily discontinuing the telemetry or sending a specialized individual with the patient to monitor for cardiac events.

**Patient line status:** Inpatients will have a variety of ostomies, surgical drains, catheters and the like that will require maintenance and specialized positioning within the scanner. Because these devices will contain patient secretions that may be radioactive, additional caution to

**Isolation:** In an era of increasingly resistant microorganisms, more and more inpatients will be discovered to be colonized with bacteria that cannot be treated with conventional antibiotics. The vast majority of hospital infection control protocols require that once a patient has been characterized as having a resistant microorganism, the patient must be isolated from other patients and staff. The more common resistant bacteria include methicillin resistant staph aureus (MRSA) and vancomycin resistant enterococcus (VRE) [46-48]. Clostridium difficile (C. diff.) isolation also has become problematic in these same hospital scenarios [49]. Since many hospital organizations cannot afford multiple PET-CT scanners, the prospect of needing to scan isolation patients in the midst of a busy outpa‐ tient workflow is not uncommon. Internal protocols that uphold cleaning the patient's uptake room, PET-CT scan room, and scanner itself must be consistently applied to reduce

limited to corticosteroids, chemotherapy infusions, and insulin [45].

minimize the likelihood of contamination in the scanner will be required.

erations include but are not limited to the following:

CT environment.

binding sites as exogenous 18FDG [45].

**Figure 14.** a: Patient positioned for RT planning on RT pallet with simulation position device. Note that external RT planning laser array has been aligned to patient's fiducials. b: Additional view of patient positioned for RT planning on RT pallet with simulation position device. Note patient has been fitted with thermoplastic mask that will be utilized for each RT treatment event. Intravenous contrast dual injector has also been positioned and is ready to use for optimized CT. Fiducials visualized on axial reconstructed images

a high-quality PET-CT scan. The RN should be available to perform a true peer-to-peer interaction with the patient's RN prior to the patient's actual arrival. This helps to insure the patient can be transported and maintained in the PET-CT department safely. Primary consid‐ erations include but are not limited to the following:

**Ambulation and falls:** Minimizing falls is at the center of patient safety in any clinical service and becomes especially important when caring for inpatients. The public health and hospital safety literature have repeatedly reported the poor outcomes and compromised care that falls cause in the hospital setting [41-43]. The prevention of falls has arisen to such a level that it has garnered the attention of the Joint Commission as a National Patient Safety Goal [44]. Pre‐ venting falls for inpatients undergoing PET-CT will require a peer-to-peer RN interaction whenever possible to reduce the likelihood of the patient falling upon transition to the PET-CT environment.

**Diabetes:** In an oncology setting, diabetes can be the single most challenging inpatient management regimen as the patient's medication schedule and diet must be carefully con‐ trolled to achieve a euglycemic state compatible with high quality 18FDG PET-CT imaging. If blood glucose levels exceed 200 mg/dL, the PET imaging cannot be undertaken [45]. This is true because image quality will be suboptimal as endogenous glucose competes with the same binding sites as exogenous 18FDG [45].

**Medications:** Many inpatients receive intravenous medications in an excipient such as dextrose that will make the PET-CT impossible to perform due to glucose receptor saturation. There are also numerous medications that create difficult circumstances for blood sugar control and achieving the desired serum glucose level prior to the PET-CT. These include but are not limited to corticosteroids, chemotherapy infusions, and insulin [45].

**Telemetry:** Contemporary higher acuity inpatient practice has incorporated routine usage of telemetry as a proactive means of discovering and treating cardiac events. In the peer-to-peer interaction, a plan must be formulated either for safely and temporarily discontinuing the telemetry or sending a specialized individual with the patient to monitor for cardiac events.

**Patient line status:** Inpatients will have a variety of ostomies, surgical drains, catheters and the like that will require maintenance and specialized positioning within the scanner. Because these devices will contain patient secretions that may be radioactive, additional caution to minimize the likelihood of contamination in the scanner will be required.

**Isolation:** In an era of increasingly resistant microorganisms, more and more inpatients will be discovered to be colonized with bacteria that cannot be treated with conventional antibiotics. The vast majority of hospital infection control protocols require that once a patient has been characterized as having a resistant microorganism, the patient must be isolated from other patients and staff. The more common resistant bacteria include methicillin resistant staph aureus (MRSA) and vancomycin resistant enterococcus (VRE) [46-48]. Clostridium difficile (C. diff.) isolation also has become problematic in these same hospital scenarios [49]. Since many hospital organizations cannot afford multiple PET-CT scanners, the prospect of needing to scan isolation patients in the midst of a busy outpa‐ tient workflow is not uncommon. Internal protocols that uphold cleaning the patient's uptake room, PET-CT scan room, and scanner itself must be consistently applied to reduce

a high-quality PET-CT scan. The RN should be available to perform a true peer-to-peer interaction with the patient's RN prior to the patient's actual arrival. This helps to insure the

CT. Fiducials visualized on axial reconstructed images

**Figure 14.** a: Patient positioned for RT planning on RT pallet with simulation position device. Note that external RT planning laser array has been aligned to patient's fiducials. b: Additional view of patient positioned for RT planning on RT pallet with simulation position device. Note patient has been fitted with thermoplastic mask that will be utilized for each RT treatment event. Intravenous contrast dual injector has also been positioned and is ready to use for optimized

50 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

the likelihood that immuno-compromised outpatients do not contract a resistant bacterial strain from a scheduled inpatient.

**Attire:** Inpatients will typically be attired in standard hospital gowns which may contain metal snaps that can result in beam hardening and scatter on the CT phase of the imaging. This same metal can also introduce artifacts into the attenuation corrected PET-CT images. Therefore, it is beneficial to proactively remove said gowns or provide alternative attire such as scrubs prior to the scanning event.

**Pain management:** Given the higher acuity of inpatients as compared to outpatients, it is not surprising that a greater degree of patient pain management may be required. It is helpful to identify additional pain management needs in a peer-to-peer interaction prior to the inpatient's arrival. This will be paramount to maximizing patient comfort such that motion is minimized and a successful PET-CT scanning event will occur. Along with the pain evaluation, the RN can ascertain the patient's need for anxiolytics targeted at minimizing claustrophobia-related distress. To standardize the care of inpatients and enhance a safe time for the patient in PET-CT, it is highly desirable to collect, review, and access all of the aforementioned information prior to the patient's arrival. Figure 15 shows an example of an inpatient criteria sheet that assists the PET-CT staff with determining if an inpatient can safely be transported and scanned:

#### **10. PET-CT image data distribution**

Once the PET-CT image data has been acquired and processed, a convenient, rapid, and reliable system must exist to archive the image data. The historical arc of image archiv‐ ing has spanned from hard-copy radiographic film systems to present day systems that permit viewing digital soft-copies of PET-CT images in Picture Archiving and Communica‐ tion Systems (PACS). In most radiology and medical imaging settings, PACS has emerged as the preferred archival strategy although there continues to be a diversity of images rendered in the varied hospital and imaging center environments across the United States and globally.

PACS has been configured to support the extensive tomographic image production which is the result of torso axial coverage in the typical PET-CT. This has been especially important as multi-detector CT associated with PET has advanced and resulted in thinner and increased number of slices. It is not unusual for the combined PET-CT image set to contain in excess of 2000 image slices that require rapid transfer to the PACS server and correspond‐ ing distribution to image review workstations. Image transfer rates and efficiency will be a function of the bandwidth available throughout the hospital or imaging system net‐ work. Rate of image transfer is central to availability of image data on centralized and remote workstations. System slow-downs will also impact the performance of the PET-CT acquisitions if the processed data cannot be rapidly transferred to the PACS. This phenomenon is both vendor and system topology dependant but best practices require that an entire study be transmitted in under 5 minutes for a busy PET-CT imaging center. Figure

16 graphically depicts the relationship between image data transfer rate and transfer time. There is a clear exponential relationship which is quickly realized within the imaging

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**Figure 15.** Inpatient criteria sheet example

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the likelihood that immuno-compromised outpatients do not contract a resistant bacterial

52 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**Attire:** Inpatients will typically be attired in standard hospital gowns which may contain metal snaps that can result in beam hardening and scatter on the CT phase of the imaging. This same metal can also introduce artifacts into the attenuation corrected PET-CT images. Therefore, it is beneficial to proactively remove said gowns or provide alternative attire such as scrubs prior

**Pain management:** Given the higher acuity of inpatients as compared to outpatients, it is not surprising that a greater degree of patient pain management may be required. It is helpful to identify additional pain management needs in a peer-to-peer interaction prior to the inpatient's arrival. This will be paramount to maximizing patient comfort such that motion is minimized and a successful PET-CT scanning event will occur. Along with the pain evaluation, the RN can ascertain the patient's need for anxiolytics targeted at minimizing claustrophobia-related distress. To standardize the care of inpatients and enhance a safe time for the patient in PET-CT, it is highly desirable to collect, review, and access all of the aforementioned information prior to the patient's arrival. Figure 15 shows an example of an inpatient criteria sheet that assists the PET-CT staff with determining if

Once the PET-CT image data has been acquired and processed, a convenient, rapid, and reliable system must exist to archive the image data. The historical arc of image archiv‐ ing has spanned from hard-copy radiographic film systems to present day systems that permit viewing digital soft-copies of PET-CT images in Picture Archiving and Communica‐ tion Systems (PACS). In most radiology and medical imaging settings, PACS has emerged as the preferred archival strategy although there continues to be a diversity of images rendered in the varied hospital and imaging center environments across the United States

PACS has been configured to support the extensive tomographic image production which is the result of torso axial coverage in the typical PET-CT. This has been especially important as multi-detector CT associated with PET has advanced and resulted in thinner and increased number of slices. It is not unusual for the combined PET-CT image set to contain in excess of 2000 image slices that require rapid transfer to the PACS server and correspond‐ ing distribution to image review workstations. Image transfer rates and efficiency will be a function of the bandwidth available throughout the hospital or imaging system net‐ work. Rate of image transfer is central to availability of image data on centralized and remote workstations. System slow-downs will also impact the performance of the PET-CT acquisitions if the processed data cannot be rapidly transferred to the PACS. This phenomenon is both vendor and system topology dependant but best practices require that an entire study be transmitted in under 5 minutes for a busy PET-CT imaging center. Figure

strain from a scheduled inpatient.

an inpatient can safely be transported and scanned:

**10. PET-CT image data distribution**

to the scanning event.

and globally.

**Figure 15.** Inpatient criteria sheet example

16 graphically depicts the relationship between image data transfer rate and transfer time. There is a clear exponential relationship which is quickly realized within the imaging workflow because transfer rate and time delays can cause backlogs and impair overall PET-CT system performance.

**Figure 16.** Relationship between rate of image transfer and archival time:

Given the opportunity, PET-CT, medical informatics professions, and information technology professionals should begin to collaborate early in the process of configuring PET-CT opera‐ tions. This working relationship has become an imperative as image acquisition and corre‐ sponding PET-CT report turn-around-time have become an important metric in quantifying standard-of-care. The shape and layout of the network and nodes (topology) should be considered both before and during the establishing of the PET-CT infrastructure. For large hospital systems with multiple sites and remote viewing requirements, having a scalable network with very high bandwidth and redundancies will be paramount. This becomes a complicated and expensive undertaking as network cabling, switches, servers, and all manner of information technology infrastructure will need to be considered, purchased, deployed, and maintained over the course of many years. Figure17 illustrates an example of the configuration of a typical PET-CT system topology and interconnectivity. A clear understanding of the connectivity, dependence, and relationship of both hardware and software items is vital to initial troubleshooting during system failure. Many issues such as physical disconnection between devices due to lose cabling or locating of devices requiring a reboot can be identified simply by knowing the system topology and understanding the interrelationship of system components.

**Figure 17.** Example PET-CT system topology

**11.1. PACS workflows**

**11. PET-CT image archiving and retrieval**

A consistent, reproducible, and accessible PACS workflow should be conceived and followed by the PET-CT staff who generate the images. In particular, it will be important to consider ancillary information that the radiologist requires to read the images and the accessibility of said materials [1, 38]. The PET-CT images are certainly the centerpiece of the exam but additional information such as pathology reports, consults, and imaging reports augment the interpretation process. There are three approaches to incorporating this information into the PACS workflow effectively. The first option will be to simply printout and provide the radiologist with any ancillary clinical information that will be used to render the report. This is the least desirable method because it involves a substantial shuffling of paper and usage of printer resources. However, many institutions still use the standard paper method because of the imaging culture of the institution. The 2nd option will be to forego any printing of documents and deliver these to the radiologist in a purely "paperless" or soft format. This will

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**Figure 17.** Example PET-CT system topology

#### **11. PET-CT image archiving and retrieval**

#### **11.1. PACS workflows**

workflow because transfer rate and time delays can cause backlogs and impair overall PET-

54 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Given the opportunity, PET-CT, medical informatics professions, and information technology professionals should begin to collaborate early in the process of configuring PET-CT opera‐ tions. This working relationship has become an imperative as image acquisition and corre‐ sponding PET-CT report turn-around-time have become an important metric in quantifying standard-of-care. The shape and layout of the network and nodes (topology) should be considered both before and during the establishing of the PET-CT infrastructure. For large hospital systems with multiple sites and remote viewing requirements, having a scalable network with very high bandwidth and redundancies will be paramount. This becomes a complicated and expensive undertaking as network cabling, switches, servers, and all manner of information technology infrastructure will need to be considered, purchased, deployed, and maintained over the course of many years. Figure17 illustrates an example of the configuration of a typical PET-CT system topology and interconnectivity. A clear understanding of the connectivity, dependence, and relationship of both hardware and software items is vital to initial troubleshooting during system failure. Many issues such as physical disconnection between devices due to lose cabling or locating of devices requiring a reboot can be identified simply by knowing the system topology and understanding the interrelationship of system

CT system performance.

components.

**Figure 16.** Relationship between rate of image transfer and archival time:

A consistent, reproducible, and accessible PACS workflow should be conceived and followed by the PET-CT staff who generate the images. In particular, it will be important to consider ancillary information that the radiologist requires to read the images and the accessibility of said materials [1, 38]. The PET-CT images are certainly the centerpiece of the exam but additional information such as pathology reports, consults, and imaging reports augment the interpretation process. There are three approaches to incorporating this information into the PACS workflow effectively. The first option will be to simply printout and provide the radiologist with any ancillary clinical information that will be used to render the report. This is the least desirable method because it involves a substantial shuffling of paper and usage of printer resources. However, many institutions still use the standard paper method because of the imaging culture of the institution. The 2nd option will be to forego any printing of documents and deliver these to the radiologist in a purely "paperless" or soft format. This will require a favorable and convenient adjacency of the Health Information System/Radiology Information System (HIS/RIS) to the PACS workstation. It also requires support staff to scan in any documents that are not native to the hospital or imaging center. The third option that occurs in highly integrated healthcare environments is a merger of PACS, HIS, & RIS all within the PACS environment. This requires maximum collaboration and cooperation of Radiology and Medical Informatics as well as appropriately planned monitor and screen real estate. In a well-planned and executed fully integrated PACS/HIS/RIS, the radiologist can readily navigate and among the aforementioned applications with minimal paper waste and stream lined workflow. Figure 18 shows a fully functional PACS/HIS/RIS configuration.

Hospital or imaging centers with virtual private networking (VPN) capability may use file transfer protocol (FTP) as a means of securely and reliably transferring image data. With contemporary firewall systems, this often becomes a challenging undertaking fraught with information technology issues that will require an advanced user with administrative system access capabilities. Invariably, however, many institutions lack a full PACS or means of securely transmitting image data via ftp. This includes many surgical suites outside of the hospital or imaging center where the PET-CT originated, as well as community-based oncology groups, and virtually any location beyond the reach of native PACS. For such situations, the next best option for viewing images will be client-server based viewing capabilities. This will involve providing the remote user with a username and password to authenticate with the PACS server and then streaming data to the remote user's monitor. The distinct disadvantage of this method is that almost no PC-based client server monitors possess the appropriate resolution inherent to a PACS monitor that has true DICOM gray scale

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There are instances in which PACS does not provide a desirable location for storage. This is particularly true in instances whereby raw data sets such as PET or CT sinograms must be stored. This situation will commonly occur and be an imperative for research protocols that require the original raw data to be available in perpetuity. Sending the PET and/or CT sinograms across the network from the modality to PACS invariably results in raw data corruption resulting either in transmission failure or unusable data. Offline storage devices such as Redundant Arrays of Independent Disks (RAID) or terabyte hard drives are viable solutions in these cases. The compatibility of these options must first be vetted with the PET-CT scanner vendor to ensure long-term stability and recoverability of the raw data. These systems do have the advantage of being scalable as additional disk space can be added both

From PET's primary research-oriented imaging in the 1970s and 1980s to contemporary PET-CT routinely used for oncology and neurology, PET continues to play an important role in the management of and characterization of a wide variety of disease processes. PET-CT as practiced today remains one of the most challenging and complex type of imaging studies performed in most hospital or imaging center environment. This derives largely from the integration of 2 somewhat divergent modalities along with the multifaceted diagnostic requirements of patients in oncology and neurology. An understanding of the acquisition, processing, and archiving of PET-CT data is central to sustaining a safe, patient-centered and

to RAID and other types of offline hard drive systems [1, 38, 40].

standard rendering [50, 51].

**13. Conclusion**

high-quality PET-CT image product.

**12. Internal archival methods**

**Figure 18.** Fully-integrated PACS together with HIS & RIS. Note that full voice recognition transcription functionality has also been incorporated into the process for the most optimized report turn-around-time.

#### **11.2. Non-PACS image distribution methodologies**

In addition to PACS-based image viewing systems, it is inevitably necessary to view PET-CT images in other venues where PACS may not be available. Given that all data is DICOM-based, the best solution is to obtain the images on a solid-state media such as compact disk (CD) or digital video disk (DVD) and upload the data to PACS for viewing. This option also has the advantage of being executed on the user's computer regardless of bandwidth limitations.

Hospital or imaging centers with virtual private networking (VPN) capability may use file transfer protocol (FTP) as a means of securely and reliably transferring image data. With contemporary firewall systems, this often becomes a challenging undertaking fraught with information technology issues that will require an advanced user with administrative system access capabilities. Invariably, however, many institutions lack a full PACS or means of securely transmitting image data via ftp. This includes many surgical suites outside of the hospital or imaging center where the PET-CT originated, as well as community-based oncology groups, and virtually any location beyond the reach of native PACS. For such situations, the next best option for viewing images will be client-server based viewing capabilities. This will involve providing the remote user with a username and password to authenticate with the PACS server and then streaming data to the remote user's monitor. The distinct disadvantage of this method is that almost no PC-based client server monitors possess the appropriate resolution inherent to a PACS monitor that has true DICOM gray scale standard rendering [50, 51].

#### **12. Internal archival methods**

require a favorable and convenient adjacency of the Health Information System/Radiology Information System (HIS/RIS) to the PACS workstation. It also requires support staff to scan in any documents that are not native to the hospital or imaging center. The third option that occurs in highly integrated healthcare environments is a merger of PACS, HIS, & RIS all within the PACS environment. This requires maximum collaboration and cooperation of Radiology and Medical Informatics as well as appropriately planned monitor and screen real estate. In a well-planned and executed fully integrated PACS/HIS/RIS, the radiologist can readily navigate and among the aforementioned applications with minimal paper waste and stream

56 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**Figure 18.** Fully-integrated PACS together with HIS & RIS. Note that full voice recognition transcription functionality

In addition to PACS-based image viewing systems, it is inevitably necessary to view PET-CT images in other venues where PACS may not be available. Given that all data is DICOM-based, the best solution is to obtain the images on a solid-state media such as compact disk (CD) or digital video disk (DVD) and upload the data to PACS for viewing. This option also has the advantage of being executed on the user's computer regardless of bandwidth limitations.

has also been incorporated into the process for the most optimized report turn-around-time.

**11.2. Non-PACS image distribution methodologies**

lined workflow. Figure 18 shows a fully functional PACS/HIS/RIS configuration.

There are instances in which PACS does not provide a desirable location for storage. This is particularly true in instances whereby raw data sets such as PET or CT sinograms must be stored. This situation will commonly occur and be an imperative for research protocols that require the original raw data to be available in perpetuity. Sending the PET and/or CT sinograms across the network from the modality to PACS invariably results in raw data corruption resulting either in transmission failure or unusable data. Offline storage devices such as Redundant Arrays of Independent Disks (RAID) or terabyte hard drives are viable solutions in these cases. The compatibility of these options must first be vetted with the PET-CT scanner vendor to ensure long-term stability and recoverability of the raw data. These systems do have the advantage of being scalable as additional disk space can be added both to RAID and other types of offline hard drive systems [1, 38, 40].

#### **13. Conclusion**

From PET's primary research-oriented imaging in the 1970s and 1980s to contemporary PET-CT routinely used for oncology and neurology, PET continues to play an important role in the management of and characterization of a wide variety of disease processes. PET-CT as practiced today remains one of the most challenging and complex type of imaging studies performed in most hospital or imaging center environment. This derives largely from the integration of 2 somewhat divergent modalities along with the multifaceted diagnostic requirements of patients in oncology and neurology. An understanding of the acquisition, processing, and archiving of PET-CT data is central to sustaining a safe, patient-centered and high-quality PET-CT image product.

#### **Acknowledgements**

The author wishes to thank Dr. Paul Shreve and the staff of the Spectrum Health Lemmen Holton PET-CT Cancer Pavilion for their insight and support in writing this chapter.

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gust 2012)

622-629, 2007

68(5):2256-63, 2005.

31 August 2012)

gy, 238(2), 405-422, 2006.

2007

#### **Author details**

Todd Faasse\*

Address all correspondence to: todd.faasse@spectrumhealth.org

Spectrum Health, Grand Rapids, Michigan, USA

#### **References**


[11] Kinehan P., Positron Emission Tomography-Computed Tomography Standardized Uptake Values in Clinical Practice and Assessing Response to Therapy. Sem. in Ul‐ trasound CT MR. 31(6) 496-505, 2010

**Acknowledgements**

**Author details**

Todd Faasse\*

**References**

The author wishes to thank Dr. Paul Shreve and the staff of the Spectrum Health Lemmen Holton PET-CT Cancer Pavilion for their insight and support in writing this chapter.

58 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

[1] Faasse T. and Shreve, P., Positron Emission Tomography-Computed Tomography Patient Management and Workflow. Sem. in Ultrasound CT MR. 29(4):277-82, 2008

[3] Townsend D. Combined PET/CT: A Historical Perspective. Sem. in Ultrasound CT

[4] Bendriem B., Townsend, D. editor-The Theory and Practice of 3D PET. Kluwer Aca‐

[5] Bacharach, Stephen. PET/CT Attenuation Correction: Breathing Lessons. J. Nucl.

[6] Kinehan P. Quantitative Attenuation Correction for PET/CT Using Iterative Recon‐ struction of Low-Dose Dual-Energy CT. Institute of Electrical and Electronics Engi‐ neers (IEEE). http://web.eecs.umich.edu/~fessler/papers/files/proc/04/web/

[7] Moses W. Nucl. Instrum. Methods Phys. Res. A. 648(1): 236–240, 2011 http:// www.ncbi.nlm.nih.gov/pmc/articles/PMC3144741/ (accessed 29 August 2012).

[8] Moses W. Recent Advances and Future Advances in PET Time-of-Flight. Nucl. Ins‐ trum. Methods Phys. Res. A. 580(2): 919–924, 2007 http://

[9] Karp J. Benefit of Time-of-Flight in PET: Experimental and Clinical Results. J. Nucl.

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[10] Melcher C. Scintillation Crystals for PET. J. Nucl. Med. 2000 Jun;41(6):1051-1055

[2] Shreve P., Establishing a PET-CT Practice. AJR 184(5):146-151, 2005.

Address all correspondence to: todd.faasse@spectrumhealth.org

Spectrum Health, Grand Rapids, Michigan, USA

MR. 29(4): 232–235, 2008.

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kinahan-04-qac.pdf (accessed 20 August 2012).


[25] Computers in Radiology Series: PACS, RIS/HIS, DR/CR (Part 2) http://www.ceessen‐ tials.net/article10.html (accessed 31 August 2012).

[40] Shreve P., Positron Emission Tomography-Computed Tomography Protocols for Ra‐ diation Therapy Planning and Therapy Response Assessment. Sem. in Ultrasound

Positron Emission Tomography-Computed Tomography Data Acquisition and Image Management

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[41] Gray-Micelli D. Preventing falls in acute care. Evidence-based geriatric nursing pro‐ tocols for best practice. 3rd ed. New York (NY): Springer Publishing Company; 2008.

[42] Degelau J, Belz M, Bungum L, Flavin PL, Harper C, Leys K, Lundquist L, Webb B, Institute for Clinical Systems Improvement (ICSI). Prevention of falls (acute care). Health care protocol. Bloomington (MN): Institute for Clinical Systems Improvement

[43] Nadzam D., Preventing Falls-Patient Safety and Quality Care. Joint Commission Re‐ sources. http://www.jcrinc.com/Preventing-Patient-Falls/ (accessed 1 September

[44] Joint Commission National Patient Safety Goals. http://www.jointcommission.org/

[46] Murray BE., Vancomycin-resistant enterococcal infections. N. Engl. J Med. 342:710–

[47] Rice LB., Antimicrobial resistance in gram-positive bacteria. Am. J. Infect Control

[48] David, M., Community-Associated Methicillin-Resistant Staphylococcus aureus: Epi‐ demiology and Clinical Consequences of an Emerging Epidemics. Clin. Microbiol.

[49] Lipp MJ, The impact of hospital-acquired Clostridium difficile. J. Gastroenterol. Hep‐

[50] Lowe J., Variations in Performance of LCDs Are Still Evident After DICOM Gray-

[51] Indrajit R., Monitor Displays in Radiology: Part 2. Indian J. Radiol. Imaging. 19(2):

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[45] Shreve P., Clinical PET-CT in Oncology. New York. Springer: 2008.

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[25] Computers in Radiology Series: PACS, RIS/HIS, DR/CR (Part 2) http://www.ceessen‐

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[28] Timmerman R. editor. Image-Guided and Adaptive Radiation Therapy, Lippincott,

[29] Walsh B., PET/CT: Charting the Treatment Course. http://www.healthimaging.com/ index.php?option=com\_articles&view=article&id=6589 (accessed 31 August 2012).

[30] IMV Medical PET Benchmark report. http://www.imvinfo.com/index.aspx?

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[33] McQuattie S. Pediatric PET/CT Imaging: Tips and Techniques. J. Nucl. Med. Tech‐

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[36] Blodgett T., Best Practices: Consensus on Performing Positron Emission Tomogra‐ phy-Computed Tomography for Radiation Therapy Planning and for Therapy Re‐

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2012).


**Chapter 3**

**Basic PET Data Analysis Techniques**

Additional information is available at the end of the chapter

In many neuroscience-based PET research labs, procedures for data analyses are developed in-house and passed along as students, staff and post-doctoral fellows transition through training cycles. Although image processing and data analysis techniques are quite similar across many groups, there has not been any formal information available to the general scientific public. This becomes problematic from an instructional standpoint, as the increas‐ ingly cross-disciplinary nature of neuroimaging attracts researchers with vastly diverse backgrounds. It is not uncommon to find behavioral pharmacologists, bench neuroscientists, neuropsychologists, and neuroradiologists interested in using neuroimaging techniques for their research. However, often these individuals cannot pursue formal training in PET because of time constraints from other job demands. Although it is easy for seasoned PET researchers to quickly train someone in a laboratory-codified stream of image processing, the "why" of the steps may not get communicated sufficiently, which is a clear disservice to the trainees. This chapter was designed to remedy this problem. The intent of this chapter is to provide a broad foundation of the concepts behind basic PET image processing and data analyses, using

The reader is expected to have a basic working understanding of positron emission, gamma

First and foremost, the scientific question at hand should drive the research process. The first question to answer should be: does your institution have the capability to synthesize or obtain the ligand you need to answer your burning question about neuroscience? If the answer is yes, then the next step is in-depth consultation with the research PET experts at the institution, so

> © 2013 Yoder; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

data and images from several neuroligands to illustrate key points.

ray generation, and photon detection by the PET scanner.

**1.2. Importance of study planning**

Karmen K. Yoder

**1. Introduction**

**1.1. Purpose of chapter**

http://dx.doi.org/10.5772/57126

### **Basic PET Data Analysis Techniques**

Karmen K. Yoder

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57126

#### **1. Introduction**

#### **1.1. Purpose of chapter**

In many neuroscience-based PET research labs, procedures for data analyses are developed in-house and passed along as students, staff and post-doctoral fellows transition through training cycles. Although image processing and data analysis techniques are quite similar across many groups, there has not been any formal information available to the general scientific public. This becomes problematic from an instructional standpoint, as the increas‐ ingly cross-disciplinary nature of neuroimaging attracts researchers with vastly diverse backgrounds. It is not uncommon to find behavioral pharmacologists, bench neuroscientists, neuropsychologists, and neuroradiologists interested in using neuroimaging techniques for their research. However, often these individuals cannot pursue formal training in PET because of time constraints from other job demands. Although it is easy for seasoned PET researchers to quickly train someone in a laboratory-codified stream of image processing, the "why" of the steps may not get communicated sufficiently, which is a clear disservice to the trainees. This chapter was designed to remedy this problem. The intent of this chapter is to provide a broad foundation of the concepts behind basic PET image processing and data analyses, using data and images from several neuroligands to illustrate key points.

The reader is expected to have a basic working understanding of positron emission, gamma ray generation, and photon detection by the PET scanner.

#### **1.2. Importance of study planning**

First and foremost, the scientific question at hand should drive the research process. The first question to answer should be: does your institution have the capability to synthesize or obtain the ligand you need to answer your burning question about neuroscience? If the answer is yes, then the next step is in-depth consultation with the research PET experts at the institution, so

© 2013 Yoder; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

that the study design and data analysis pathway(s) are clearly defined from the outset. The study design, data acquisition protocols, image processing stream, and analysis will differ from study to study, and will depend heavily on both the radioligand and the neurophysio‐ logical phenomenon of interest. Types of questions that need to be addressed include (but are not limited to) the following:

be presented in a linear fashion. However, the ultimate choices an investigator makes regard‐

Basic PET Data Analysis Techniques http://dx.doi.org/10.5772/57126 65

It is important to note that it is not the author's intent to endorse any one particular product or software platform. Examples used here are based primarily on the author's experience, and it is highly likely that many excellent programs are not mentioned. Choices of hardware and software should be made based on investigator preference and availability of individual and/

*Dynamic acquisitions*: The term "dynamic data" refers to acquiring data in such a manner so that we may observe the long-term behavior of the tracer in tissue. Image acquisition begins immediately upon tracer injection, and the tracer's radioactivity is monitored continuously or near-continuously during the course of the scan. Dynamic data generates "time-activity curves" (TACs) of the tissue concentration of radioactivity (e.g., Bq/mL) over time. Dynamic data acquisition is the only way to obtain truly quantitative measurements of the system of interest. Said another way, "quantitative" measurements are operationally defined by pharmacokinetic and pharmacodynamic properties of a system (for example, *B* max, *K* D). The behavior of the tracer in the system (the TACs) can be described by sets of differential equa‐ tions; the solutions to these equations yield quantitative outcome parameters. Common parameters of interest include terms such as "volume of distribution" and "binding potential." An excellent review of the definition and derivation of quantitative outcome variables can be found in Innis et al. (2007). In most cases, quantitative outcomes are preferable to semiquantitative measures (see below). However, quantitative data requires information about the tracer in either arterial plasma of interest, or in a tissue that contains little or no targets of the

Dynamic data can be acquired in two ways. One is by pre-specifying "frame times" for the acquisition, usually of increasing duration (for example, 6 frames at 10 seconds, 12 frames at 20 seconds, 5x60s, 5x120s, 4x300s, 2x600s). The scanner records all the coincidence events that occur during each specified time frame, and the reconstructed image consists of the average amount of radioactivity detected at each voxel during each time frame. The other method is "listmode acquisition", where the scanner records all the coincidence events continuously over time. After acquisition, the investigator specifies how the data should be binned into time frames during reconstruction. Listmode acquisition offers more flexibility for the investigator, especially when the ideal time frame sequence has not been identified. The capability for

*"Static" Acquisition*: In the strictest sense, this refers to specifying one time frame over the course of scan acquisition. The result is a single frame that represents the average amount of radio‐ activity during the scan period. Only semi-quantitative information can be derived from static acquisitions, the most common of which is Standardized Uptake Value (SUV). SUV is the amount of radioactivity in the tissue (e.g., kBq/mL) divided by the injected dose per body‐

ing a processing/analysis scheme will depend on multiple factors.

**2. Types of PET data – Definitions and purpose**

or institutional licenses.

ligand ("reference region").

listmode acquisition varies across scanner platforms.

*What types of data analyses are available/accepted for the tracer?* In the clinic, non-quantitative (i.e., visual inspection) of PET images is perfectly acceptable- is the lesion still there? Getting larger? Shrinking? However, in research, there is a requirement for numerical characterization of the dependent variable. For most neuroligand tracers, extensive work has been done to determine what the best and most appropriate approaches are for generating the endpoint of interest. These can range from relatively simple, semi-quantitative methods, to conceptually complex and mathematically rigorous processes that may require additional invasive procedures (arterial cannulation), as well as computational expertise for implementation. Ultimately, the success of a neuroligand PET study will depend on understanding what the field accepts as reasonable outcome measures for a given tracer, and ensuring that the proper infrastructure exists to provide this information.

*What type of effect size is expected?* This is relevant for determining the number of subjects needed for the study – which, given the great expense of PET, is a nontrivial concern. If possible, it is helpful to know the test-retest reliability of a particular ligand, and to have a general idea of whether your effect of interest is expected to rise above this inherent background noise in the data. In the absence of this, relative variance could be ascertained from previously published data. If no previous documentation exists on the ligand in the species/population of interest, then caution should be used to not over-reach with study design in the beginning. Small pilot studies are very useful at providing initial data on anticipated effect sizes of group, treatment, and/or condition. Study design is a key component of arriving at a sample size: Are the tests to be single measurements between groups (for example, relative receptor availability between healthy normals and a disease condition), or multiple measurements within subjects? Is the tracer known for having either poor or stellar signal-to-noise ratio? All these factors- and others- will affect the ability to detect significant differences.

Group size is not the only consideration- knowledge of the expected spatial extent of the effect is also important. The newer-generation human PET scanners (and most small animal PET scanners) have excellent spatial resolution (1-2 mm3 ), but excitement about this technological progress may be mitigated if your hypothesis is restricted to the CA3 region of the hippocam‐ pus in humans, or even the whole hippocampus in a mouse. Additionally, the spatial extent of the effect in question will affect the decision to use a region-of-interest based approach versus a voxel-wise analysis (see below).

At this point, hopefully the reader is now familiar with the importance of understanding the type of data that will result from the study, even before the study begins. Although study design is critically important, a thorough discussion of this topic is beyond the scope of this chapter. The remainder of the text will focus on defining concepts and outlining processes for preparing and analyzing neuroligand PET data. Within each subsection, the descriptions will be presented in a linear fashion. However, the ultimate choices an investigator makes regard‐ ing a processing/analysis scheme will depend on multiple factors.

It is important to note that it is not the author's intent to endorse any one particular product or software platform. Examples used here are based primarily on the author's experience, and it is highly likely that many excellent programs are not mentioned. Choices of hardware and software should be made based on investigator preference and availability of individual and/ or institutional licenses.

#### **2. Types of PET data – Definitions and purpose**

that the study design and data analysis pathway(s) are clearly defined from the outset. The study design, data acquisition protocols, image processing stream, and analysis will differ from study to study, and will depend heavily on both the radioligand and the neurophysio‐ logical phenomenon of interest. Types of questions that need to be addressed include (but are

64 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

*What types of data analyses are available/accepted for the tracer?* In the clinic, non-quantitative (i.e., visual inspection) of PET images is perfectly acceptable- is the lesion still there? Getting larger? Shrinking? However, in research, there is a requirement for numerical characterization of the dependent variable. For most neuroligand tracers, extensive work has been done to determine what the best and most appropriate approaches are for generating the endpoint of interest. These can range from relatively simple, semi-quantitative methods, to conceptually complex and mathematically rigorous processes that may require additional invasive procedures (arterial cannulation), as well as computational expertise for implementation. Ultimately, the success of a neuroligand PET study will depend on understanding what the field accepts as reasonable outcome measures for a given tracer, and ensuring that the proper infrastructure

*What type of effect size is expected?* This is relevant for determining the number of subjects needed for the study – which, given the great expense of PET, is a nontrivial concern. If possible, it is helpful to know the test-retest reliability of a particular ligand, and to have a general idea of whether your effect of interest is expected to rise above this inherent background noise in the data. In the absence of this, relative variance could be ascertained from previously published data. If no previous documentation exists on the ligand in the species/population of interest, then caution should be used to not over-reach with study design in the beginning. Small pilot studies are very useful at providing initial data on anticipated effect sizes of group, treatment, and/or condition. Study design is a key component of arriving at a sample size: Are the tests to be single measurements between groups (for example, relative receptor availability between healthy normals and a disease condition), or multiple measurements within subjects? Is the tracer known for having either poor or stellar signal-to-noise ratio? All these factors- and

Group size is not the only consideration- knowledge of the expected spatial extent of the effect is also important. The newer-generation human PET scanners (and most small animal PET

progress may be mitigated if your hypothesis is restricted to the CA3 region of the hippocam‐ pus in humans, or even the whole hippocampus in a mouse. Additionally, the spatial extent of the effect in question will affect the decision to use a region-of-interest based approach

At this point, hopefully the reader is now familiar with the importance of understanding the type of data that will result from the study, even before the study begins. Although study design is critically important, a thorough discussion of this topic is beyond the scope of this chapter. The remainder of the text will focus on defining concepts and outlining processes for preparing and analyzing neuroligand PET data. Within each subsection, the descriptions will

), but excitement about this technological

not limited to) the following:

exists to provide this information.

others- will affect the ability to detect significant differences.

scanners) have excellent spatial resolution (1-2 mm3

versus a voxel-wise analysis (see below).

*Dynamic acquisitions*: The term "dynamic data" refers to acquiring data in such a manner so that we may observe the long-term behavior of the tracer in tissue. Image acquisition begins immediately upon tracer injection, and the tracer's radioactivity is monitored continuously or near-continuously during the course of the scan. Dynamic data generates "time-activity curves" (TACs) of the tissue concentration of radioactivity (e.g., Bq/mL) over time. Dynamic data acquisition is the only way to obtain truly quantitative measurements of the system of interest. Said another way, "quantitative" measurements are operationally defined by pharmacokinetic and pharmacodynamic properties of a system (for example, *B* max, *K* D). The behavior of the tracer in the system (the TACs) can be described by sets of differential equa‐ tions; the solutions to these equations yield quantitative outcome parameters. Common parameters of interest include terms such as "volume of distribution" and "binding potential." An excellent review of the definition and derivation of quantitative outcome variables can be found in Innis et al. (2007). In most cases, quantitative outcomes are preferable to semiquantitative measures (see below). However, quantitative data requires information about the tracer in either arterial plasma of interest, or in a tissue that contains little or no targets of the ligand ("reference region").

Dynamic data can be acquired in two ways. One is by pre-specifying "frame times" for the acquisition, usually of increasing duration (for example, 6 frames at 10 seconds, 12 frames at 20 seconds, 5x60s, 5x120s, 4x300s, 2x600s). The scanner records all the coincidence events that occur during each specified time frame, and the reconstructed image consists of the average amount of radioactivity detected at each voxel during each time frame. The other method is "listmode acquisition", where the scanner records all the coincidence events continuously over time. After acquisition, the investigator specifies how the data should be binned into time frames during reconstruction. Listmode acquisition offers more flexibility for the investigator, especially when the ideal time frame sequence has not been identified. The capability for listmode acquisition varies across scanner platforms.

*"Static" Acquisition*: In the strictest sense, this refers to specifying one time frame over the course of scan acquisition. The result is a single frame that represents the average amount of radio‐ activity during the scan period. Only semi-quantitative information can be derived from static acquisitions, the most common of which is Standardized Uptake Value (SUV). SUV is the amount of radioactivity in the tissue (e.g., kBq/mL) divided by the injected dose per body‐ weight (e.g., MBq/kg). Static acquisitions are often preceded by a tracer uptake period outside of the scanner environment. Some "static" protocols incorporate a "dynamic" component to facilitate motion-correction (see below), for instance, a 30-minute uptake period followed by five, five-minute frames. Even though multiple time frames are specified, because no image information is captured during the uptake period, this protocol is not considered to be truly "dynamic" data. The intensity values from the acquired frames are typically averaged to generate the mean radioactivity concentration during the scan – the functional equivalent of a "static" scan.

Finally, certain types of data analysis – specifically, voxel-wise analyses – require that all subjects brains be in the same coordinate space. We describe the process that "spatially normalizes" MRI images so that data can be sampled objectively and equivalently across subjects. The processing stream described herein has the goal of translating the PET image(s) into MRI space, so that spatial normalization parameters derived for the MRI likewise can be

Basic PET Data Analysis Techniques http://dx.doi.org/10.5772/57126 67

A wealth of literature and scholarly work has been published on the mathematical basis for algorithms that shift, realign, warp, and reslice three-dimensional images from different modalities so they align correctly. The purpose of this section is to provide a basic, qualitative description of some of these algorithms in context of why they are useful for PET data.

Note: some image processing programs use the terms like "realign" and "co-register" to designate a very specific series of algorithm implementations. To avoid confusion, we will use these terms generically, without attaching any algorithmic meaning to either. We leave it to the reader to investigate the semantics and procedural implementations of a particular

**Figure 1.** Representative examples of spatially normalized, co-registered images from a healthy subject. Images are axial slices at the level of the striatum and thalamus. Left, a "static" PET image of [18F]flurodeoxyglucose (FDG) Right, the corresponding anatomic T1-weighted MRI. Note that the FDG image contains a high degree of anatomic informa‐

*Rigid body transformations*. Algorithms that perform rigid body transformations are based on the assumption that the rigid bodies (in our case, the PET and MRI image volumes of the same brain) are roughly the same size and geometry. Rigid body transforms only perform transla‐ tions within object space, they do not allow for "stretching" or "shrinking". To move one object in space to match another's orientation, six parameters are required. Three translations are made along the *x*, *y*, and *z* axes (typically considered right-left, superior-inferior, and anterior-

tion that is shared with the MRI (cohesive brain outline and subcortical structure delineation).

applied to the PET data.

program.

When deciding upon a static versus dynamic protocol, it should be kept in mind that capturing dynamic data leaves open the possibility for quantitative metrics (if the proper methods are available); static acquisition does not. Static images can always be created from dynamic data by calculating the weighted average of radioactivity over a specified set of time frames. However, static data cannot be "undone" into dynamic data.

#### **3. Image processing algorithms – Qualitative description and functions**

The advantage of PET imaging is that it provides unique information about the chemistry and physiology of the brain. However, even with high-resolution scanners, PET data often do not contain sufficient neuroanatomic information for identification of specific structures within the brain. The solution to this apparent conundrum is to collect an anatomic Magnetic Resonance Image (MRI) sequence (often an "T1-weighted" sequence) in the same subjects that underwent PET imaging. Having the MRI data confers many advantages to the PET image processing stream, as will be evident below. However, the PET images and MRI images, fresh off the scanner and reconstruction queues, will not be automatically matched up in image space. This is caused by many factors, but the biggest one is differences in final voxel dimen‐ sions and final image volume. One of the major objectives of post-processing of PET images is to move the PET and MRI images from the same subject into the same three-dimensional space.

A second main objective of post-processing is motion correction of the PET data. PET acquis‐ itions typically require the subject to try and lay still for as little as 15 minutes, or for up to 90 minutes at a time. It is not uncommon for subjects to move their heads- from coughing, talking, or falling asleep (singing subjects have also been observed). In some protocols, subjects are allowed to get up for a break during the scan acquisition – which automatically means that the PET data will not be in the same exact place in the scanner. Some institutions have developed sophisticated motion-detection and correction systems that work at the level of the recon‐ struction; however, most investigators do not have access to this technology. Here, we describe a post-hoc method for motion correction after the image has been generated. Because the brain is encased by the skull, there is little concern about movement of the brain within its external bony boundaries. Therefore, the concept of using temporal gating to correct for organ motion, which is a major concern for cardiac and pulmonary imaging, will not be addressed here.

Finally, certain types of data analysis – specifically, voxel-wise analyses – require that all subjects brains be in the same coordinate space. We describe the process that "spatially normalizes" MRI images so that data can be sampled objectively and equivalently across subjects. The processing stream described herein has the goal of translating the PET image(s) into MRI space, so that spatial normalization parameters derived for the MRI likewise can be applied to the PET data.

weight (e.g., MBq/kg). Static acquisitions are often preceded by a tracer uptake period outside of the scanner environment. Some "static" protocols incorporate a "dynamic" component to facilitate motion-correction (see below), for instance, a 30-minute uptake period followed by five, five-minute frames. Even though multiple time frames are specified, because no image information is captured during the uptake period, this protocol is not considered to be truly "dynamic" data. The intensity values from the acquired frames are typically averaged to generate the mean radioactivity concentration during the scan – the functional equivalent of

66 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

When deciding upon a static versus dynamic protocol, it should be kept in mind that capturing dynamic data leaves open the possibility for quantitative metrics (if the proper methods are available); static acquisition does not. Static images can always be created from dynamic data by calculating the weighted average of radioactivity over a specified set of time frames.

**3. Image processing algorithms – Qualitative description and functions**

The advantage of PET imaging is that it provides unique information about the chemistry and physiology of the brain. However, even with high-resolution scanners, PET data often do not contain sufficient neuroanatomic information for identification of specific structures within the brain. The solution to this apparent conundrum is to collect an anatomic Magnetic Resonance Image (MRI) sequence (often an "T1-weighted" sequence) in the same subjects that underwent PET imaging. Having the MRI data confers many advantages to the PET image processing stream, as will be evident below. However, the PET images and MRI images, fresh off the scanner and reconstruction queues, will not be automatically matched up in image space. This is caused by many factors, but the biggest one is differences in final voxel dimen‐ sions and final image volume. One of the major objectives of post-processing of PET images is to move the PET and MRI images from the same subject into the same three-dimensional

A second main objective of post-processing is motion correction of the PET data. PET acquis‐ itions typically require the subject to try and lay still for as little as 15 minutes, or for up to 90 minutes at a time. It is not uncommon for subjects to move their heads- from coughing, talking, or falling asleep (singing subjects have also been observed). In some protocols, subjects are allowed to get up for a break during the scan acquisition – which automatically means that the PET data will not be in the same exact place in the scanner. Some institutions have developed sophisticated motion-detection and correction systems that work at the level of the recon‐ struction; however, most investigators do not have access to this technology. Here, we describe a post-hoc method for motion correction after the image has been generated. Because the brain is encased by the skull, there is little concern about movement of the brain within its external bony boundaries. Therefore, the concept of using temporal gating to correct for organ motion, which is a major concern for cardiac and pulmonary imaging, will not be addressed here.

However, static data cannot be "undone" into dynamic data.

a "static" scan.

space.

A wealth of literature and scholarly work has been published on the mathematical basis for algorithms that shift, realign, warp, and reslice three-dimensional images from different modalities so they align correctly. The purpose of this section is to provide a basic, qualitative description of some of these algorithms in context of why they are useful for PET data.

Note: some image processing programs use the terms like "realign" and "co-register" to designate a very specific series of algorithm implementations. To avoid confusion, we will use these terms generically, without attaching any algorithmic meaning to either. We leave it to the reader to investigate the semantics and procedural implementations of a particular program.

**Figure 1.** Representative examples of spatially normalized, co-registered images from a healthy subject. Images are axial slices at the level of the striatum and thalamus. Left, a "static" PET image of [18F]flurodeoxyglucose (FDG) Right, the corresponding anatomic T1-weighted MRI. Note that the FDG image contains a high degree of anatomic informa‐ tion that is shared with the MRI (cohesive brain outline and subcortical structure delineation).

*Rigid body transformations*. Algorithms that perform rigid body transformations are based on the assumption that the rigid bodies (in our case, the PET and MRI image volumes of the same brain) are roughly the same size and geometry. Rigid body transforms only perform transla‐ tions within object space, they do not allow for "stretching" or "shrinking". To move one object in space to match another's orientation, six parameters are required. Three translations are made along the *x*, *y*, and *z* axes (typically considered right-left, superior-inferior, and anteriorposterior axes, respectively). Rotations are also made around the three axes; these are called pitch, roll, and yaw.

Rigid body algorithms typically "converge" (that is, come to the final, ostensibly correct answer) fairly quickly, and most co-registrations of PET and MRI are successful. However, the algorithms typically rely on the PET and MRI to share a sufficient amount of contrast and outline among anatomic structures for the alignment to work. In cases in which the PET data "looks" sufficiently similar to the structural MR (Figure 1), the registration process is straight‐ forward, and the PET and MR can be aligned without additional steps. However, in the case of dynamic data, the tracer distribution and resulting structural information changes signifi‐ cantly over time. Additionally, different tracers will provide varying degrees of structural information (Figure 2). Because of the lack of similarity to the MRI, attempts to co-register individual early or late-time images will likely fail. Here, an intermediate strategy is often successful: create a PET image that shares sufficient features with *both* the MRI and *all* dynamic PET images so that the co-registration algorithm is successful. The general idea is as follows: (1) Create an average or summed image of early PET frames that will share properties with the MR (structural outlines/contrasts) and early and late-time PET data (Figure 3). At this time, performing an alignment or co-registration of the selected subset of PET frames to the first frame is helpful for eliminating spatial variance introduced by motion. The final balance of images to include will be unique to each tracer and frame sequence. Empirical testing is the best way to determine what will be an acceptable combination. For all tracers, early time images are dominated by "blood flow kinetics", or the extraction of tracer from the blood into the tissue. Thus, the early images will trace the general outline of the brain. In the case of tracers like [11C]raclopride and [18F]fallypride, mid-and late time images will be dominated by binding in the striatum, and the brain outline becomes diffuse (e.g., Figure 2a). Inclusion of too many of these striatal images will skew the registration process and should be avoided. For tracers that may not necessarily have a lot of tracer retention (e.g., amyloid in the example of [11C]PiB, inflammation for [11C]PBR28), the entire set of dynamic images may be needed to generate a sufficiently robust brain PET image. (2) Co-register the mean PET to the native-space structural MRI. Make sure the transformation parameters have been saved in the header files of the resliced PET. (3) Co-register all the dynamic PET frames to the co-registered mean PET (which is now in native MR space). Because all the frames are being registered to the same target, this step has the convenient function of also providing a robust method for motion correction. Additional refinements for motion-correction may be needed in cases in which the motion may be too severe to be corrected by a rigid-body algorithm alone. Occasionally, "manual" repositioning of a timeframe (meaning, the user specifies the translations to change the orientation) can be used to provide the registration algorithm with a better "initial guess." It is our experience that manually adjusting the position of a poorly aligned timeframe and rerunning the algorithm can result in a successful motion correction. Representative timeactivity curves from before and after manual manipulation of two errant time frames are given in Figure 4.

**Figure 2. (a)** Differential behavior of tracers over time. Multi-panel figure of early, mid, and late time frames from

Basic PET Data Analysis Techniques http://dx.doi.org/10.5772/57126 69

18F]fallypride (top panels) and [11C]raclopride (bottom panels). Both tracers are dopamine D2/D3 antagonists; each has different kinetic and signal-to-noise properties. Underneath each panel: start time of each frame relative to tracer in‐ jection (min), and duration of each frame (s). **(b)** Differential behavior of tracers over time. Multi-panel figure of early, mid, and late time frames from [11C]PiB in an Alzheimer's Disease subject (top panels) and [11C]PBR28 in a healthy eld‐ erly control (bottom panels). [11C]PiB binds to β-amyloid plaques, one of the primary pathological hallmarks of Alz‐ heimer's Disease. The majority of healthy elderly subjects have no discernable [11C]PiB uptake. [11C]PBR28 binds to the Translocator Protein 18kDa, a mitochondrial marker associated with inflammation. There is some degree of consistent

11C]PBR28 brain uptake in healthy subjects; the pathological patterns of [11C]PBR28 in neurological and psychiatric disease are not yet well-understood. Underneath each panel: start time of each frame relative to tracer injection (min),

[

[

and duration of each frame (s).

posterior axes, respectively). Rotations are also made around the three axes; these are called

68 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Rigid body algorithms typically "converge" (that is, come to the final, ostensibly correct answer) fairly quickly, and most co-registrations of PET and MRI are successful. However, the algorithms typically rely on the PET and MRI to share a sufficient amount of contrast and outline among anatomic structures for the alignment to work. In cases in which the PET data "looks" sufficiently similar to the structural MR (Figure 1), the registration process is straight‐ forward, and the PET and MR can be aligned without additional steps. However, in the case of dynamic data, the tracer distribution and resulting structural information changes signifi‐ cantly over time. Additionally, different tracers will provide varying degrees of structural information (Figure 2). Because of the lack of similarity to the MRI, attempts to co-register individual early or late-time images will likely fail. Here, an intermediate strategy is often successful: create a PET image that shares sufficient features with *both* the MRI and *all* dynamic PET images so that the co-registration algorithm is successful. The general idea is as follows: (1) Create an average or summed image of early PET frames that will share properties with the MR (structural outlines/contrasts) and early and late-time PET data (Figure 3). At this time, performing an alignment or co-registration of the selected subset of PET frames to the first frame is helpful for eliminating spatial variance introduced by motion. The final balance of images to include will be unique to each tracer and frame sequence. Empirical testing is the best way to determine what will be an acceptable combination. For all tracers, early time images are dominated by "blood flow kinetics", or the extraction of tracer from the blood into the tissue. Thus, the early images will trace the general outline of the brain. In the case of tracers like [11C]raclopride and [18F]fallypride, mid-and late time images will be dominated by binding in the striatum, and the brain outline becomes diffuse (e.g., Figure 2a). Inclusion of too many of these striatal images will skew the registration process and should be avoided. For tracers that may not necessarily have a lot of tracer retention (e.g., amyloid in the example of [11C]PiB, inflammation for [11C]PBR28), the entire set of dynamic images may be needed to generate a sufficiently robust brain PET image. (2) Co-register the mean PET to the native-space structural MRI. Make sure the transformation parameters have been saved in the header files of the resliced PET. (3) Co-register all the dynamic PET frames to the co-registered mean PET (which is now in native MR space). Because all the frames are being registered to the same target, this step has the convenient function of also providing a robust method for motion correction. Additional refinements for motion-correction may be needed in cases in which the motion may be too severe to be corrected by a rigid-body algorithm alone. Occasionally, "manual" repositioning of a timeframe (meaning, the user specifies the translations to change the orientation) can be used to provide the registration algorithm with a better "initial guess." It is our experience that manually adjusting the position of a poorly aligned timeframe and rerunning the algorithm can result in a successful motion correction. Representative timeactivity curves from before and after manual manipulation of two errant time frames are given

pitch, roll, and yaw.

in Figure 4.

**Figure 2. (a)** Differential behavior of tracers over time. Multi-panel figure of early, mid, and late time frames from [ 18F]fallypride (top panels) and [11C]raclopride (bottom panels). Both tracers are dopamine D2/D3 antagonists; each has different kinetic and signal-to-noise properties. Underneath each panel: start time of each frame relative to tracer in‐ jection (min), and duration of each frame (s). **(b)** Differential behavior of tracers over time. Multi-panel figure of early, mid, and late time frames from [11C]PiB in an Alzheimer's Disease subject (top panels) and [11C]PBR28 in a healthy eld‐ erly control (bottom panels). [11C]PiB binds to β-amyloid plaques, one of the primary pathological hallmarks of Alz‐ heimer's Disease. The majority of healthy elderly subjects have no discernable [11C]PiB uptake. [11C]PBR28 binds to the Translocator Protein 18kDa, a mitochondrial marker associated with inflammation. There is some degree of consistent [ 11C]PBR28 brain uptake in healthy subjects; the pathological patterns of [11C]PBR28 in neurological and psychiatric disease are not yet well-understood. Underneath each panel: start time of each frame relative to tracer injection (min), and duration of each frame (s).

*Nonlinear transformations*. Nonlinear transforms are most commonly used to "warp" anatomic MRI brain images into a common stereotaxic coordinate space. This is necessary when a "voxelwise" approach for data analysis is desired (see below). Typically, each individual subject brain is "warped" to a canonical template brain, typically supplied by the program that hosts the spatial transformation algorithm. However, canonical templates may not be the best repre‐ sentation of a given population sample, especially in patient populations that have unique structural disorders. Many investigators prefer to generate study-specific unique templates; this is definitely desirable in animal studies. Approaches to creating templates range from simple averaging of MRI (or PET) data across a sample to more sophisticated approaches that carefully map subject brains onto an existing defined coordinate system (e.g., Schweinhardt et al., 2003). It is up to the investigator to determine the optimal approach for their respective

Basic PET Data Analysis Techniques http://dx.doi.org/10.5772/57126 71

If the investigator intends to rely on region-of-interest (ROI) analysis based on subject-specific ROIs from native-space MRIs, then this step may not be needed. Our laboratory uses a

It should be noted that while the working assumption is that the deformations applied to subject data will render the brain totally "warped" to the template, not all individual variation in anatomy is lost. This should be taken into consideration when interpreting voxel-wise analyses (see below), or using template or group-averaged normalized MRs as starting points

The term "partial volume effect" (PVE) and "partial volume correction" have become general terms in neuroimaging. However, it can mean very different things to MRI and PET experts. Even in PET, there can be confusion about between PVE and "spill-out/spill-in" effects.

**Spatial Resolution Effect:** This is often what is referred to as PVE. However, the term "spatial resolution effect" is more accurate. PET does not provide a spatially pristine representation of the radioactivity in the tissue – it is a "fuzzy" picture of the true concentration of radioactivity. This can be especially problematic when attempting to measure radioactivity in very small or very thin structures that are smaller than the inherent resolution of the scanner. For example, imagine a very small, very " hot" object (like a 1 mm sphere) that is surrounded by tissue that contains no radioactivity. If the intrinsic resolution of the scanner is e.g., 5 mm (please see Phelps (2006) and Bailey (2005) for details on how resolution is defined and specified), the geometry and properties of the scanner will inevitably blur the apparent concentration of radioactivity, effectively assigning spatial location of the radioactivity that originated from the object to the surrounding tissue. The amount of radioactivity measured in the object will be underestimated (from "spill-out"), and surrounding tissue will appear to have radioactivity ("spill-in"; please refer to Morris et al., 2004, for an excellent illustration and mathematical explanation of this phenomenon). Several strategies exist to correct for spatial resolution

combined approach for ROI analysis (see below).

**4. Partial volume effects and partial volume correction**

Therefore, definitions are warranted to prevent confusion.

study.

for ROIs.

**Figure 3.** Example of how a mean dynamic image can be used to facilitate successful co-registration with an anatomic MRI. Left, spatially normalized "early" mean PET, consisting of the first ~10 minutes of dynamic [11C]raclopride data. The number of frames required to achieve a balance of flow/binding for co-registration with the MRI depends heavily on the individual tracer kinetics, and must be determined empirically by each investigator for the particular tracer and acquisition sequence. This particular combination happens to work well for [11C]raclopride. Note the general similarity to the FDG scan in Figure 2. Right, corresponding spatially normalized MRI from the same subject.

**Figure 4.** Time-activity curves (TACs) from a [11C]raclopride scan with and without manual motion correction. Left: TAC from the right putamen of a subject after initial automated motion correction was conducted. Subject motion was severe enough that at least two frames could not be corrected by the algorithm (arrows). Right: resultant TACs after several frames were re-oriented manually and the co-registration algorithm was re-run. The improved initial guesses given by the manual manipulation resulted in better convergence for the algorithm and much smoother curves. This illustrates the need for use of TACs to check for motion in addition to the use of cine loops. It also illustrates the ad‐ vantage of shorter time frames for capturing motion artifacts.

*Nonlinear transformations*. Nonlinear transforms are most commonly used to "warp" anatomic MRI brain images into a common stereotaxic coordinate space. This is necessary when a "voxelwise" approach for data analysis is desired (see below). Typically, each individual subject brain is "warped" to a canonical template brain, typically supplied by the program that hosts the spatial transformation algorithm. However, canonical templates may not be the best repre‐ sentation of a given population sample, especially in patient populations that have unique structural disorders. Many investigators prefer to generate study-specific unique templates; this is definitely desirable in animal studies. Approaches to creating templates range from simple averaging of MRI (or PET) data across a sample to more sophisticated approaches that carefully map subject brains onto an existing defined coordinate system (e.g., Schweinhardt et al., 2003). It is up to the investigator to determine the optimal approach for their respective study.

If the investigator intends to rely on region-of-interest (ROI) analysis based on subject-specific ROIs from native-space MRIs, then this step may not be needed. Our laboratory uses a combined approach for ROI analysis (see below).

It should be noted that while the working assumption is that the deformations applied to subject data will render the brain totally "warped" to the template, not all individual variation in anatomy is lost. This should be taken into consideration when interpreting voxel-wise analyses (see below), or using template or group-averaged normalized MRs as starting points for ROIs.

#### **4. Partial volume effects and partial volume correction**

**Figure 3.** Example of how a mean dynamic image can be used to facilitate successful co-registration with an anatomic MRI. Left, spatially normalized "early" mean PET, consisting of the first ~10 minutes of dynamic [11C]raclopride data. The number of frames required to achieve a balance of flow/binding for co-registration with the MRI depends heavily on the individual tracer kinetics, and must be determined empirically by each investigator for the particular tracer and acquisition sequence. This particular combination happens to work well for [11C]raclopride. Note the general similarity

70 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**Figure 4.** Time-activity curves (TACs) from a [11C]raclopride scan with and without manual motion correction. Left: TAC from the right putamen of a subject after initial automated motion correction was conducted. Subject motion was severe enough that at least two frames could not be corrected by the algorithm (arrows). Right: resultant TACs after several frames were re-oriented manually and the co-registration algorithm was re-run. The improved initial guesses given by the manual manipulation resulted in better convergence for the algorithm and much smoother curves. This illustrates the need for use of TACs to check for motion in addition to the use of cine loops. It also illustrates the ad‐

vantage of shorter time frames for capturing motion artifacts.

to the FDG scan in Figure 2. Right, corresponding spatially normalized MRI from the same subject.

The term "partial volume effect" (PVE) and "partial volume correction" have become general terms in neuroimaging. However, it can mean very different things to MRI and PET experts. Even in PET, there can be confusion about between PVE and "spill-out/spill-in" effects. Therefore, definitions are warranted to prevent confusion.

**Spatial Resolution Effect:** This is often what is referred to as PVE. However, the term "spatial resolution effect" is more accurate. PET does not provide a spatially pristine representation of the radioactivity in the tissue – it is a "fuzzy" picture of the true concentration of radioactivity. This can be especially problematic when attempting to measure radioactivity in very small or very thin structures that are smaller than the inherent resolution of the scanner. For example, imagine a very small, very " hot" object (like a 1 mm sphere) that is surrounded by tissue that contains no radioactivity. If the intrinsic resolution of the scanner is e.g., 5 mm (please see Phelps (2006) and Bailey (2005) for details on how resolution is defined and specified), the geometry and properties of the scanner will inevitably blur the apparent concentration of radioactivity, effectively assigning spatial location of the radioactivity that originated from the object to the surrounding tissue. The amount of radioactivity measured in the object will be underestimated (from "spill-out"), and surrounding tissue will appear to have radioactivity ("spill-in"; please refer to Morris et al., 2004, for an excellent illustration and mathematical explanation of this phenomenon). Several strategies exist to correct for spatial resolution problems. They typically are both computationally and labor-intensive, and require a very detailed anatomic MRI image and robust a priori knowledge of the tracer distribution (Mawlawi et al., 2001; Morris et al., 2004). In deciding on whether or not to apply correction for spatial resolution, the key question is: How important is absolute quantitation? Does having absolute certainty of radioactivity concentration increase the ability to detect differences between groups or conditions? In many cases, it may be reasonable to assume that variability contributed by spatial resolution effects is homogenous across/within subjects, and therefore spatial resolution correction is not warranted. However, in cases where "spill-out" drastically reduces the dynamic range of signal, or interferes with the ability to detect signal above background (such as in small structures, especially in rodent PET studies), spatial resolution correction may be an important option to consider.

tion from the carotid artery, left ventricle of the heart, or even lungs). Obtaining quantitative endpoints with tracer kinetic modeling and arterial plasma input functions is the "gold standard." The choice of either reference region and image-derived inputs must be substanti‐ ated by the literature and validated by extensive testing by kinetic modeling experts. Once time-activity curves (TACs) from both your input function and tissue of interest are at hand, the parameter estimation can begin. Explanation of the types of kinetic models, the assump‐ tions of each, the parameters they yield, and advantages/disadvantages of each are beyond the intent of the present text. Regardless, the investigator should be aware that different model implementations may behave differently with different tracers. Consult with your local PET modeling expert to determine which methods are most appropriate and most convenient. *Semi-quantitative.* This discussion refers to "static" images (see above). The voxel values within the PET image are in values of tissue radioactivity concentration, such as Bq/cc or kBq/mL. However, taken in isolation, these values are not meaningful and cannot be used as the final endpoint for analysis. Too many factors affect the radioactivity concentration, including the total dose injected, and the body weight of the individual. At a minimum, the data must be

Basic PET Data Analysis Techniques http://dx.doi.org/10.5772/57126 73

The most common method used for data normalization is the index of "Standardized Uptake Value" (SUV), in which the radioactivity concentration is divided by injected dose per body weight (e.g., MBq/kg). This index comes with one major assumption, which is that the tracer has been distributed equally across the entire body- that is, all tissues have had an equal opportunity to be exposed to the tracer. If a "sink" for the tracer exists outside the target of interest, such that a great amount of tracer is sequestered during first pass circulation, then the tracer is not being distributed equally across the body. The whole-body distribution assump‐ tion has then been violated, and body weight is no longer the proper denominator. In this case, SUV measurements are rendered incorrect, and become unreliable as a dependent variable. Another type of normalization with SUV is "SUVR", which is the ratio of SUV from tissue that has specific binding of the tracer to tissue that does not (a reference region). This method was proposed for [11C]PiB, and was evaluated thoroughly for this tracer against arterial and reference region kinetic approaches (Lopresti et al., 2005). If investigators are using a relatively new neuroligand and seek to use SUV or SUVR as endpoints, it is highly recommended the stability of the semi-quantitative index be assessed against either VT or BP, either with real data

Broadly speaking, a region-of-interest (ROI) refers to a user-defined set of voxels (or voxel) on an image, from which PET data are extracted. First, we will address anatomically-defined ROIs. Using anatomically-defined ROIs remains a popular approach for analyzing neuroligand PET data. Typically, anatomic ROIs are defined on a subject's MRI, and then transferred to the dynamic PET data (which is in register with the MRI). An average time-activity curve for the ROI is generated (that is, the time-activity curves of all voxels within the ROI are averaged),

normalized to account for injected tracer dose.

*What kind of analysis do you want? Region-of-Interest versus Voxel-Wise.*

and the TAC is fed into a model for estimation of VT or BP.

or via simulation studies.

**Anatomic ROI Analyses**

**Partial Volume Effect:** True PVE actually is a problem of tissue heterogeneity within a "volume." A volume could be a voxel, or a large region of interest that spans many different tissue types (e.g., a brain lesion). Even with MRI's superior spatial resolution, MRI voxels that sit on the borders between gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) may actually contain components of more than one type of signal. In MRI, this problem is addressed (in part) with probabilistic "segmentation" algorithms that assign voxels to either GM, WM, or CSF. These algorithms create tissue-specific maps, which are useful for many purposes, including creation of anatomic masks which can be used to restrict spatial extent of voxel-wise statistical analyses. Gray matter maps are also a good starting point for generation of subject-specific ROIs.

The source of concern of PVE in PET focuses mainly on quantitative analyses. Regardless of tracer, GM, WM, and CSF will have inherently different kinetics (although CSF does not have "kinetics" per se). This heterogeneity would necessitate accounting for multiple sets of tracer behaviors, complicating and potentially confounding quantitation via mathematical model‐ ing. However, tissue heterogeneity in neuroligand PET data is typically not addressed. This is in part because scanner resolution has improved significantly, and in part because PET processing and analyses rely heavily on structural information from the MRI, which helps restrict the analyses to specific structures/tissue types.

#### **5. Data analyses**

So, the PET studies have been designed and data have been collected. Now what?

*Quantitative Analyses.* If dynamic data were acquired, it is possible to get quantitative infor‐ mation about the ligand in the brain- provided that an "input function" and software imple‐ mentation of the proper tracer kinetic models are available. The two most common parameters of interest are "Volume of Distribution" (VT) and "Binding Potential" (BP), both of which provide physiologically relevant data regarding tracer retention. Input functions are necessary to drive the tracer kinetic modeling procedures – they provide key information about free tracer concentration in the plasma (or parameters related to it). There are three main types of input functions: arterial plasma, reference region, and image-derived (for example, informa‐ tion from the carotid artery, left ventricle of the heart, or even lungs). Obtaining quantitative endpoints with tracer kinetic modeling and arterial plasma input functions is the "gold standard." The choice of either reference region and image-derived inputs must be substanti‐ ated by the literature and validated by extensive testing by kinetic modeling experts. Once time-activity curves (TACs) from both your input function and tissue of interest are at hand, the parameter estimation can begin. Explanation of the types of kinetic models, the assump‐ tions of each, the parameters they yield, and advantages/disadvantages of each are beyond the intent of the present text. Regardless, the investigator should be aware that different model implementations may behave differently with different tracers. Consult with your local PET modeling expert to determine which methods are most appropriate and most convenient.

*Semi-quantitative.* This discussion refers to "static" images (see above). The voxel values within the PET image are in values of tissue radioactivity concentration, such as Bq/cc or kBq/mL. However, taken in isolation, these values are not meaningful and cannot be used as the final endpoint for analysis. Too many factors affect the radioactivity concentration, including the total dose injected, and the body weight of the individual. At a minimum, the data must be normalized to account for injected tracer dose.

The most common method used for data normalization is the index of "Standardized Uptake Value" (SUV), in which the radioactivity concentration is divided by injected dose per body weight (e.g., MBq/kg). This index comes with one major assumption, which is that the tracer has been distributed equally across the entire body- that is, all tissues have had an equal opportunity to be exposed to the tracer. If a "sink" for the tracer exists outside the target of interest, such that a great amount of tracer is sequestered during first pass circulation, then the tracer is not being distributed equally across the body. The whole-body distribution assump‐ tion has then been violated, and body weight is no longer the proper denominator. In this case, SUV measurements are rendered incorrect, and become unreliable as a dependent variable. Another type of normalization with SUV is "SUVR", which is the ratio of SUV from tissue that has specific binding of the tracer to tissue that does not (a reference region). This method was proposed for [11C]PiB, and was evaluated thoroughly for this tracer against arterial and reference region kinetic approaches (Lopresti et al., 2005). If investigators are using a relatively new neuroligand and seek to use SUV or SUVR as endpoints, it is highly recommended the stability of the semi-quantitative index be assessed against either VT or BP, either with real data or via simulation studies.

*What kind of analysis do you want? Region-of-Interest versus Voxel-Wise.*

#### **Anatomic ROI Analyses**

problems. They typically are both computationally and labor-intensive, and require a very detailed anatomic MRI image and robust a priori knowledge of the tracer distribution (Mawlawi et al., 2001; Morris et al., 2004). In deciding on whether or not to apply correction for spatial resolution, the key question is: How important is absolute quantitation? Does having absolute certainty of radioactivity concentration increase the ability to detect differences between groups or conditions? In many cases, it may be reasonable to assume that variability contributed by spatial resolution effects is homogenous across/within subjects, and therefore spatial resolution correction is not warranted. However, in cases where "spill-out" drastically reduces the dynamic range of signal, or interferes with the ability to detect signal above background (such as in small structures, especially in rodent PET studies), spatial resolution

72 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**Partial Volume Effect:** True PVE actually is a problem of tissue heterogeneity within a "volume." A volume could be a voxel, or a large region of interest that spans many different tissue types (e.g., a brain lesion). Even with MRI's superior spatial resolution, MRI voxels that sit on the borders between gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) may actually contain components of more than one type of signal. In MRI, this problem is addressed (in part) with probabilistic "segmentation" algorithms that assign voxels to either GM, WM, or CSF. These algorithms create tissue-specific maps, which are useful for many purposes, including creation of anatomic masks which can be used to restrict spatial extent of voxel-wise statistical analyses. Gray matter maps are also a good starting point for generation

The source of concern of PVE in PET focuses mainly on quantitative analyses. Regardless of tracer, GM, WM, and CSF will have inherently different kinetics (although CSF does not have "kinetics" per se). This heterogeneity would necessitate accounting for multiple sets of tracer behaviors, complicating and potentially confounding quantitation via mathematical model‐ ing. However, tissue heterogeneity in neuroligand PET data is typically not addressed. This is in part because scanner resolution has improved significantly, and in part because PET processing and analyses rely heavily on structural information from the MRI, which helps

So, the PET studies have been designed and data have been collected. Now what?

*Quantitative Analyses.* If dynamic data were acquired, it is possible to get quantitative infor‐ mation about the ligand in the brain- provided that an "input function" and software imple‐ mentation of the proper tracer kinetic models are available. The two most common parameters of interest are "Volume of Distribution" (VT) and "Binding Potential" (BP), both of which provide physiologically relevant data regarding tracer retention. Input functions are necessary to drive the tracer kinetic modeling procedures – they provide key information about free tracer concentration in the plasma (or parameters related to it). There are three main types of input functions: arterial plasma, reference region, and image-derived (for example, informa‐

correction may be an important option to consider.

restrict the analyses to specific structures/tissue types.

of subject-specific ROIs.

**5. Data analyses**

Broadly speaking, a region-of-interest (ROI) refers to a user-defined set of voxels (or voxel) on an image, from which PET data are extracted. First, we will address anatomically-defined ROIs.

Using anatomically-defined ROIs remains a popular approach for analyzing neuroligand PET data. Typically, anatomic ROIs are defined on a subject's MRI, and then transferred to the dynamic PET data (which is in register with the MRI). An average time-activity curve for the ROI is generated (that is, the time-activity curves of all voxels within the ROI are averaged), and the TAC is fed into a model for estimation of VT or BP.

**Pros:** The anatomic ROI approach is a good choice when the study hypothesis anticipates that the effect of group (or condition) with be consistent across the entire anatomic extent of the structure (that is, the ROI is chemically and/or functionally homogeneous). Additionally, if the ROIs are reasonably sized, the TACs are usually smooth. This results in more robust parameter estimates (noisy time-activity curves typically induce a negative bias, or lower values) (see below, and Figure 5).

from our subject sample. These two sources are combined to generate a "starting point" MRI, which is then edited to explicitly conform to an individual's subject anatomy. Regardless of chosen method, the investigator should take care to ensure that the anatomic ROIs are spatially

Basic PET Data Analysis Techniques http://dx.doi.org/10.5772/57126 75

Choice of statistical analysis of ROIs depends on the study design: independent t-tests, paired t-tests, one-way ANOVA, mixed effects models, ANCOVA, correlations, etc. Regardless of the test, when multiple ROIs are being tested for between-group or between-condition effects, or for correlations with e.g., a particular subject characteristic, there is always the question of whether the results need to be corrected for multiple comparisons. This is a relevant but somewhat controversial issue. It is indeed the case that multiple comparisons can lead to false positive results (Type I error), and results that survive statistical adjustments for the multiple tests (e.g., a Bonferroni correction) can help assure the investigator that the effects are real. However, arguments have been made that in pilot studies and/or with exploratory data, such corrections are overtly stringent and unwarranted (Perneger, 1998). Investigators should be prepared to justify omission of correction for multiple comparisons based on the exploratory

Technically speaking, a voxel is the smallest ROI that is possible within an image. Voxel-wise analyses assume that all subject brain data are in the same coordinate space (see above). Voxelwise studies demand "parametric images", that is, voxels cannot be in units of radioactivity concentration, but must be converted to either a quantitative (e.g., VT or BP) or semi-quanti‐ tative (e.g., SUV) value. (In this context, "parametric" simply carries the general meaning of a uniformly normalized or an explicit physiologically descriptive value, and should not be confused with "parameter estimation" used to describe the process of kinetic modeling). In the case of quantitative values, the parameter of interest is generated based on the time-activity curve for each voxel (the input function is the same for all voxels). Taking a page from MRI processing procedures, many investigators will spatially smooth the parametric images to remove any spuriously high or low voxel values. The smoothing kernel should be roughly the size of the practical resolution of the PET scanner (not the ideal, intrinsic resolution). Statistical models are specified based on study design, and statistical testing is performed at each voxel. Most image analysis packages include the flexibility to specify different statistical thresholds, which allows investigators to interrogate the data for subthreshold effects. They also have the capacity to apply stringent corrections for a true multiple comparisons problem: performing statistical tests at tens of thousands of voxels across the brain simultaneously. Areas of

significant results are shown as "clusters" (groups of contiguous voxels).

Although first-pass voxel-wise analyses does not necessarily have to correct for multiple comparisons, there may be logical reasons to spatially restrict the initial voxel-wise analyses. If the tracer is only anticipated to have specific binding in gray matter, use of an average gray matter mask (derived from the sample) would be appropriate to exclude WM and CSF voxels. [11C]raclopride (a dopamine D2/D3 antagonist) is another good example- the signal-to-noise properties of this tracer are such that it cannot be used to quantitate D2/D3 receptor binding in areas outside the striatum (which has the highest concentration of D2/D3 in the brain). In our

appropriate for each individual subject.

nature of the study and/or sample size.

**Voxel-Wise Analyses (voxels are ROIs, too)**

**Figure 5.** Time-activity curves (TACs) of [11C]raclopride from, Left: a single voxel in the left ventral striatum (BPND = 2.09) and Right: from the whole left ventral striatum region-of-interest (ROI) (BPND = 2.74). BPND values were estimated with MRTM (Ichise et al., 2003), using the same cerebellar input function. Note that the average TAC from the whole ROI is much smoother than the single voxel TAC. The slight difference in intensity scale of the single voxel could be attributed to its location in the more ventral aspect of the striatum, close to the base of the brain, which makes it more susceptible to "spillout" artifact.

**Cons:** ROI analyses may miss subtle effects that are spatially constrained to a small area within the larger ROI. If an effect is only present in a subset of voxels, then this may get lost (smoothed out) when all the TACs from all voxels are averaged together.

There are many ways to generate anatomic ROIs. Often, ROIs are painstakingly drawn by hand, which is labor- and time-intensive (and fairly boring for the individual charged with this task). This also has the risk of inducing subjective bias to the ROI definition, with the ensuing possibility data may not be completely comparable across institutions. However, adherence to strict and consistent anatomic definitions based on accepted atlas(es) (e.g., Martinez et al., 2003; Mawlawi et al., 2001) helps mitigate any investigator-induced bias. There are many software programs that offer sets of pre-defined ROIs, which are often defined from a single-subject MR. In our experience, these ROIs are not very representative and do not match well to our subject samples. We have also found that ROIs drawn by our lab on "canonical" average multi-subject T1 templates (again, available in many software packages) do not conform well to our subject samples. Yet another option is to utilize sophisticated software that automatically extract hundreds of ROIs by parcellation of a subjects' MRI. Our laboratory uses a combined approach, in which we start with an individual subjects' spatially normalized gray matter map and a template ROI (e.g., ventral striatum) generated from an average MR from our subject sample. These two sources are combined to generate a "starting point" MRI, which is then edited to explicitly conform to an individual's subject anatomy. Regardless of chosen method, the investigator should take care to ensure that the anatomic ROIs are spatially appropriate for each individual subject.

Choice of statistical analysis of ROIs depends on the study design: independent t-tests, paired t-tests, one-way ANOVA, mixed effects models, ANCOVA, correlations, etc. Regardless of the test, when multiple ROIs are being tested for between-group or between-condition effects, or for correlations with e.g., a particular subject characteristic, there is always the question of whether the results need to be corrected for multiple comparisons. This is a relevant but somewhat controversial issue. It is indeed the case that multiple comparisons can lead to false positive results (Type I error), and results that survive statistical adjustments for the multiple tests (e.g., a Bonferroni correction) can help assure the investigator that the effects are real. However, arguments have been made that in pilot studies and/or with exploratory data, such corrections are overtly stringent and unwarranted (Perneger, 1998). Investigators should be prepared to justify omission of correction for multiple comparisons based on the exploratory nature of the study and/or sample size.

#### **Voxel-Wise Analyses (voxels are ROIs, too)**

**Pros:** The anatomic ROI approach is a good choice when the study hypothesis anticipates that the effect of group (or condition) with be consistent across the entire anatomic extent of the structure (that is, the ROI is chemically and/or functionally homogeneous). Additionally, if the ROIs are reasonably sized, the TACs are usually smooth. This results in more robust parameter estimates (noisy time-activity curves typically induce a negative bias, or lower values) (see

74 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**Figure 5.** Time-activity curves (TACs) of [11C]raclopride from, Left: a single voxel in the left ventral striatum (BPND = 2.09) and Right: from the whole left ventral striatum region-of-interest (ROI) (BPND = 2.74). BPND values were estimated with MRTM (Ichise et al., 2003), using the same cerebellar input function. Note that the average TAC from the whole ROI is much smoother than the single voxel TAC. The slight difference in intensity scale of the single voxel could be attributed to its location in the more ventral aspect of the striatum, close to the base of the brain, which makes it more

**Cons:** ROI analyses may miss subtle effects that are spatially constrained to a small area within the larger ROI. If an effect is only present in a subset of voxels, then this may get lost (smoothed

There are many ways to generate anatomic ROIs. Often, ROIs are painstakingly drawn by hand, which is labor- and time-intensive (and fairly boring for the individual charged with this task). This also has the risk of inducing subjective bias to the ROI definition, with the ensuing possibility data may not be completely comparable across institutions. However, adherence to strict and consistent anatomic definitions based on accepted atlas(es) (e.g., Martinez et al., 2003; Mawlawi et al., 2001) helps mitigate any investigator-induced bias. There are many software programs that offer sets of pre-defined ROIs, which are often defined from a single-subject MR. In our experience, these ROIs are not very representative and do not match well to our subject samples. We have also found that ROIs drawn by our lab on "canonical" average multi-subject T1 templates (again, available in many software packages) do not conform well to our subject samples. Yet another option is to utilize sophisticated software that automatically extract hundreds of ROIs by parcellation of a subjects' MRI. Our laboratory uses a combined approach, in which we start with an individual subjects' spatially normalized gray matter map and a template ROI (e.g., ventral striatum) generated from an average MR

out) when all the TACs from all voxels are averaged together.

below, and Figure 5).

susceptible to "spillout" artifact.

Technically speaking, a voxel is the smallest ROI that is possible within an image. Voxel-wise analyses assume that all subject brain data are in the same coordinate space (see above). Voxelwise studies demand "parametric images", that is, voxels cannot be in units of radioactivity concentration, but must be converted to either a quantitative (e.g., VT or BP) or semi-quanti‐ tative (e.g., SUV) value. (In this context, "parametric" simply carries the general meaning of a uniformly normalized or an explicit physiologically descriptive value, and should not be confused with "parameter estimation" used to describe the process of kinetic modeling). In the case of quantitative values, the parameter of interest is generated based on the time-activity curve for each voxel (the input function is the same for all voxels). Taking a page from MRI processing procedures, many investigators will spatially smooth the parametric images to remove any spuriously high or low voxel values. The smoothing kernel should be roughly the size of the practical resolution of the PET scanner (not the ideal, intrinsic resolution). Statistical models are specified based on study design, and statistical testing is performed at each voxel. Most image analysis packages include the flexibility to specify different statistical thresholds, which allows investigators to interrogate the data for subthreshold effects. They also have the capacity to apply stringent corrections for a true multiple comparisons problem: performing statistical tests at tens of thousands of voxels across the brain simultaneously. Areas of significant results are shown as "clusters" (groups of contiguous voxels).

Although first-pass voxel-wise analyses does not necessarily have to correct for multiple comparisons, there may be logical reasons to spatially restrict the initial voxel-wise analyses. If the tracer is only anticipated to have specific binding in gray matter, use of an average gray matter mask (derived from the sample) would be appropriate to exclude WM and CSF voxels. [11C]raclopride (a dopamine D2/D3 antagonist) is another good example- the signal-to-noise properties of this tracer are such that it cannot be used to quantitate D2/D3 receptor binding in areas outside the striatum (which has the highest concentration of D2/D3 in the brain). In our laboratory, we use a striatal mask to restrict the search area to the striatum. However, with tracers that can bind to processes that are not restricted to gray or white matter, whole-brain sampling would be more appropriate (unless the investigator has an a priori hypothesis that targets a specific region). An example of this would be [11C]PBR28, which is a marker of neuroinflammatory processes. Additionally, if the investigator has specific a priori hypotheses about a structure of interest, it is reasonable to use an anatomic ROI to restrict analysis to a particular nucleus or cortical area. By now, the reader should appreciate that the distinctions between voxel-wise and ROI analyses begin to blur a bit.

**6. Quality control and automation**

is a sample checklist:

Many of the processes discussed here involve computer-based procedures. However, it is unwise to assume that the algorithms will work perfectly and that the data will always be robust. In order to assure the quality of the study, quality control by real humans is requiredat every point along the processing and analysis stream. Simple visual checks can be made to determine the success of the co-registration, motion correction, and normalization steps. Here

Basic PET Data Analysis Techniques http://dx.doi.org/10.5772/57126 77

**1.** MR-PET co-registration: Is the mean/summed PET in the same space as the native MR? Multiple anatomic landmarks should be assessed- from outer cortical layers to subcortical landmarks such as striatal boundaries, ventricles, and corpus callosum. Cortical land‐ marks may be the best visual assessment for PET studies that do not contain much

**2.** MR normalization. The "warping" of the native space MR to the target coordinate space should be checked against the coordinate template. This step does not always converge appropriately, and some very strange brains can result from incorrect convergence of the spatial normalization algorithm. A helpful step to ensure successful normalization is to first perform a rigid-body co-registration between the subject native space MR and the

**3.** PET normalization. To perform this QC step, create a mean or summed PET from all the spatially normalized dynamic PET frames (or spatially normalized single static frame), and compare it to both the subject's normalized MR and the template MR. If the MR normalization step was successful, then in most cases the PET normalization will be fine

**4.** Motion-correction. Programs that read in multiple 3D volumes in a cine loop are extremely useful for visually detecting motion. Make sure that the program can read in the numerical convention of sequential mages (i.e., decimal or hexadecimal). Investigators must learn to distinguish between true anatomic subject motion and the random noise inherent in PET

**5.** Anatomic regions of interest. This QC should be done during the generation of the regions of interest, but is still a crucial trouble-shooting step, especially if a subject's data appears to be a high or low outlier relative to the sample. It is extremely important to check the overlay of the ROIs on the PET data. Reslicing of the PET data during the motion correction and spatial normalization can result in "chopping off" of brain regions, especially cerebellum and frontal cortex. It is very important to make sure the anatomic ROIs are not sampling image "air". This is especially important for quantitative analyses that utilize BP with a "reference regions" (see above). If the reference region is corrupted by white matter, CSF, or "air", then the BP estimate of the target region (or voxel) will be corrupted.

**6.** Time-activity curves. Even if the investigator intends to only run a voxel-wise analysis, it is always a good idea to visually check the TACs from at least one, if not several, anatomic

subcortical binding (for example, [11C]PiB in healthy controls)

canonical template, then perform the spatial normalization step.

– but this should never be taken for granted.

images- which can create an optical illusion of motion.

**Pros:** Voxel-based analyses have two main advantages over ROI analyses. First, they sample the entire brain (or a spatially restricted region) objectively. Second, a voxel-wise approach they can pick up spatially discrete areas of effect that may be "washed away" by an ROI approach.

**Cons:** TACs at the voxel level can be extremely noisy (Figure 5). In many kinetic models, noise can cause underestimation of the quantitative parameters. However, if subjects have received approximately the same dose of tracer, then the noise at the voxel level should be uniform across subjects. Gray-matter voxels that share boundaries with CSF, air (sinuses), or white matter are especially subject to spatial resolution problems (see above); results that seem to outline "edges" of ventricles or other structures near white matter should be considered with caution. Also, even including one or two subjects with severe atrophy not corrected for by spatial normalization can skew voxel-wise results. Again, this brings to light the care an investigator must take with understanding the data (see QC section, below).

#### **Congratulations, you've got statistically significant results with a voxel-wise analysis. Now what?**

The output of most voxel-wise analyses is a series of parametric maps with *t*-statistic values at each voxel where there was a statistically significantly effect at a given *p*-threshold. How‐ ever, the programs typically don't give you direct information about the actual effect size you are detecting. In addition to the statistical results, investigators should report the quantitative description of the data such as what the percent change was between groups/conditions, what the nature of the correlation was, etc.

Many analysis programs will allow you to save out a cluster of significant voxels as an ROI; single voxels may even be used as ROIs (this would be useful for characterizing peak effects). You may also choose to use a predefined anatomic ROI, especially when the effect of interest spans areas of interest, or the region was part of an *a priori* hypothesis. Once the ROI has been designated, there are two main methods for extracting the data. The ROIs can be applied to all subject's parametric images, and then the mean values (e.g., VT, BP, SUV) for the ROI can be compiled across groups, conditions, etc. Alternatively, the ROIs can be applied directly to the dynamic data to extract the average TAC from the ROI, which is then fed into a modeling program to estimate the parameter of interest (as described above).

#### **6. Quality control and automation**

laboratory, we use a striatal mask to restrict the search area to the striatum. However, with tracers that can bind to processes that are not restricted to gray or white matter, whole-brain sampling would be more appropriate (unless the investigator has an a priori hypothesis that targets a specific region). An example of this would be [11C]PBR28, which is a marker of neuroinflammatory processes. Additionally, if the investigator has specific a priori hypotheses about a structure of interest, it is reasonable to use an anatomic ROI to restrict analysis to a particular nucleus or cortical area. By now, the reader should appreciate that the distinctions

76 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**Pros:** Voxel-based analyses have two main advantages over ROI analyses. First, they sample the entire brain (or a spatially restricted region) objectively. Second, a voxel-wise approach they can pick up spatially discrete areas of effect that may be "washed away" by an ROI

**Cons:** TACs at the voxel level can be extremely noisy (Figure 5). In many kinetic models, noise can cause underestimation of the quantitative parameters. However, if subjects have received approximately the same dose of tracer, then the noise at the voxel level should be uniform across subjects. Gray-matter voxels that share boundaries with CSF, air (sinuses), or white matter are especially subject to spatial resolution problems (see above); results that seem to outline "edges" of ventricles or other structures near white matter should be considered with caution. Also, even including one or two subjects with severe atrophy not corrected for by spatial normalization can skew voxel-wise results. Again, this brings to light the care an

**Congratulations, you've got statistically significant results with a voxel-wise analysis. Now**

The output of most voxel-wise analyses is a series of parametric maps with *t*-statistic values at each voxel where there was a statistically significantly effect at a given *p*-threshold. How‐ ever, the programs typically don't give you direct information about the actual effect size you are detecting. In addition to the statistical results, investigators should report the quantitative description of the data such as what the percent change was between groups/conditions, what

Many analysis programs will allow you to save out a cluster of significant voxels as an ROI; single voxels may even be used as ROIs (this would be useful for characterizing peak effects). You may also choose to use a predefined anatomic ROI, especially when the effect of interest spans areas of interest, or the region was part of an *a priori* hypothesis. Once the ROI has been designated, there are two main methods for extracting the data. The ROIs can be applied to all subject's parametric images, and then the mean values (e.g., VT, BP, SUV) for the ROI can be compiled across groups, conditions, etc. Alternatively, the ROIs can be applied directly to the dynamic data to extract the average TAC from the ROI, which is then fed into a modeling

investigator must take with understanding the data (see QC section, below).

program to estimate the parameter of interest (as described above).

between voxel-wise and ROI analyses begin to blur a bit.

approach.

**what?**

the nature of the correlation was, etc.

Many of the processes discussed here involve computer-based procedures. However, it is unwise to assume that the algorithms will work perfectly and that the data will always be robust. In order to assure the quality of the study, quality control by real humans is requiredat every point along the processing and analysis stream. Simple visual checks can be made to determine the success of the co-registration, motion correction, and normalization steps. Here is a sample checklist:


regions of interest. This may help identify motion that needs to be corrected, or may shed light on other data quality problems that should be addressed.

information from the headholder material may need to be edited out to render a more purely anatomic image and facilitate co-registration with the PET (which will not show the presence of the holder). Again, there is no "set" approach, and it is up to the investigator to empirically

Basic PET Data Analysis Techniques http://dx.doi.org/10.5772/57126 79

Regardless if an ROI or voxel-wise approach is used for small animal PET data analysis, it is important that the investigator appreciate the practical resolution limitations of the imaging modality. Even with the most advanced small animal PET scanners, it is difficult to resolve structures below a ~1mm3 volume. This is true even if high-resolution anatomic MR data are

**1.** The presence of micron resolution in an MR image co-registered to a PET image does not guarantee micron resolution in the PET dataset (see above section for discussion on partial

**2.** The voxel size in a PET image does not necessarily correspond to the practical resolution of the scanner. Images can be resliced almost infinitely to very small voxels by relatively simple interpolation of the original PET data. However, this does not change the actual resolution of the scanner. If the final PET voxel size is one 0.25mm x 0.25mm x 0.25mm, and the practical scanner resolution is 1mm x 1mm x 1mm, then the resolution is still 1mm x 1mm x 1mm. Information is not gained by voxel sizes that are smaller than the intrinsic scanner resolution. Check with your local PET expert to determine what the resolution of

Voxel-wise studies in small animal PET data require careful consideration with respect to how spatial normalization will be achieved, especially with rodent data. Brain structure between rodent strains is likely to be quite different; it should not be assumed that one-rat (or mouse) brain-fits-all. Additional factors like gender, age, and weight of the animal also influence brain shape and structure. Of particular note is that brain development and growth in rodents is nonlinear across structures (Sullivan et al., 2006), and therefore a younger brain should not simply be scaled up to the size of an older rodent brain. Three-dimensional templates and atlases of mice and rat brains are becoming more common. However, when possible, the investigator should consider generating an in-house brain template specific to the strain, age,

Image processing and data analysis of neuroligand PET data requires multiple steps. There are an almost infinite number of possible iterations and refinements to data processing streams. Hopefully, this chapter has provided a useful overview of the key concepts investigators need to consider when working with these expensive and often complex datasets. Regardless of the exact sequence of processing procedures selected, a thorough working knowledge of the rationale behind each step will help ensure the fidelity and quality of the laboratory's datasets.

determine what is most appropriate for their particular imaging system.

available. Two key concepts are worth emphasizing:

voluming artifacts).

the small animal scanner is.

gender, and weight of the sample being studied.

**8. Summary**

**7.** Parametric images. Regardless of outcome variable (e.g., SUV VT, BP), the parametric images should be examined to make sure the values are reasonable. If outlying values are observed, then more intensive investigation is warranted to identify the source of the (apparently) aberrant data.

Executing all the image processing steps individually can be time-consuming and laborintensive. With many programs, it is possible to automate, or "batch", many steps together through the use of scripts. In fact, automation is often implemented at the level of multiple subjects at once. The degree of automation implemented must be up to the discretion of the laboratory and what works best with the current laboratory culture, which encompasses both available manpower and study completion rate. Some labs may run hundreds of subjects, then perform QC steps for each step in batches for each QC point. Other labs may choose to implement QC for each individual subject as those data come through. Workload distribution of QC is ultimately up to each investigator, based on their needs.

#### **7. Small animal PET considerations (especially rodent)**

In general, the same principles described above regarding types of data (semi-quantitative, quantitative) and analyses (ROI, voxel-wise) apply to PET imaging in small animals. Having said that, some special concerns need to be addressed (or alleviated). In most studies, animals will be anesthetized during imaging. If the animal is restrained by a device that prohibits head motion (e.g., for neuroimaging, a stereotaxic head-holder), then motion correction for the dynamic PET data may not be needed. (Again, gating acquisition methods for thoracic and abdominal imaging are beyond the scope of this discussion). If the animal's skull is not explicitly restrained, then head motion may occur from breathing, and motion-correction algorithms may be warranted.

If one acquires parallel data in other modalities for the purposes of co-registration, the nature of the PET data must be considered within the context of aligning one modality to another. Tracer kinetics in rodents can be vastly different than what is observed in humans. Some tracers may have very little apparent brain uptake, and therefore the outline of the brain may not be obvious. If there is little information about brain shape in the PET data, a co-registration algorithm may not work accurately, or may even crash. If alternate modality images are acquired and needed for co-registration (e.g., CT for attenuation correction; MR for anatomic localization of anatomic structures), then image editing may be required for successful coregistration between the PET data and MRI and/or CT. For example, if the lack of a coherent brain outline in the PET image data is problematic, it may be useful to edit out the skull in CT or MR images. On the other hand, in rodents, tracers with high uptake areas (e.g., dopami‐ nergic ligands in the striatum) may not register well to a rodent MR, which will not have clear delineation between subcortical nuclei in rodents. In this case, an early-time PET image may be useful for registration. Finally, if the animal is restrained with a headholder, the extra image information from the headholder material may need to be edited out to render a more purely anatomic image and facilitate co-registration with the PET (which will not show the presence of the holder). Again, there is no "set" approach, and it is up to the investigator to empirically determine what is most appropriate for their particular imaging system.

Regardless if an ROI or voxel-wise approach is used for small animal PET data analysis, it is important that the investigator appreciate the practical resolution limitations of the imaging modality. Even with the most advanced small animal PET scanners, it is difficult to resolve structures below a ~1mm3 volume. This is true even if high-resolution anatomic MR data are available. Two key concepts are worth emphasizing:


Voxel-wise studies in small animal PET data require careful consideration with respect to how spatial normalization will be achieved, especially with rodent data. Brain structure between rodent strains is likely to be quite different; it should not be assumed that one-rat (or mouse) brain-fits-all. Additional factors like gender, age, and weight of the animal also influence brain shape and structure. Of particular note is that brain development and growth in rodents is nonlinear across structures (Sullivan et al., 2006), and therefore a younger brain should not simply be scaled up to the size of an older rodent brain. Three-dimensional templates and atlases of mice and rat brains are becoming more common. However, when possible, the investigator should consider generating an in-house brain template specific to the strain, age, gender, and weight of the sample being studied.

#### **8. Summary**

regions of interest. This may help identify motion that needs to be corrected, or may shed

**7.** Parametric images. Regardless of outcome variable (e.g., SUV VT, BP), the parametric images should be examined to make sure the values are reasonable. If outlying values are observed, then more intensive investigation is warranted to identify the source of the

78 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Executing all the image processing steps individually can be time-consuming and laborintensive. With many programs, it is possible to automate, or "batch", many steps together through the use of scripts. In fact, automation is often implemented at the level of multiple subjects at once. The degree of automation implemented must be up to the discretion of the laboratory and what works best with the current laboratory culture, which encompasses both available manpower and study completion rate. Some labs may run hundreds of subjects, then perform QC steps for each step in batches for each QC point. Other labs may choose to implement QC for each individual subject as those data come through. Workload distribution

In general, the same principles described above regarding types of data (semi-quantitative, quantitative) and analyses (ROI, voxel-wise) apply to PET imaging in small animals. Having said that, some special concerns need to be addressed (or alleviated). In most studies, animals will be anesthetized during imaging. If the animal is restrained by a device that prohibits head motion (e.g., for neuroimaging, a stereotaxic head-holder), then motion correction for the dynamic PET data may not be needed. (Again, gating acquisition methods for thoracic and abdominal imaging are beyond the scope of this discussion). If the animal's skull is not explicitly restrained, then head motion may occur from breathing, and motion-correction

If one acquires parallel data in other modalities for the purposes of co-registration, the nature of the PET data must be considered within the context of aligning one modality to another. Tracer kinetics in rodents can be vastly different than what is observed in humans. Some tracers may have very little apparent brain uptake, and therefore the outline of the brain may not be obvious. If there is little information about brain shape in the PET data, a co-registration algorithm may not work accurately, or may even crash. If alternate modality images are acquired and needed for co-registration (e.g., CT for attenuation correction; MR for anatomic localization of anatomic structures), then image editing may be required for successful coregistration between the PET data and MRI and/or CT. For example, if the lack of a coherent brain outline in the PET image data is problematic, it may be useful to edit out the skull in CT or MR images. On the other hand, in rodents, tracers with high uptake areas (e.g., dopami‐ nergic ligands in the striatum) may not register well to a rodent MR, which will not have clear delineation between subcortical nuclei in rodents. In this case, an early-time PET image may be useful for registration. Finally, if the animal is restrained with a headholder, the extra image

light on other data quality problems that should be addressed.

of QC is ultimately up to each investigator, based on their needs.

**7. Small animal PET considerations (especially rodent)**

(apparently) aberrant data.

algorithms may be warranted.

Image processing and data analysis of neuroligand PET data requires multiple steps. There are an almost infinite number of possible iterations and refinements to data processing streams. Hopefully, this chapter has provided a useful overview of the key concepts investigators need to consider when working with these expensive and often complex datasets. Regardless of the exact sequence of processing procedures selected, a thorough working knowledge of the rationale behind each step will help ensure the fidelity and quality of the laboratory's datasets.

#### **Acknowledgements**

The author would like to thank Daniel Albrecht and Dr. Shannon Risacher for processing the PET data presented in this report, and for providing data for the figures.

[6] Mawlawi O, Martinez D, Slifstein M, Broft A, Chatterjee R, Hwang DR, Huang Y, Simpson N, Ngo K, Van Heertum R, Laruelle M. 2001. Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and preci‐ sion of D(2) receptor parameter measurements in ventral striatum. J Cereb Blood

Basic PET Data Analysis Techniques http://dx.doi.org/10.5772/57126 81

[7] Morris ED, Endres CJ, Schmidt KC, Christian BT, Muzik Jr. RF, Fisher RE. 2004. Ki‐ netic modeling in positron emission tomography. In: Wernick MN, Aarsvold JN, edi‐ tors. Emission tomography: the fundamentals of PET and SPECT: Elsevier. p.

[8] Perneger TV. 1998. What's wrong with Bonferroni adjustments. BMJ 316(7139):

[9] Phelps ME, editor. 2006. PET: Physics, instrumentation, and scanners. New York:

[10] Schweinhardt P, Fransson P, Olson L, Spenger C, Andersson JL. 2003. A template for spatial normalisation of MR images of the rat brain. J Neurosci Methods 129(2):

[11] Sullivan EV, Adalsteinsson E, Sood R, Mayer D, Bell R, McBride W, Li TK, Pfeffer‐ baum A. 2006. Longitudinal brain magnetic resonance imaging study of the alcoholpreferring rat. Part I: adult brain growth. Alcohol Clin Exp Res 30(7):1234-1247.

Flow Metab 21(9):1034-1057.

499-540.

1236-1238.

Springer.

105-113.

#### **Author details**

Karmen K. Yoder

Indiana University School of Medicine, Department of Radiology and Imaging Sciences, In‐ diana Institute for Biomedical Imaging Sciences, Center for Neuroimaging, Indianapolis, In‐ diana, USA

#### **References**


[6] Mawlawi O, Martinez D, Slifstein M, Broft A, Chatterjee R, Hwang DR, Huang Y, Simpson N, Ngo K, Van Heertum R, Laruelle M. 2001. Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and preci‐ sion of D(2) receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab 21(9):1034-1057.

**Acknowledgements**

**Author details**

Karmen K. Yoder

diana, USA

**References**

The author would like to thank Daniel Albrecht and Dr. Shannon Risacher for processing the

80 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Indiana University School of Medicine, Department of Radiology and Imaging Sciences, In‐ diana Institute for Biomedical Imaging Sciences, Center for Neuroimaging, Indianapolis, In‐

[1] Bailey DL. 2005. Data acquisition and performance characterization in PET. In: Bailey DL, Townsend DW, Valk PE, Maisey MN, editors. Positron emission tomography:

[2] Ichise M, Liow JS, Lu JQ, Takano A, Model K, Toyama H, Suhara T, Suzuki K, Innis RB, Carson RE. 2003. Linearized reference tissue parametric imaging methods: appli‐ cation to [11C]DASB positron emission tomography studies of the serotonin trans‐

[3] Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, Holden J, Houle S, Huang SC, Ichise M, Iida H, Ito H, Kimura Y, Koeppe RA, Knudsen GM, Knuuti J, Lammertsma AA, Laruelle M, Logan J, Maguire RP, Mintun MA, Morris ED, Parsey R, Price JC, Slifstein M, Sossi V, Suhara T, Votaw JR, Wong DF, Carson RE. 2007. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J

[4] Lopresti BJ, Klunk WE, Mathis CA, Hoge JA, Ziolko SK, Lu X, Meltzer CC, Schimmel K, Tsopelas ND, DeKosky ST, Price JC. 2005. Simplified quantification of Pittsburgh Compound B amyloid imaging PET studies: a comparative analysis. J Nucl Med

[5] Martinez D, Slifstein M, Broft A, Mawlawi O, Hwang DR, Huang Y, Cooper T, Ke‐ geles L, Zarahn E, Abi-Dargham A, Haber SN, Laruelle M. 2003. Imaging human mesolimbic dopamine transmission with positron emission tomography. Part II: am‐ phetamine-induced dopamine release in the functional subdivisions of the striatum. J

porter in human brain. J Cereb Blood Flow Metab 23(9):1096-1112.

PET data presented in this report, and for providing data for the figures.

Basic sciences. London: Springer-Verlag. p. 41-62.

Cereb Blood Flow Metab 27(9):1533-1539.

Cereb Blood Flow Metab 23(3):285-300.

46(12):1959-1972.


**Section 2**

**PET Applications in Neurological and Behavioral**

**Research**

**PET Applications in Neurological and Behavioral Research**

**Chapter 4**

**Functional Imaging Studies of Human Cognition Using**

In past times behavioural neurologists have shown how discrete brain lesions provoked different types of cognitive disorders such as language, praxic, gnostic, spatial or memory

They interpreted these anatomo-clinical associations conjecturing that the normal brain function (impaired by brain damage) was localized within the lesioned region (lesional hypothesis) and had been impaired from brain damage (Marshall & Fink, 2003). They also hypothesized that cognitive impairments could arise from lesions that spared the functional centers but disconnected them from other centers (disconnectional hypothesis). According this argument "basic psychological functions" are localized in a punctate fashion and complex psychological functions are constituted from many such basic functions joined together in distributed circuits. It follows that the symptoms may have arisen from a reconfiguration of

During the late 19th century, the advent of structural brain imaging, first the computed tomography (CT) and later the magnetic resonance imaging (MRI), gave the possibility to study anatomical localization of the cognitive deficits that were manifest after brain injury. Since then neuroimaging studies have helped medical doctors in clinical practice to identify cerebral damage caused by spaced-occupying lesions, strokes or degenerative processes.

During the 20th century other instrumental techniques such as single photon computed tomography (SPECT), positron emission tomography (PET), functional magnetic resonance imaging (f-MRI) or magnetoencephalography (MEG) started to be used for evaluation of cognitive activation not only in patients with cerebral lesions, but also in living normal brains and localize mental faculties in different regions of the brain. Further, functional techniques

> © 2013 Misciagna; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Positron Emission Tomography**

Additional information is available at the end of the chapter

the entire circuit in response to cerebral damage.

Sandro Misciagna

**1. Introduction**

domain.

http://dx.doi.org/10.5772/57124

## **Functional Imaging Studies of Human Cognition Using Positron Emission Tomography**

Sandro Misciagna

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57124

#### **1. Introduction**

In past times behavioural neurologists have shown how discrete brain lesions provoked different types of cognitive disorders such as language, praxic, gnostic, spatial or memory domain.

They interpreted these anatomo-clinical associations conjecturing that the normal brain function (impaired by brain damage) was localized within the lesioned region (lesional hypothesis) and had been impaired from brain damage (Marshall & Fink, 2003). They also hypothesized that cognitive impairments could arise from lesions that spared the functional centers but disconnected them from other centers (disconnectional hypothesis). According this argument "basic psychological functions" are localized in a punctate fashion and complex psychological functions are constituted from many such basic functions joined together in distributed circuits. It follows that the symptoms may have arisen from a reconfiguration of the entire circuit in response to cerebral damage.

During the late 19th century, the advent of structural brain imaging, first the computed tomography (CT) and later the magnetic resonance imaging (MRI), gave the possibility to study anatomical localization of the cognitive deficits that were manifest after brain injury. Since then neuroimaging studies have helped medical doctors in clinical practice to identify cerebral damage caused by spaced-occupying lesions, strokes or degenerative processes.

During the 20th century other instrumental techniques such as single photon computed tomography (SPECT), positron emission tomography (PET), functional magnetic resonance imaging (f-MRI) or magnetoencephalography (MEG) started to be used for evaluation of cognitive activation not only in patients with cerebral lesions, but also in living normal brains and localize mental faculties in different regions of the brain. Further, functional techniques

© 2013 Misciagna; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and both can be thought as originating from imaging and functional technologies: neuroelec‐ trical (MEG and electroencephalography), and hemodynamic (PET, SPECT, fMRI, optical).

"**Functional effective connectivity**" consists in the measure of correlation of connectivity among brain regions or better the influence of brain nodes on each other. PET studies have been applied to quantify causal interactions between brain regions (McIntosh et al., 1994; Horwitz et al., 2005). This measure estimates the strength of connectivity between cerebral areas and statistically infers a causal effect of connectivity. For example a PET study of human working memory for faces has suggested that the network for underlying activity changes as the task requirements change (McIntosh et al., 1996). Models of connectivity have been explored with PET in the study dynamic neural networks underlying **language processing** using specific tasks such as word generation (Warburton et al., 1996) or reading (Price and Friston, 1997). PET studies have also been applied to demonstrate **hemispheric dominance of language**. The laterality of language is usually achieved by activating language areas and comparing the relative strength of activation between the right and the left hemispheres (Stippich et al., 2003; Lohmann et al., 2004). Studies on multiple groups have reported a strong correlation with PET or fMRI compared with intraoperative mapping techniques and the results of classical Wada test (Roux et al., 2003; Woermann et al., 2003; Atlas et al., 1996).

Functional Imaging Studies of Human Cognition Using Positron Emission Tomography

http://dx.doi.org/10.5772/57124

87

PET or task-activated fMRI can locate, with a high spatial resolution, both receptive and productive language areas. One practical application of PET for language localization consists in the presurgical evaluation of epileptic or brain tumor patients. This PET neurosurgical application makes possible a precise **localization of essential language** areas in individual patient rather then participating areas. Essential language areas are ones that when removed result in a language deficit; while participating areas are ones that are activated during language paradigms, but do not result in a post-operative language deficit after surgical resection, because these are areas of redundant processing or because other areas learn to take over the same function. Currently, there is no way to distinguish essential from participating areas with non-invasive imaging and improving the detection of essential areas is a major goal of clinical functional imaging. Language areas found to be lateralized in left hemisphere with a variety of language tasks are essentials four: prefrontal cortex (inferior frontal gyrus, superior frontal gyrus and the anterior cingulate), angular gyrus (excluding the supramarginal gyrus), ventrolateral temporal lobe (superior temporal, middle temporal, inferior temporal and fusiform gyri) and retrosplenial cortex. This means that studies on patients with lesion of anterior lateral prefrontal cortex (known as Broca's area) overemphasize the role of these cerebral areas in onset of language disorder (Broca's aphasia) as confirmed by patients with isolated lesions of "Broca's areas" having only apraxis deficits of articulation rather then aphasia. On the other hands a real and permanent Broca's aphasia requires more extensive cerebral lesions involving anterior frontal gyrus, middle frontal gyrus and peri-central gyri. These functional studies suggest that a wide area of left frontal lobe participate in language processing outside the classical confines of Broca's area, as confirmed by clinical cases of people with large frontal stroke and receptive aphasia which later may evolve into a so-called expressive aphasia. Task activated fMRI provide evidence of cortical reorganization of

language areas, do to tumoral lesions or after a surgical resection.

PET, fMRI, MEG and EEG have been used in numerous studies to **investigate the cerebral sites of declarative memory** (for a review see Gazzaniga, 2004) that consists in explicit memory

These advances in medical technology have led to study structural brain imaging early in patients, explore relationship between structure and function or hypothesize brain cognitive functioning also in normal subjects.

For example Positron Emission Tomography has been used in healthy volunteers to study brain activation during specific goal-directed behaviours (Raichle et al., 2001) such as arith‐ metical computation (Dehaene et al., 1996), memory tasks, visuoconstructive abilities or specific language tasks.

Since then various neuroimaging technologies have also been applied to identify and measure a range of biological processes that occur along neurological disease associated with cognitive impairment as in neurodegenerative conditions.

In this chapter we will review some applications of PET in understanding the cognitive functions in normal subjects, in patients with cognitive deficits during normal aging or following vascular or degenerative damage.

We will also discuss how PET scanning of glucose metabolism, could be used to differentiate Alzheimer's disease from other forms of dementia such as Vascular dementia, Lewy boby dementia or Frontotemporal dementia, which helps to guide clinicians in symptomatic treatment strategies.

We will also expose how PET exam could be useful to identify potential risk of developing dementia in persons with mild cognitive impairment (MCI) resulting useful in predicting further cognitive decline.

#### **2. Pet study of human cognitive functions**

The human brain is an extremely complex organ. The energy required for this complex structure is almost exclusively covered by oxidative metabolism of glucose (Clarke and Sokoloff, 1999). Since PET is a technology based on study of glucose metabolism has great impact on research in study of human cerebral activity.

PET has been adopted in normal subject to study cognitive functions in a particular case of functional connectivity that is the so-called default mode or "**resting state connectivity**", successively extended with fMRI studies. It quantified the spatial correlation of brain activity in the absence of a specific cognitive task. Typically, this is performed by having the subject fixate a visual cue in the absence of a cognitive task (Raichle and Mintun, 2006). The baseline activity of the resting state has spatial correlations that involve the same prefrontal, medial temporal lobe and parietal lobe systems involved in some memory tasks. It could be hypothe‐ sized that memory system, especially the declarative memory system, might be activated in the resting state (Vincent et al., 2006).

"**Functional effective connectivity**" consists in the measure of correlation of connectivity among brain regions or better the influence of brain nodes on each other. PET studies have been applied to quantify causal interactions between brain regions (McIntosh et al., 1994; Horwitz et al., 2005). This measure estimates the strength of connectivity between cerebral areas and statistically infers a causal effect of connectivity. For example a PET study of human working memory for faces has suggested that the network for underlying activity changes as the task requirements change (McIntosh et al., 1996). Models of connectivity have been explored with PET in the study dynamic neural networks underlying **language processing** using specific tasks such as word generation (Warburton et al., 1996) or reading (Price and Friston, 1997). PET studies have also been applied to demonstrate **hemispheric dominance of language**. The laterality of language is usually achieved by activating language areas and comparing the relative strength of activation between the right and the left hemispheres (Stippich et al., 2003; Lohmann et al., 2004). Studies on multiple groups have reported a strong correlation with PET or fMRI compared with intraoperative mapping techniques and the results of classical Wada test (Roux et al., 2003; Woermann et al., 2003; Atlas et al., 1996).

and both can be thought as originating from imaging and functional technologies: neuroelec‐ trical (MEG and electroencephalography), and hemodynamic (PET, SPECT, fMRI, optical).

86 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

These advances in medical technology have led to study structural brain imaging early in patients, explore relationship between structure and function or hypothesize brain cognitive

For example Positron Emission Tomography has been used in healthy volunteers to study brain activation during specific goal-directed behaviours (Raichle et al., 2001) such as arith‐ metical computation (Dehaene et al., 1996), memory tasks, visuoconstructive abilities or

Since then various neuroimaging technologies have also been applied to identify and measure a range of biological processes that occur along neurological disease associated with cognitive

In this chapter we will review some applications of PET in understanding the cognitive functions in normal subjects, in patients with cognitive deficits during normal aging or

We will also discuss how PET scanning of glucose metabolism, could be used to differentiate Alzheimer's disease from other forms of dementia such as Vascular dementia, Lewy boby dementia or Frontotemporal dementia, which helps to guide clinicians in symptomatic

We will also expose how PET exam could be useful to identify potential risk of developing dementia in persons with mild cognitive impairment (MCI) resulting useful in predicting

The human brain is an extremely complex organ. The energy required for this complex structure is almost exclusively covered by oxidative metabolism of glucose (Clarke and Sokoloff, 1999). Since PET is a technology based on study of glucose metabolism has great

PET has been adopted in normal subject to study cognitive functions in a particular case of functional connectivity that is the so-called default mode or "**resting state connectivity**", successively extended with fMRI studies. It quantified the spatial correlation of brain activity in the absence of a specific cognitive task. Typically, this is performed by having the subject fixate a visual cue in the absence of a cognitive task (Raichle and Mintun, 2006). The baseline activity of the resting state has spatial correlations that involve the same prefrontal, medial temporal lobe and parietal lobe systems involved in some memory tasks. It could be hypothe‐ sized that memory system, especially the declarative memory system, might be activated in

functioning also in normal subjects.

impairment as in neurodegenerative conditions.

following vascular or degenerative damage.

**2. Pet study of human cognitive functions**

impact on research in study of human cerebral activity.

the resting state (Vincent et al., 2006).

specific language tasks.

treatment strategies.

further cognitive decline.

PET or task-activated fMRI can locate, with a high spatial resolution, both receptive and productive language areas. One practical application of PET for language localization consists in the presurgical evaluation of epileptic or brain tumor patients. This PET neurosurgical application makes possible a precise **localization of essential language** areas in individual patient rather then participating areas. Essential language areas are ones that when removed result in a language deficit; while participating areas are ones that are activated during language paradigms, but do not result in a post-operative language deficit after surgical resection, because these are areas of redundant processing or because other areas learn to take over the same function. Currently, there is no way to distinguish essential from participating areas with non-invasive imaging and improving the detection of essential areas is a major goal of clinical functional imaging. Language areas found to be lateralized in left hemisphere with a variety of language tasks are essentials four: prefrontal cortex (inferior frontal gyrus, superior frontal gyrus and the anterior cingulate), angular gyrus (excluding the supramarginal gyrus), ventrolateral temporal lobe (superior temporal, middle temporal, inferior temporal and fusiform gyri) and retrosplenial cortex. This means that studies on patients with lesion of anterior lateral prefrontal cortex (known as Broca's area) overemphasize the role of these cerebral areas in onset of language disorder (Broca's aphasia) as confirmed by patients with isolated lesions of "Broca's areas" having only apraxis deficits of articulation rather then aphasia. On the other hands a real and permanent Broca's aphasia requires more extensive cerebral lesions involving anterior frontal gyrus, middle frontal gyrus and peri-central gyri. These functional studies suggest that a wide area of left frontal lobe participate in language processing outside the classical confines of Broca's area, as confirmed by clinical cases of people with large frontal stroke and receptive aphasia which later may evolve into a so-called expressive aphasia. Task activated fMRI provide evidence of cortical reorganization of language areas, do to tumoral lesions or after a surgical resection.

PET, fMRI, MEG and EEG have been used in numerous studies to **investigate the cerebral sites of declarative memory** (for a review see Gazzaniga, 2004) that consists in explicit memory for facts and events. Declarative memory has often been studied using the so-called "subse‐ quent memory effect" that is brain activity during encoding of items that are subsequently forgotten. On the other way the retrieval of declarative memory has been studied with the "old/new effect" that consists is the comparison of brain activity recorded during correctly recognized old items versus correctly identified new items. Memory for events involves processing in the medial temporal lobes (Milner et al., 1998) and in the prefrontal cortex. Frontal lobe activity is related to both encoding and retrieval of memory events for both long-term and short-term memory.

these techniques may provide benefits especially to neurosurgeon (Fischl et al., 2001; Dale et

Functional Imaging Studies of Human Cognition Using Positron Emission Tomography

http://dx.doi.org/10.5772/57124

89

Cerebrovascular disease affects prominently elderly persons through alterations in brain structure and metabolism that produce cognitive decline. Cognitive deficit revealed in cerebrovascular disease regards especially the domains of executive functions (Starkstein et al., 1996), attention, language (Powell et al., 1998) and less prominent memory deficits (Villardita, 1993; Tierney et al., 2001). Vascular cognitive disorders may be caused by multiple neuropathological substrates, including multi-infarct encephalopathy, single infarcts in strategic areas, lacunas and lacunar states, Biswanger's leukoencephalopathy and leukoarariosis, hippocampal sclerosis, watershed infarcts and neuronal loss/atrophy due to diffuse hypoperfusion (Ferrer, 2010). These substrates can be a consequence of different vascular diseases including atherosclerosis, small vessel disease, hypertensive angiopathy, inflammatory disease of blood vessels, inherited vascular disorders such as amyloid angiopathy and CADASIL (central autonomic dominant arteriopathy with subcortical infarcts and leukoencephalopathy) or the consequence of single or multiple cerebral

Despite the considerable degree of accuracy in diagnosing Alzheimer's disease (AD), the clinical differentiation with Vascular cognitive impairment (cognitive impairment in absence of dementia) and mixed dementia (Alzheimer's disease plus cerebrovascular disease) remains a matter of controversial opinions and one of the most challenging diagnostic issues (Misciagna et al., 2005). Dementia in older adults is frequently caused by the combined conditions of Alzheimer disease and cerebrovascular disease (mixed disease) since frequently occur together in overlap presentations (such as vascular lesions in Alzheimer Disease or cerebral atrophic condition in Cerebrovascular Disease). Nevertheless, there is evidence that they contribute separately to the development of cognitive impairment and dementia (Snowdon et al., 1997;

The differential diagnosis between Alzheimer disease and dementia in cerebrovascular disease known as Vascular Dementia (VaD) is based on presence of vascular risk factors (such as hypertension, atrial fibrillation, obstructive arteriopathy, previous strokes or transitory ischemic attacks), clinical features (such as acute onset, stepwise progression, emotional lability) (Hachinski et al., 1974) and is supported by results of neuropsychological tests and neuroimaging. Whereas computed tomography or magnetic resonance are able to detect morphological lesions related to vascular disease, these modalities cannot determine func‐ tional impairment. PET allows imaging of the localized and/or diffuse metabolic disturbances responsible for cognitive impairment and dementia and is effective in differentiating vascular from degenerative dementia (Heiss and Zimmermann-Meinzingen, 2012). In particular PET can differentiate areas of focal cortical and subcortical hypometabolism that differ from the typical metabolic pattern seen in AD characterized by marked hypometabolism in association

**3. Pet study of cognitive functions in cerebrovascular disease**

al., 2000).

hemorrhages.

Bennett, 2001).

Functional memory localization has been applied in presurgical evaluation of epileptic (Detre, 2004) or brain tumor patients and predicts post-surgical memory deficits following temporal lobectomy (Rabin et al., 2004).

Episodic (conscious memory of events) and semantic memory (memory concerned with ideas, meanings, and concepts which are not related to personal experiences) might recruit different brain areas (Tulving and Markowitsch, 1998). In fact, amnesic patients with specific episodic memory impairment (intact priming, category learning, learning of artificial grammars) have temporal lobe damage, while patients with semantic deficits show dysfunction in prefrontal cortex. In particular left prefrontal cortex increases activity during semantic encoding while right prefrontal cortex increases activity during retrieval task. Recent neuroimaging studies implicate also the parietal lobe in episodic memory (Wagner et al., 2005).

Functional studies on **working memory** (memory that makes possible the temporary retention of information) suggest an overlapping of brain mechanism with attention (Jha, 2002) and associative learning in prefrontal cortex (Fuster et al., 2000). This association has also been demonstrated on behavioural studies (Sheth and Shimojo, 2003). Many of the changes in cerebral activation studied with PET during working memory tests are task specific. PET studies executed during Wisconsin Card sorting Test, which depends heavily on working memory, has demonstrated reduction of activation with age in the dorsolateral prefrontal cortex. On the other hand PET executed during Raven's Progressive Matrices, which also has a working memory component, but depends more on visuospatial processing, has demon‐ strated reduction of activation with age in in portions of the inferolateral temporal cortex more involved in visuo-spatial processing (Esposito ed al., 1999).

Recent PET studies of brain activation during tasks of **visuospatial processing** have reported that age-related cognitive changes are accompanied by altered cerebral activation in temporooccipital and extrastriate regions (Grady et al., 1994). Increased prefrontal activation was found both during face and location processing (Grady et al., 1994) and during memory recall (Cabeza et al., 1997a), while reduced prefrontal activation was reported during memory encoding (Grady et al., 1995; Cabeza et al., 1997b).

Temporal resolution of hemodynamic techniques such as PET or fMRI can be improved combining the activation maps from these imaging modalities with high-temporal resolution information obtained by other sources such as EEG/MEG or information on tissue oxygenation obtained from diffusion optical tomography. Recent methods of statistical combination of these techniques may provide benefits especially to neurosurgeon (Fischl et al., 2001; Dale et al., 2000).

#### **3. Pet study of cognitive functions in cerebrovascular disease**

for facts and events. Declarative memory has often been studied using the so-called "subse‐ quent memory effect" that is brain activity during encoding of items that are subsequently forgotten. On the other way the retrieval of declarative memory has been studied with the "old/new effect" that consists is the comparison of brain activity recorded during correctly recognized old items versus correctly identified new items. Memory for events involves processing in the medial temporal lobes (Milner et al., 1998) and in the prefrontal cortex. Frontal lobe activity is related to both encoding and retrieval of memory events for both long-term

88 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Functional memory localization has been applied in presurgical evaluation of epileptic (Detre, 2004) or brain tumor patients and predicts post-surgical memory deficits following temporal

Episodic (conscious memory of events) and semantic memory (memory concerned with ideas, meanings, and concepts which are not related to personal experiences) might recruit different brain areas (Tulving and Markowitsch, 1998). In fact, amnesic patients with specific episodic memory impairment (intact priming, category learning, learning of artificial grammars) have temporal lobe damage, while patients with semantic deficits show dysfunction in prefrontal cortex. In particular left prefrontal cortex increases activity during semantic encoding while right prefrontal cortex increases activity during retrieval task. Recent neuroimaging studies

Functional studies on **working memory** (memory that makes possible the temporary retention of information) suggest an overlapping of brain mechanism with attention (Jha, 2002) and associative learning in prefrontal cortex (Fuster et al., 2000). This association has also been demonstrated on behavioural studies (Sheth and Shimojo, 2003). Many of the changes in cerebral activation studied with PET during working memory tests are task specific. PET studies executed during Wisconsin Card sorting Test, which depends heavily on working memory, has demonstrated reduction of activation with age in the dorsolateral prefrontal cortex. On the other hand PET executed during Raven's Progressive Matrices, which also has a working memory component, but depends more on visuospatial processing, has demon‐ strated reduction of activation with age in in portions of the inferolateral temporal cortex more

Recent PET studies of brain activation during tasks of **visuospatial processing** have reported that age-related cognitive changes are accompanied by altered cerebral activation in temporooccipital and extrastriate regions (Grady et al., 1994). Increased prefrontal activation was found both during face and location processing (Grady et al., 1994) and during memory recall (Cabeza et al., 1997a), while reduced prefrontal activation was reported during memory encoding

Temporal resolution of hemodynamic techniques such as PET or fMRI can be improved combining the activation maps from these imaging modalities with high-temporal resolution information obtained by other sources such as EEG/MEG or information on tissue oxygenation obtained from diffusion optical tomography. Recent methods of statistical combination of

implicate also the parietal lobe in episodic memory (Wagner et al., 2005).

involved in visuo-spatial processing (Esposito ed al., 1999).

(Grady et al., 1995; Cabeza et al., 1997b).

and short-term memory.

lobectomy (Rabin et al., 2004).

Cerebrovascular disease affects prominently elderly persons through alterations in brain structure and metabolism that produce cognitive decline. Cognitive deficit revealed in cerebrovascular disease regards especially the domains of executive functions (Starkstein et al., 1996), attention, language (Powell et al., 1998) and less prominent memory deficits (Villardita, 1993; Tierney et al., 2001). Vascular cognitive disorders may be caused by multiple neuropathological substrates, including multi-infarct encephalopathy, single infarcts in strategic areas, lacunas and lacunar states, Biswanger's leukoencephalopathy and leukoarariosis, hippocampal sclerosis, watershed infarcts and neuronal loss/atrophy due to diffuse hypoperfusion (Ferrer, 2010). These substrates can be a consequence of different vascular diseases including atherosclerosis, small vessel disease, hypertensive angiopathy, inflammatory disease of blood vessels, inherited vascular disorders such as amyloid angiopathy and CADASIL (central autonomic dominant arteriopathy with subcortical infarcts and leukoencephalopathy) or the consequence of single or multiple cerebral hemorrhages.

Despite the considerable degree of accuracy in diagnosing Alzheimer's disease (AD), the clinical differentiation with Vascular cognitive impairment (cognitive impairment in absence of dementia) and mixed dementia (Alzheimer's disease plus cerebrovascular disease) remains a matter of controversial opinions and one of the most challenging diagnostic issues (Misciagna et al., 2005). Dementia in older adults is frequently caused by the combined conditions of Alzheimer disease and cerebrovascular disease (mixed disease) since frequently occur together in overlap presentations (such as vascular lesions in Alzheimer Disease or cerebral atrophic condition in Cerebrovascular Disease). Nevertheless, there is evidence that they contribute separately to the development of cognitive impairment and dementia (Snowdon et al., 1997; Bennett, 2001).

The differential diagnosis between Alzheimer disease and dementia in cerebrovascular disease known as Vascular Dementia (VaD) is based on presence of vascular risk factors (such as hypertension, atrial fibrillation, obstructive arteriopathy, previous strokes or transitory ischemic attacks), clinical features (such as acute onset, stepwise progression, emotional lability) (Hachinski et al., 1974) and is supported by results of neuropsychological tests and neuroimaging. Whereas computed tomography or magnetic resonance are able to detect morphological lesions related to vascular disease, these modalities cannot determine func‐ tional impairment. PET allows imaging of the localized and/or diffuse metabolic disturbances responsible for cognitive impairment and dementia and is effective in differentiating vascular from degenerative dementia (Heiss and Zimmermann-Meinzingen, 2012). In particular PET can differentiate areas of focal cortical and subcortical hypometabolism that differ from the typical metabolic pattern seen in AD characterized by marked hypometabolism in association areas (Benson et al., 1983). In patients with severe Vascular Dementia, PET reveals a signifi‐ cative reduction of metabolism in widespread cerebral regions as middle frontal cortex, temporoparietal cortex, basal ganglia, cerebellum and brainstem (Mielke et al., 1992). Hypo‐ metabolism is more marked than AD in subcortical areas and primary sensorimotor cortex, while it is less affected in the association areas.

**4. Pet study of cognitive functions in normal ageing, mild cognitive**

With normal aging neocortical neurons are lost in specific regions (Morrison, 1997), dendridic trees undergo progressive regression and axons degenerate leading to an age-related axonal loss. This process leads to a decrease of myelinated nerve fibers of 45% from the age of 20 to 80 years (Marner et al., 2003) and a reduction of the number of synapses by 15 to 50% (Pannese, 2011). The cerebral morphological changes that occur during normal ageing develop cognitive changes in particular about memory that could be considered age-related and a physiological process. These cognitive changes are related to physiological age-related brain atrophy with concomitant ventricular enlargement (Rusinek et al., 2003) and to a diffuse and frontally accentuated degrease of glucose metabolism as revealed with PET (Pawlik et al., 1989). The condition of "age associated memory impairment" is characterized by self perception of memory loss and standardised memory test score that shows low performances in memory tasks compared with younger adults. By contrast, "mild cognitive impairment" (MCI) is considered a transitional state between normal ageing and dementia (Petersen, 2004). Subjects with MCI are indipendent in activity daily living even if suffer with cognitive deficits in particular in the area of memory (in the amnestic form of MCI) typically in delayed recall, althought non-memory cognitive domains might also be impaired (in non-amnestic form of MCI). Patients with the amnestic subtype of MCI frequently progress to Alzheimer disease (AD) (Petersen et al., 2006) so that MCI is associated with an increased risk of developing dementia. When cognitive impairment concerns not only memory, but also other cognitive domains (such as abstract reasoning, judgment capabilities, language, praxic, gnostic or spatial function) dementia is often diagnosed (American Psychiatric Association, 2000). Alzheimer Disease is the most common cause of progressive form dementia in which cognitive decline interferes significantly with activities of daily living. Other causes of common degenerative dementia include dementia with Lewy bodies (characterized by fluctuating consciousness, parkinsonian symptoms and progressive decline in visuospatial, visuoperceptual, literacy and praxic skills, including visual allucinations) and Frontotemporal dementia (characterized by executive dysfunction, changes in personality and behaviour, semantic deficits and progres‐ sive aphasia). Secondary forms of dementia include depression (pseudo-depressive dementia),

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91

Many of brain changes that occur in neurodegenerative disease can be evidenced by neuroi‐ maging technologies designed to identify alterations of cerebral biological processes. The main brain change consists in focal or diffuse cerebral atrophy induced from neuronal synaptic degeneration and loss of neurons. Some forms of dementia have a particular pattern of athophy (Josephs et al., 2007). For example, widespread atrophy or medial temporal atrophy points toward a pathologic diagnosis of Alzheimer Disease, fronto-temporal loss suggest a diagnosis of Frontotemporal Dementia (Neary et al., 2005), more focal atrophy predominantly involving the premotor and supplemental motor area suggests Corticobasal Degeneration (CBD) or Progressive Supranuclear Palsy (PSP) (Whitwell et al., 2010); on the contrary Lewy bodies disease is characterised by posterior cortical atrophy (Crutch et al., 2012). Other cerebral

**impairment and degenerative dementias**

drug toxic effects or other medical conditions.

The metabolic ratio, which reflects the pattern of metabolic pathology in AD, is generally higher in VaD than in AD. Both in VaD and AD there is a parallel decline of the metabolic ratio with increasing dementia severity suggesting equal ability to discriminate VaD and AD in early and advanced stages of the disease. The volume of functional loss detected with PET is also important since it includes the effects of incompletely infarcted tissue and morphologically intact but deafferented cortex. Diagnostic accuracy for classification of patients in VaD versus AD is clearly superior for FDG PET even in patients with mild cognitive impairment (Mielke et al., 1994).

In a study on 153 subjects PET differentiated VaD from AD demonstrating lower metabolism in deep gray nucley, cerebellum, primary cortices, middle temporal gyrus and anterior cingulate cortex in VaD, whereas in AD showed lower metabolism in hippocampal region, orbitofrontal, posterior cingulate and posterior parietal cortices (Kerrouche et al., 2006).

PET can also detect vascular inflammatory changes (Mehta et al., 2012) and their interaction with amyloid depositions for development of mixed dementias after stroke (Heiss & Zimmer‐ mann-Meinzingen, 2012). Microglia activation that occurs in patients with mild cognitive deficits is not proven to be correlated with amyloid deposition as imaged by 11C-PIB (Okello et al., 2009). However, in animal models, the inflammation due to an infarct is exacerbated in the presence of amyloid; compared to animals without amyloid deposition the infarcts induced in presence of amyloid grew over time (Whitehead et al., 2007). The interaction of inflammatory reaction and amyloid deposition can be relevant for development of dementia in cerebrovas‐ cular disease as studied by multitracer PET with PK 11195 and PIB (Mok et al., 2010).

Episodic memory decline and hippocampal cerebral volume (typically associated with Alzhemier disease) are related to temporo-parietal hypometabolism (Desgranges, Chételat and Eustache, 2004) while executive dysfunction and white matters hyperintensities (typical of cerebrovascular disease) correlate with frontal lobe hypometabolism (Tullberg et al 2004). On the bases of this hypothesis a fluorodeoxyglucose-PET longitudinal study on 38 subjects ranging from normal condition to dementia in a follow up of 2 years have demonstrated a different pattern of metabolic decline in condition of dementia in Alzheimer disease or in cerebrovascular disease. In fact low baseline hippocampal volume can predict develop‐ ment of medial temporal hypometabolism; on the other hand white matter hyperintensi‐ ties can predict hypometabolism over time in the fronto-parietal regions (Kuczynski et al., 2008). These studies suggest that pattern of cognitive decline studied with neuropsycholog‐ ical test batteries, anatomic changes and study of cerebral metabolism are useful in defining etiology of dementia in cerebrovascular disease and understand future evolution of cognitive deficits.

### **4. Pet study of cognitive functions in normal ageing, mild cognitive impairment and degenerative dementias**

areas (Benson et al., 1983). In patients with severe Vascular Dementia, PET reveals a signifi‐ cative reduction of metabolism in widespread cerebral regions as middle frontal cortex, temporoparietal cortex, basal ganglia, cerebellum and brainstem (Mielke et al., 1992). Hypo‐ metabolism is more marked than AD in subcortical areas and primary sensorimotor cortex,

90 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

The metabolic ratio, which reflects the pattern of metabolic pathology in AD, is generally higher in VaD than in AD. Both in VaD and AD there is a parallel decline of the metabolic ratio with increasing dementia severity suggesting equal ability to discriminate VaD and AD in early and advanced stages of the disease. The volume of functional loss detected with PET is also important since it includes the effects of incompletely infarcted tissue and morphologically intact but deafferented cortex. Diagnostic accuracy for classification of patients in VaD versus AD is clearly superior for FDG PET even in patients with mild cognitive impairment (Mielke

In a study on 153 subjects PET differentiated VaD from AD demonstrating lower metabolism in deep gray nucley, cerebellum, primary cortices, middle temporal gyrus and anterior cingulate cortex in VaD, whereas in AD showed lower metabolism in hippocampal region, orbitofrontal, posterior cingulate and posterior parietal cortices (Kerrouche et al., 2006).

PET can also detect vascular inflammatory changes (Mehta et al., 2012) and their interaction with amyloid depositions for development of mixed dementias after stroke (Heiss & Zimmer‐ mann-Meinzingen, 2012). Microglia activation that occurs in patients with mild cognitive deficits is not proven to be correlated with amyloid deposition as imaged by 11C-PIB (Okello et al., 2009). However, in animal models, the inflammation due to an infarct is exacerbated in the presence of amyloid; compared to animals without amyloid deposition the infarcts induced in presence of amyloid grew over time (Whitehead et al., 2007). The interaction of inflammatory reaction and amyloid deposition can be relevant for development of dementia in cerebrovas‐

cular disease as studied by multitracer PET with PK 11195 and PIB (Mok et al., 2010).

Episodic memory decline and hippocampal cerebral volume (typically associated with Alzhemier disease) are related to temporo-parietal hypometabolism (Desgranges, Chételat and Eustache, 2004) while executive dysfunction and white matters hyperintensities (typical of cerebrovascular disease) correlate with frontal lobe hypometabolism (Tullberg et al 2004). On the bases of this hypothesis a fluorodeoxyglucose-PET longitudinal study on 38 subjects ranging from normal condition to dementia in a follow up of 2 years have demonstrated a different pattern of metabolic decline in condition of dementia in Alzheimer disease or in cerebrovascular disease. In fact low baseline hippocampal volume can predict develop‐ ment of medial temporal hypometabolism; on the other hand white matter hyperintensi‐ ties can predict hypometabolism over time in the fronto-parietal regions (Kuczynski et al., 2008). These studies suggest that pattern of cognitive decline studied with neuropsycholog‐ ical test batteries, anatomic changes and study of cerebral metabolism are useful in defining etiology of dementia in cerebrovascular disease and understand future evolution of

while it is less affected in the association areas.

et al., 1994).

cognitive deficits.

With normal aging neocortical neurons are lost in specific regions (Morrison, 1997), dendridic trees undergo progressive regression and axons degenerate leading to an age-related axonal loss. This process leads to a decrease of myelinated nerve fibers of 45% from the age of 20 to 80 years (Marner et al., 2003) and a reduction of the number of synapses by 15 to 50% (Pannese, 2011). The cerebral morphological changes that occur during normal ageing develop cognitive changes in particular about memory that could be considered age-related and a physiological process. These cognitive changes are related to physiological age-related brain atrophy with concomitant ventricular enlargement (Rusinek et al., 2003) and to a diffuse and frontally accentuated degrease of glucose metabolism as revealed with PET (Pawlik et al., 1989). The condition of "age associated memory impairment" is characterized by self perception of memory loss and standardised memory test score that shows low performances in memory tasks compared with younger adults. By contrast, "mild cognitive impairment" (MCI) is considered a transitional state between normal ageing and dementia (Petersen, 2004). Subjects with MCI are indipendent in activity daily living even if suffer with cognitive deficits in particular in the area of memory (in the amnestic form of MCI) typically in delayed recall, althought non-memory cognitive domains might also be impaired (in non-amnestic form of MCI). Patients with the amnestic subtype of MCI frequently progress to Alzheimer disease (AD) (Petersen et al., 2006) so that MCI is associated with an increased risk of developing dementia. When cognitive impairment concerns not only memory, but also other cognitive domains (such as abstract reasoning, judgment capabilities, language, praxic, gnostic or spatial function) dementia is often diagnosed (American Psychiatric Association, 2000). Alzheimer Disease is the most common cause of progressive form dementia in which cognitive decline interferes significantly with activities of daily living. Other causes of common degenerative dementia include dementia with Lewy bodies (characterized by fluctuating consciousness, parkinsonian symptoms and progressive decline in visuospatial, visuoperceptual, literacy and praxic skills, including visual allucinations) and Frontotemporal dementia (characterized by executive dysfunction, changes in personality and behaviour, semantic deficits and progres‐ sive aphasia). Secondary forms of dementia include depression (pseudo-depressive dementia), drug toxic effects or other medical conditions.

Many of brain changes that occur in neurodegenerative disease can be evidenced by neuroi‐ maging technologies designed to identify alterations of cerebral biological processes. The main brain change consists in focal or diffuse cerebral atrophy induced from neuronal synaptic degeneration and loss of neurons. Some forms of dementia have a particular pattern of athophy (Josephs et al., 2007). For example, widespread atrophy or medial temporal atrophy points toward a pathologic diagnosis of Alzheimer Disease, fronto-temporal loss suggest a diagnosis of Frontotemporal Dementia (Neary et al., 2005), more focal atrophy predominantly involving the premotor and supplemental motor area suggests Corticobasal Degeneration (CBD) or Progressive Supranuclear Palsy (PSP) (Whitwell et al., 2010); on the contrary Lewy bodies disease is characterised by posterior cortical atrophy (Crutch et al., 2012). Other cerebral anomalies observed in auptoptical studies conducted in middle-aged adults (Price & Morris, 1999), patients with MCI (Petersen et al., 2006) or Alzheimer Disease (Braak & Braak, 1991) consist in presence of plaques of amyloid ß and neurofibrillary tangles of tau protein.

regions have been found to predict future cognitive decline in older APOE ε4 carriers than non-carriers (Small et al., 2000). Moreover several [18]FDG-PET studies have shown that patients with MCI and AD-like metabolic pattern are hightly predictive of conversion to AD within several years, in particular in patiens that are APOE ε4 carriers (Mosconi et al., 2004).

Functional Imaging Studies of Human Cognition Using Positron Emission Tomography

[18]FDG-PET scans, when combined with Magnetic Resonance imaging and other biomarkers, are likely to improve diagnostic accuracy (Mueller et al., 2005) and might be used to monitor

Characteristic patterns of regional hypometabolism are also seen in other degenerative dementia (Bohnen et al., 2012). Frontotemporal dementia is identified by distinct frontal or frontotemporal metabolic impairment that are typically quite asymmetrically centered in the frontolateral cortex and the anterior pole of temporal lobe. Dementia with Lewy bodies shows reduction of glucose metabolism in primary visual cortex in addition to that in posterior association areas. Other degenerative disorders show typical hypomethabolism in the specifically affected brain structures: the putamen and cortex in corticobasal degeneration, the caudate nucleus in Huntington's chorea, the frontal cortex and midbrain in progressive

In recent years different small molecule probes have been developed for use with PET to measure deposits of amyloid- ß plaques and tau tangles in vivo (Klunk et al., 2004; Kudo et

Compound B) which is a derivative of thioflavin-T amyloid dye that binds specifically amyloid-ß plaques but not neurofibrillary tangles. Studies using [11C]PIB-PET have demon‐ strated cortical retention in patients with AD compared with normal subjects (Klunk et al., 2004). Studies of MCI patients have showed that [11C]PIB uptake is increased in approximately 50% of them (Kemppainen et al., 2007). [11C]PIB-PET could potentially be used to diagnose cerebral amyloid angiopathy since it also detects cerebrovascular amyloid (Johnson et al., 2007). PET studies with [11C]PIB is useful in differential diagnosis of degenerative type of dementia, since patients with Lewy bodies dementia show lower binding than in AD, while patients affected with Fronto-temporal dementia show no cortical binding (Rowe et al., 2007).

Recently several 18F labelled amyloid tracers are commercially available permitting large scale

**18F]-BAY94-9172-PET,** based on amyloid legand florine-18, could be used to discriminate patients with AD from frontotemporal dementia and healthy controls (Rowe et al., 2008).

Tau deposition in neurofibrillary tangles together with amyloid can be specifically detect by

Other PET legands have been used in research to measure functionality of many neurotrans‐ mitter systems such as serotoninergic, cholinerdic and dopaminergic. The neurotrasmitters systems are impaired in various types of dementia and may help in differential diagnosis and in the definition of pathophysiological process. **MPPF** (4-[18F]-fluoro-N-piperazynil-N-2 methoxy-phenyl-pyridinil benzamide) is a molecular imaging probe for 5-HT1A receptors which density correlates with the number of pyramidal neurons of the hippocampus (Kepe et

**18F]-FDDNP**, providing additional insight in AD pathology (Small et al., 2008).

**11C]PIB** ([11C]-labelled Pittsburg

http://dx.doi.org/10.5772/57124

93

treatment that affect cerebral blood flow, metabolism, or neuronal dysfunction.

supranuclear palsy, pons and cerebellum in olivopontocerebellar atrophy.

al., 2007). The most studied amyloid-binding radiotracer is **[**

clinical use (Rowe and Villemagne, 2011).

**[**

the tracer **[**

Neurofibrillary tangles have been observed in the hippocampus and temporal regions in MCI, in neocortical areas (frontal and parietal cortex) as MCI progress to AD. Patients with autoptical diagnosis of Alzheimer disease have a hight number of both amyloid plaques and neurofi‐ brillary tangles (McKhann et al., 1984).

Cerebrospinal fluids (CSF) studies conducted on patients with AD (Sidoryk-Wegrzynowicz et al., 2011) or post-mortem (Reinikainen et al., 1990) have documented alterations in cholinergic, serotonergic, dopaminergic, somatostatinergic, noradrenergic and glutamatergic neurotrans‐ mitters. These and other pathogenetic mechanism as insulin resistance (Craft, 2006) contribute to compromise cerebral regional glucose metabolism studied in PET techniques.

Studies conducted on patients with AD often use the radiolabelled glucose analogue FDG (**[18]FDG-PET**) to measure cerebral glucose metabolism, which indicates the levels of neuro‐ synaptic activity. PET studies have demonstrated that Alzheimer's disease is characterized by regional impairment of cerebral glucose metabolism in neocortical association areas (posterior cingulate, temporoparietal and frontal multimodal association cortex), whereas the primary visual and sensorimotor cortex, basal ganglia, and cerebellum are relatively well preserved (for a review see Herholz, 2003).

An automated voxel-based analysis of FDG-PET images can distinct AD from controls with 93% sensitivity and 93% specificity as dimonstrated in a multicentre study comprising 10 PET centers (Herholz et al., 2002).

These studies have shown that cortical brain alterations begin in the posterior cingulate regions and spread to the temporal and prefrontal cortices. This pattern of brain metabolism is useful to differentiate patients with AD from other forms of dementia and from cognetively health people (Silverman et al., 2001).

Regional cortical hypometabolism also correlates with greater cognitive losses so that [18]FDG-PET can differentiate patients with MCI from others with AD or normal subjects (Small et al., 2006).

When [18]FDG-PET is added to standard clinical assessment, diagnostic accuracy for dementia of Alzheimer type increases sensitivity and specificity (Jagust et al., 2007). [18]FDG-PET is important in helping differential diagnosis between AD and Frontotemporal Dementia since the latter dementia do not seem to respond well to currently available symptomatic treatments.

Longitudinal studies of patients with MCI have found that if baseline assessment with [18]FDG-PET scan suggests an AD-like pattern, the probability of conversion in AD within several years is extremely hight (Drzezga et al., 2005; Chételat et al., 2003). Therefore in these MCI patients pharmacological treatment with specific anti-dementia drugs could be achieved, so that might be modified the trend of the desease and reduce social costs of illness.

[18]FDG-PET assists the diagnosis of AD when combined with specific genetic assessment. In fact hypomethabolism in posterior cingulate, parietal, prefrontal, entorhinal and temporal regions have been found to predict future cognitive decline in older APOE ε4 carriers than non-carriers (Small et al., 2000). Moreover several [18]FDG-PET studies have shown that patients with MCI and AD-like metabolic pattern are hightly predictive of conversion to AD within several years, in particular in patiens that are APOE ε4 carriers (Mosconi et al., 2004).

anomalies observed in auptoptical studies conducted in middle-aged adults (Price & Morris, 1999), patients with MCI (Petersen et al., 2006) or Alzheimer Disease (Braak & Braak, 1991)

Neurofibrillary tangles have been observed in the hippocampus and temporal regions in MCI, in neocortical areas (frontal and parietal cortex) as MCI progress to AD. Patients with autoptical diagnosis of Alzheimer disease have a hight number of both amyloid plaques and neurofi‐

Cerebrospinal fluids (CSF) studies conducted on patients with AD (Sidoryk-Wegrzynowicz et al., 2011) or post-mortem (Reinikainen et al., 1990) have documented alterations in cholinergic, serotonergic, dopaminergic, somatostatinergic, noradrenergic and glutamatergic neurotrans‐ mitters. These and other pathogenetic mechanism as insulin resistance (Craft, 2006) contribute

Studies conducted on patients with AD often use the radiolabelled glucose analogue FDG (**[18]FDG-PET**) to measure cerebral glucose metabolism, which indicates the levels of neuro‐ synaptic activity. PET studies have demonstrated that Alzheimer's disease is characterized by regional impairment of cerebral glucose metabolism in neocortical association areas (posterior cingulate, temporoparietal and frontal multimodal association cortex), whereas the primary visual and sensorimotor cortex, basal ganglia, and cerebellum are relatively well preserved

An automated voxel-based analysis of FDG-PET images can distinct AD from controls with 93% sensitivity and 93% specificity as dimonstrated in a multicentre study comprising 10 PET

These studies have shown that cortical brain alterations begin in the posterior cingulate regions and spread to the temporal and prefrontal cortices. This pattern of brain metabolism is useful to differentiate patients with AD from other forms of dementia and from cognetively health

Regional cortical hypometabolism also correlates with greater cognitive losses so that [18]FDG-PET can differentiate patients with MCI from others with AD or normal subjects (Small et al.,

When [18]FDG-PET is added to standard clinical assessment, diagnostic accuracy for dementia of Alzheimer type increases sensitivity and specificity (Jagust et al., 2007). [18]FDG-PET is important in helping differential diagnosis between AD and Frontotemporal Dementia since the latter dementia do not seem to respond well to currently available symptomatic treatments. Longitudinal studies of patients with MCI have found that if baseline assessment with [18]FDG-PET scan suggests an AD-like pattern, the probability of conversion in AD within several years is extremely hight (Drzezga et al., 2005; Chételat et al., 2003). Therefore in these MCI patients pharmacological treatment with specific anti-dementia drugs could be achieved,

so that might be modified the trend of the desease and reduce social costs of illness.

[18]FDG-PET assists the diagnosis of AD when combined with specific genetic assessment. In fact hypomethabolism in posterior cingulate, parietal, prefrontal, entorhinal and temporal

consist in presence of plaques of amyloid ß and neurofibrillary tangles of tau protein.

92 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

to compromise cerebral regional glucose metabolism studied in PET techniques.

brillary tangles (McKhann et al., 1984).

(for a review see Herholz, 2003).

centers (Herholz et al., 2002).

people (Silverman et al., 2001).

2006).

[18]FDG-PET scans, when combined with Magnetic Resonance imaging and other biomarkers, are likely to improve diagnostic accuracy (Mueller et al., 2005) and might be used to monitor treatment that affect cerebral blood flow, metabolism, or neuronal dysfunction.

Characteristic patterns of regional hypometabolism are also seen in other degenerative dementia (Bohnen et al., 2012). Frontotemporal dementia is identified by distinct frontal or frontotemporal metabolic impairment that are typically quite asymmetrically centered in the frontolateral cortex and the anterior pole of temporal lobe. Dementia with Lewy bodies shows reduction of glucose metabolism in primary visual cortex in addition to that in posterior association areas. Other degenerative disorders show typical hypomethabolism in the specifically affected brain structures: the putamen and cortex in corticobasal degeneration, the caudate nucleus in Huntington's chorea, the frontal cortex and midbrain in progressive supranuclear palsy, pons and cerebellum in olivopontocerebellar atrophy.

In recent years different small molecule probes have been developed for use with PET to measure deposits of amyloid- ß plaques and tau tangles in vivo (Klunk et al., 2004; Kudo et al., 2007). The most studied amyloid-binding radiotracer is **[ 11C]PIB** ([11C]-labelled Pittsburg Compound B) which is a derivative of thioflavin-T amyloid dye that binds specifically amyloid-ß plaques but not neurofibrillary tangles. Studies using [11C]PIB-PET have demon‐ strated cortical retention in patients with AD compared with normal subjects (Klunk et al., 2004). Studies of MCI patients have showed that [11C]PIB uptake is increased in approximately 50% of them (Kemppainen et al., 2007). [11C]PIB-PET could potentially be used to diagnose cerebral amyloid angiopathy since it also detects cerebrovascular amyloid (Johnson et al., 2007). PET studies with [11C]PIB is useful in differential diagnosis of degenerative type of dementia, since patients with Lewy bodies dementia show lower binding than in AD, while patients affected with Fronto-temporal dementia show no cortical binding (Rowe et al., 2007).

Recently several 18F labelled amyloid tracers are commercially available permitting large scale clinical use (Rowe and Villemagne, 2011).

**[ 18F]-BAY94-9172-PET,** based on amyloid legand florine-18, could be used to discriminate patients with AD from frontotemporal dementia and healthy controls (Rowe et al., 2008).

Tau deposition in neurofibrillary tangles together with amyloid can be specifically detect by the tracer **[ 18F]-FDDNP**, providing additional insight in AD pathology (Small et al., 2008).

Other PET legands have been used in research to measure functionality of many neurotrans‐ mitter systems such as serotoninergic, cholinerdic and dopaminergic. The neurotrasmitters systems are impaired in various types of dementia and may help in differential diagnosis and in the definition of pathophysiological process. **MPPF** (4-[18F]-fluoro-N-piperazynil-N-2 methoxy-phenyl-pyridinil benzamide) is a molecular imaging probe for 5-HT1A receptors which density correlates with the number of pyramidal neurons of the hippocampus (Kepe et al., 2006). Patients with AD show diminished hippocampal signal, while patients with MCI show binding values intermediate between controls and Alzheimer's disease patients (Kepe et al., 2006). Since MPPF binding correlates with neuronal losses in the hippocampus, therefore it can be used as an early diagnostic measure in the continuum between MCI and dementia conversion, before onset of symptoms of dementia. PET radioligands used to visualize cholinergic nicotinic receptors correlate with cognitive measure of attention in Alzheimer's disease (Kadir et al., 2006). PET measures of cholinergic system with **11C-nicotine** can be used to assess nicotine binding sites in the brain before and after treatment with anti-cholinesterase drugs (Kadir et al., 2007).

PET investigations will increase understanding and monitor pathophysiological process of many neurological diseases, track the biological effects of treatments in clinical trials and assist in identifying responders to specific treatments (Reiman et al., 2001). Several of the neuroi‐ maging technologies in development promise in proving measurement of potential biomark‐ ers but further research is necessary to validate their use. In fact many of these methods are still used in research settings and require further studies to better understand their clinical usefulness. Another limitation to the adoption of PET techniques is the relatively high cost and lack of wide availability, but when compared costs to the high diagnostic accuracy of PET, these benefits incurred high costs (McMahon et al., 2003). In future, with more extensive use of these new PET technology, costs will also decline and improvement of diagnostic accuracy will lead to cost saving. For example healthy adults with risk factors for cognitive decline (e.g. age, previous head trauma, familiar history) might undergo a PET check scan for measures of cognitive decline risk and physicians will use medications or other interventions to prevent or

Functional Imaging Studies of Human Cognition Using Positron Emission Tomography

http://dx.doi.org/10.5772/57124

95

[1] American Psychiatric Association. Diagnostic and statistical manual of mental disor‐ ders (IV-Tr) 4th edn—text revised. Washington, DC: American Psychiatric Associa‐

[2] Atlas SW, Howard RS, Maldjian J, Alsop D, Detre JA, Listerud J, et al. Functional magnetic resonance imaging of regional brain activity in patients with intracerebral gliomas: findings and implications for clinical management. Neurosurgery. 1996 Feb;

[3] Bennett D. Public health importance of vascular dementia and Alzheimer's disease with cerebrovascular disease. Int J Clin Pract Suppl. 2001 May;(120):41–48.

[4] Benson DF, Kuhl DE, Hawkins RA, Phelps ME, Cummings JL, Tsai SY. The fluoro‐ deoxyglucose 18F scan in Alzheimer's disease and multi-infarct dementia. Arch Neu‐

[5] Bohnen NI, Djang DS, Herholz K, Anzai Y, Minoshima S. Effectiveness and safety of 18F-FDG PET in the evaluation of dementia: a review of the recent literature. J Nucl

delay onset of disease or avoid future cognitive losses.

**Author details**

Sandro Misciagna\*

**References**

tion; 2000.

38(2):329–338.

rol 11 1983;40(12):711-4.

Med Jan 2012;53(1):59-71.

Don Gnocchi Foundation, Rome, Italy

**[ 11C]ß-CFT** ([11C]2ß-carbomethoxy-3ß-4fluorophenyl tropane) is a molecular dopamine reuptake ligand used to study the cerebral dopaminergic system. Striatal uptake of [11C]ß-CFT is reduced in patients with AD (Rinne et al., 1998). The ligand **[ 11C]-PK11195** has been used in other PET research to measure microglial activation as response to neuronal degeneration in patients with Alzheimer Disease (Cagnin et al., 2001). Microglial activation seems to be an inflammatory reaction to amyloid deposition that might increase the formation of pathological protein deposits.

#### **5. Conclusions**

An enormous progress has been made in the science of human cognition using neuroimaging and integration with neuropsychological assessment, multimodal structural and functional imaging technologies based on study of cerebral glucose metabolism as in Positron Emission Tomography. PET exam has led to a revolution in understanding of the basic neuroscience principles involved in where and how the brain processes information both in normal subjects and in patients with cerebral lesions.

Different PET methodologies in combination with traditional neuroimaging techniques are more and more used to accurately localize and characterize cognition not invasively.

The current clinical applications of using PET or other functional neuroimaging to mapping cognitive function include lateralization and presurgical mapping of language and memory mapping (Stufflebeam and Rosen, 2007). The development of advanced techniques and the combination of imaging technologies is further expanding the understanding of cognitive processing and is extending the clinical applications of functional neuroimaging into new areas.

With recent advances in neuroimaging technology novel PET applications are developing to measure various biological processes or to study cognitive alterations in patients with diseases that affect central nervous system. Combining PET procedures with other neuroimaging studies, genetic risk measures and other biomarkers measures from other tissues it might increase diagnostic sensitivity and specificity in particular in differential diagnosis of demen‐ tia, in the early stages of vascular or degenerative dementia, since presence of different PET pattern (neocortical association areas in AD, frontolateral cortex and anterior pole of temporal lobe in FTD, posterior association areas in LBD).

PET investigations will increase understanding and monitor pathophysiological process of many neurological diseases, track the biological effects of treatments in clinical trials and assist in identifying responders to specific treatments (Reiman et al., 2001). Several of the neuroi‐ maging technologies in development promise in proving measurement of potential biomark‐ ers but further research is necessary to validate their use. In fact many of these methods are still used in research settings and require further studies to better understand their clinical usefulness. Another limitation to the adoption of PET techniques is the relatively high cost and lack of wide availability, but when compared costs to the high diagnostic accuracy of PET, these benefits incurred high costs (McMahon et al., 2003). In future, with more extensive use of these new PET technology, costs will also decline and improvement of diagnostic accuracy will lead to cost saving. For example healthy adults with risk factors for cognitive decline (e.g. age, previous head trauma, familiar history) might undergo a PET check scan for measures of cognitive decline risk and physicians will use medications or other interventions to prevent or delay onset of disease or avoid future cognitive losses.

#### **Author details**

al., 2006). Patients with AD show diminished hippocampal signal, while patients with MCI show binding values intermediate between controls and Alzheimer's disease patients (Kepe et al., 2006). Since MPPF binding correlates with neuronal losses in the hippocampus, therefore it can be used as an early diagnostic measure in the continuum between MCI and dementia conversion, before onset of symptoms of dementia. PET radioligands used to visualize cholinergic nicotinic receptors correlate with cognitive measure of attention in Alzheimer's

94 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

to assess nicotine binding sites in the brain before and after treatment with anti-cholinesterase

other PET research to measure microglial activation as response to neuronal degeneration in patients with Alzheimer Disease (Cagnin et al., 2001). Microglial activation seems to be an inflammatory reaction to amyloid deposition that might increase the formation of pathological

An enormous progress has been made in the science of human cognition using neuroimaging and integration with neuropsychological assessment, multimodal structural and functional imaging technologies based on study of cerebral glucose metabolism as in Positron Emission Tomography. PET exam has led to a revolution in understanding of the basic neuroscience principles involved in where and how the brain processes information both in normal subjects

Different PET methodologies in combination with traditional neuroimaging techniques are

The current clinical applications of using PET or other functional neuroimaging to mapping cognitive function include lateralization and presurgical mapping of language and memory mapping (Stufflebeam and Rosen, 2007). The development of advanced techniques and the combination of imaging technologies is further expanding the understanding of cognitive processing and is extending the clinical applications of functional neuroimaging into new

With recent advances in neuroimaging technology novel PET applications are developing to measure various biological processes or to study cognitive alterations in patients with diseases that affect central nervous system. Combining PET procedures with other neuroimaging studies, genetic risk measures and other biomarkers measures from other tissues it might increase diagnostic sensitivity and specificity in particular in differential diagnosis of demen‐ tia, in the early stages of vascular or degenerative dementia, since presence of different PET pattern (neocortical association areas in AD, frontolateral cortex and anterior pole of temporal

more and more used to accurately localize and characterize cognition not invasively.

reuptake ligand used to study the cerebral dopaminergic system. Striatal uptake of [11

C]2ß-carbomethoxy-3ß-4fluorophenyl tropane) is a molecular dopamine

**11**

**C-nicotine** can be used

**C]-PK11195** has been used in

C]ß-CFT

disease (Kadir et al., 2006). PET measures of cholinergic system with **<sup>11</sup>**

is reduced in patients with AD (Rinne et al., 1998). The ligand **[**

drugs (Kadir et al., 2007).

**C]ß-CFT** ([11

protein deposits.

**5. Conclusions**

areas.

and in patients with cerebral lesions.

lobe in FTD, posterior association areas in LBD).

**[ 11**

Sandro Misciagna\*

Don Gnocchi Foundation, Rome, Italy

#### **References**


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**Chapter 5**

**How to Study Smoking and Drinking with PET**

The era of imaging neuroreceptors in humans with PET was ushered in by Wagner et al. (1983) with a report in Science showing the first human brain scan of dopamine receptors (Wagner, 1983). The tracer was N-methylspiperone (NMSP) tagged with carbon-11. The brain that was scanned belonged to one of the authors. Ethical concerns notwithstanding, this act placed the researchers in the good company of famous scientists throughout history who had experimented on themselves. The publication of this paper excited the field and garnered some publicity as well (see Figure 1). Although the study did not employ the quantitative analysis techniques we describe below, it presaged some of the key concepts. Namely: (1) early images contain mostly blood flow information; (2) late images primarily reflect binding; (3) radioactive tracer in the target tissue can be "free" or "bound", which often necessitates the examination of a "reference region", which is devoid of receptor sites; (4) co-injection of radiolabelled tracer with an *excess* of unlabeled tracer can be used to prevent radiotracer from binding and thus measure unbound (aka, non-displaceable) signal by itself. Injection of excess unlabeled tracer is generally not performed in humans; in this case, it was done in baboons. As we discuss below, the ability to use PET to measure receptor number or some index thereof opens up additional measurement possibilities which take advantage of a key concept: competition. In the Wagner paper, the competition was between hot (labeled) and cold (unlabeled) tracer (Wagner, 1983). In another ground-breaking paper that followed it, the competition was between a radiotracer and an unlabeled neuroleptic drug (Farde et al., 1986). Farde and colleagues did what amounts to the first drug occupancy study with PET using the tracer,

11C]raclopride, in 1986. Their paper was intended to examine the occupancy level of drugs for schizophrenia in treated schizophrenics by examining the degree of tracer blocking at the dopamine D2 receptor sites achieved by each patient's respective drug. Whereas Wagner et

> © 2013 Morris et al.; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Evan D. Morris, Molly V. Lucas and Kelly P. Cosgrove

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57414

**1. Introduction**

[

**1.1. Historical background**


### **How to Study Smoking and Drinking with PET**

Evan D. Morris, Molly V. Lucas and Kelly P. Cosgrove

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57414

#### **1. Introduction**

[89] Tierney M C, Black S E, Szalai J P, Snow W G, Fisher R H, Nadon G, & Chui H C. (2001). Recognition memory and verbal fluency differentiate probable Alzheimer dis‐ ease from subcortical ischemic vascular dementia. Archives in Neurology, 58, 1654–

102 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

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rophysiol. 2006 Dec;96(6):3517–3531.

1659.

179.

Sep 9;61(5):699–701.

#### **1.1. Historical background**

The era of imaging neuroreceptors in humans with PET was ushered in by Wagner et al. (1983) with a report in Science showing the first human brain scan of dopamine receptors (Wagner, 1983). The tracer was N-methylspiperone (NMSP) tagged with carbon-11. The brain that was scanned belonged to one of the authors. Ethical concerns notwithstanding, this act placed the researchers in the good company of famous scientists throughout history who had experimented on themselves. The publication of this paper excited the field and garnered some publicity as well (see Figure 1). Although the study did not employ the quantitative analysis techniques we describe below, it presaged some of the key concepts. Namely: (1) early images contain mostly blood flow information; (2) late images primarily reflect binding; (3) radioactive tracer in the target tissue can be "free" or "bound", which often necessitates the examination of a "reference region", which is devoid of receptor sites; (4) co-injection of radiolabelled tracer with an *excess* of unlabeled tracer can be used to prevent radiotracer from binding and thus measure unbound (aka, non-displaceable) signal by itself. Injection of excess unlabeled tracer is generally not performed in humans; in this case, it was done in baboons. As we discuss below, the ability to use PET to measure receptor number or some index thereof opens up additional measurement possibilities which take advantage of a key concept: competition. In the Wagner paper, the competition was between hot (labeled) and cold (unlabeled) tracer (Wagner, 1983). In another ground-breaking paper that followed it, the competition was between a radiotracer and an unlabeled neuroleptic drug (Farde et al., 1986). Farde and colleagues did what amounts to the first drug occupancy study with PET using the tracer, [ 11C]raclopride, in 1986. Their paper was intended to examine the occupancy level of drugs for schizophrenia in treated schizophrenics by examining the degree of tracer blocking at the dopamine D2 receptor sites achieved by each patient's respective drug. Whereas Wagner et

© 2013 Morris et al.; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

al. could examine the difference between a baboon at baseline and following a co-injection of tracer with an excess of cold NMSP (Wagner, 1983), Farde et al. did not ask their patients to go off medication to get a baseline measurement of tracer binding (Farde et al., 1986). So how did they make an assessment of drug occupancy, which requires at least two measurements? They extrapolated what baseline binding might have been in their schizophrenics from a cohort of control subjects. Provocatively, they found that three schizophrenics undergoing (success‐ ful) treatment with different drugs all had receptor occupancies of very similar levels. Their approach would likely not pass muster today, but at the time, the paper was highly innovative, and it foreshadowed one of the major usages of PET and neuroreceptor tracers: measuring target occupancy by drugs in people.

individual molecules and which we may want to image are shown in Figure 2. PET can image any of these molecular targets provided two obstacles have been overcome. First, a tracer molecule that binds or interacts with the target site must exist and be labeled with a positron emitting isotope (typically, carbon-11 or fluorine-18). Second, it must be possible to deliver the tracer to the target site. In brain imaging, the most likely cause of tracer failure is the inability

How to Study Smoking and Drinking with PET

http://dx.doi.org/10.5772/57414

105

**Figure 2.** Molecular processes that can be imaged with the appropriate PET ligand. Figure modified (Pellerin et al.,

At this writing, there are tracers for many of the common neurotransmitter receptor sites: dopamine (D2/D3 and D1), serotonin (5HT1a, 5HT1b, 5HT4…), and transporter sites (DAT, SERT, NET…). Tracers generally arise through one of three pathways. (1) Radiolabeling of a dye or other molecule that is known to be selective for a particular target of interest (e.g., [11C]PIB arose from the radiolabelling of thioflavin-T) (Mathis et al., 2002). (2) Radiolabeling of a candidate drug for the target molecule of interest. Such candidate compounds may have been failed drugs (adverse drug side-effects on patients, kinetics too rapid to sustain clinically useful levels in blood and tissue) but make good tracers (no adverse side-effects, because tracers are given in micro-dose amounts, favorably rapid kinetics). (3) De novo design of new PET tracer

of the tracer to cross the blood brain barrier to access the target.

1994).

*1.2.2. Many tracers for many targets*

based on knowledge of the structure of the target molecule.

**Figure 1.** Left) Newspaper clipping from the Baltimore Sun, Sept 20, 1983, shows senior authors, Drs. Henry Wagner, Jr. and Mike Kuhar observing the first images of D2 receptors in a human brain, *in vivo*. (Right) A keepsake from the experiment adorns the offices of many of the landmark study's participants. Signatures, from the center bottom going clockwise, Wagner, Robert Dannals, Joanthan Links, Dean F. Wong, Jim Frost, and Kuhar. Photos care of M. Kuhar.

#### **1.2. Basics**

#### *1.2.1. Molecular specificity*

PET is unique among medical imaging modalities for its exquisite molecular specificity. From this specificity, PET derives its unique ability to image highly selective biological *processes* – that is, to act as a *functional* imaging modality. In the brain (and everywhere in the body), different processes are facilitated by highly specialized molecules. Individual enzyme mole‐ cules exist to catalyze highly selective and uni-purpose biochemical reactions. Unique receptors and transporters exist to bind highly specialized endogenous ligands and carry out unique physiological functions. Some of the functions of interest that are controlled by individual molecules and which we may want to image are shown in Figure 2. PET can image any of these molecular targets provided two obstacles have been overcome. First, a tracer molecule that binds or interacts with the target site must exist and be labeled with a positron emitting isotope (typically, carbon-11 or fluorine-18). Second, it must be possible to deliver the tracer to the target site. In brain imaging, the most likely cause of tracer failure is the inability of the tracer to cross the blood brain barrier to access the target.

**Figure 2.** Molecular processes that can be imaged with the appropriate PET ligand. Figure modified (Pellerin et al., 1994).

#### *1.2.2. Many tracers for many targets*

al. could examine the difference between a baboon at baseline and following a co-injection of tracer with an excess of cold NMSP (Wagner, 1983), Farde et al. did not ask their patients to go off medication to get a baseline measurement of tracer binding (Farde et al., 1986). So how did they make an assessment of drug occupancy, which requires at least two measurements? They extrapolated what baseline binding might have been in their schizophrenics from a cohort of control subjects. Provocatively, they found that three schizophrenics undergoing (success‐ ful) treatment with different drugs all had receptor occupancies of very similar levels. Their approach would likely not pass muster today, but at the time, the paper was highly innovative, and it foreshadowed one of the major usages of PET and neuroreceptor tracers: measuring

104 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**Figure 1.** Left) Newspaper clipping from the Baltimore Sun, Sept 20, 1983, shows senior authors, Drs. Henry Wagner, Jr. and Mike Kuhar observing the first images of D2 receptors in a human brain, *in vivo*. (Right) A keepsake from the experiment adorns the offices of many of the landmark study's participants. Signatures, from the center bottom going clockwise, Wagner, Robert Dannals, Joanthan Links, Dean F. Wong, Jim Frost, and Kuhar. Photos care of M. Kuhar.

PET is unique among medical imaging modalities for its exquisite molecular specificity. From this specificity, PET derives its unique ability to image highly selective biological *processes* – that is, to act as a *functional* imaging modality. In the brain (and everywhere in the body), different processes are facilitated by highly specialized molecules. Individual enzyme mole‐ cules exist to catalyze highly selective and uni-purpose biochemical reactions. Unique receptors and transporters exist to bind highly specialized endogenous ligands and carry out unique physiological functions. Some of the functions of interest that are controlled by

target occupancy by drugs in people.

**1.2. Basics**

*1.2.1. Molecular specificity*

At this writing, there are tracers for many of the common neurotransmitter receptor sites: dopamine (D2/D3 and D1), serotonin (5HT1a, 5HT1b, 5HT4…), and transporter sites (DAT, SERT, NET…). Tracers generally arise through one of three pathways. (1) Radiolabeling of a dye or other molecule that is known to be selective for a particular target of interest (e.g., [11C]PIB arose from the radiolabelling of thioflavin-T) (Mathis et al., 2002). (2) Radiolabeling of a candidate drug for the target molecule of interest. Such candidate compounds may have been failed drugs (adverse drug side-effects on patients, kinetics too rapid to sustain clinically useful levels in blood and tissue) but make good tracers (no adverse side-effects, because tracers are given in micro-dose amounts, favorably rapid kinetics). (3) De novo design of new PET tracer based on knowledge of the structure of the target molecule.

residence time) in each of the plasma, free, bound, and nonspecific pools is different (see curves in Figure 4). Thus, to identify the specific binding component of the total PET signal (green curve on Fig. 4, also called a time-activity curve (TAC)), we must (a) acquire dynamic data (over many time frames), (b) identify an input function to the system (either plasma radioac‐ tivity or image-derived), and (c) apply a mathematical model to separate the dynamic data

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**Figure 4.** Different pools (compartments) of tracer activity are distinguishable by their different kinetics. Plasma activi‐ ty (red) is cleared fastest. The free tracer pool (white) is slightly slower. The bound tracer pool (yellow) persists for lon‐

The most common endpoint for imaging neuroreceptor or neurotransmitter targets with PET is the compound parameter, binding potential (BP). The term was first introduced by Mintun and is equivalent to the steady state ratio in the target tissue of specifically bound tracer to free tracer (Mintun et al., 1984). Binding potential is a "compound" parameter, because it is equivalent to the ratio of individual rate constants (specifically, the association and dissociation rate constants). The rate constants arise in the standard compartmental model used to describe a TAC measured in a region of interest in the dynamic PET images. Readers should be aware that there are a few variations on the definition of binding potential (Innis et al., 2007). The definitions differ by what data are used as the input function to drive the particular kinetic model and by what assumptions are made. Nevertheless, the general principle can be stated: BP can be estimated as the steady state ratio of bound to free tracer. BP is also proportional to the available binding sites and inversely proportional to the equilibrium dissociation constant, KD, of the tracer for the binding site. The former concept is diagrammed in Figure 5. We see that there are four species of interest in imaging neuroreceptor targets. First, the receptor, second, the tracer molecule that binds to the target and emits a positron, third, the unlabeled tracer which also binds to the target but emits no positron, and fourth, the endogenous ligand

gest. The PET scanner measures the sum of all the radiactivity (green).

that is also specific for the target but (naturally) emits no positron.

*1.2.4. Binding potential as endpoint*

into its constituent parts.

#### *1.2.3. Specific binding vs. nonspecific background*

Tracers are administered to subjects intravenously and travel to the brain via the circulation. Once they traverse the blood brain barrier (typically by passive diffusion), they can follow three possible fates. Some tracer molecules remain free (unbound), eventually clear back to the vasculature and are removed from the organ. Other tracer molecules, once inside the tissue, may bind to the specific target of interest. Because no tracers are perfectly ideal in their behavior, some molecules are bound nonspecifically (nondisplaceably) before clearing from the tissue. Thus, in toto, radioactive emissions that are detected by the PET scanner are a (timevarying) sum of emissions of radio-isotopes on tracer molecules in all four different possible states: blood-borne, free in tissue, specifically bound to a receptor or other target molecule, or nonspecifically bound (Figure 3). The PET scanner records all of these emissions indiscrimin‐ ately. Nothing about the photons that are emitted from an annihilation event in the blood or tissue makes their original state knowable from the detected signal. Thus, on any given *static* PET image (a single image summed over a time frame), the desired signal – i.e., the amount of specifically bound tracer – cannot be discerned easily because the signal is confounded by background activity coming from tracer in its three other possible states.

**Figure 3.** Possible states of an injected radiotracer. The states can be thought of as distinct, interconnected pools. Fig‐ ure modified (Pellerin et al., 1994).

The one thing that allows us to differentiate the binding from the background is the difference in temporal behavior of the various tracer states. The persistence of activity (in a sense, the residence time) in each of the plasma, free, bound, and nonspecific pools is different (see curves in Figure 4). Thus, to identify the specific binding component of the total PET signal (green curve on Fig. 4, also called a time-activity curve (TAC)), we must (a) acquire dynamic data (over many time frames), (b) identify an input function to the system (either plasma radioac‐ tivity or image-derived), and (c) apply a mathematical model to separate the dynamic data into its constituent parts.

**Figure 4.** Different pools (compartments) of tracer activity are distinguishable by their different kinetics. Plasma activi‐ ty (red) is cleared fastest. The free tracer pool (white) is slightly slower. The bound tracer pool (yellow) persists for lon‐ gest. The PET scanner measures the sum of all the radiactivity (green).

#### *1.2.4. Binding potential as endpoint*

*1.2.3. Specific binding vs. nonspecific background*

Tracers are administered to subjects intravenously and travel to the brain via the circulation. Once they traverse the blood brain barrier (typically by passive diffusion), they can follow three possible fates. Some tracer molecules remain free (unbound), eventually clear back to the vasculature and are removed from the organ. Other tracer molecules, once inside the tissue, may bind to the specific target of interest. Because no tracers are perfectly ideal in their behavior, some molecules are bound nonspecifically (nondisplaceably) before clearing from the tissue. Thus, in toto, radioactive emissions that are detected by the PET scanner are a (timevarying) sum of emissions of radio-isotopes on tracer molecules in all four different possible states: blood-borne, free in tissue, specifically bound to a receptor or other target molecule, or nonspecifically bound (Figure 3). The PET scanner records all of these emissions indiscrimin‐ ately. Nothing about the photons that are emitted from an annihilation event in the blood or tissue makes their original state knowable from the detected signal. Thus, on any given *static* PET image (a single image summed over a time frame), the desired signal – i.e., the amount of specifically bound tracer – cannot be discerned easily because the signal is confounded by

106 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**Figure 3.** Possible states of an injected radiotracer. The states can be thought of as distinct, interconnected pools. Fig‐

The one thing that allows us to differentiate the binding from the background is the difference in temporal behavior of the various tracer states. The persistence of activity (in a sense, the

ure modified (Pellerin et al., 1994).

background activity coming from tracer in its three other possible states.

The most common endpoint for imaging neuroreceptor or neurotransmitter targets with PET is the compound parameter, binding potential (BP). The term was first introduced by Mintun and is equivalent to the steady state ratio in the target tissue of specifically bound tracer to free tracer (Mintun et al., 1984). Binding potential is a "compound" parameter, because it is equivalent to the ratio of individual rate constants (specifically, the association and dissociation rate constants). The rate constants arise in the standard compartmental model used to describe a TAC measured in a region of interest in the dynamic PET images. Readers should be aware that there are a few variations on the definition of binding potential (Innis et al., 2007). The definitions differ by what data are used as the input function to drive the particular kinetic model and by what assumptions are made. Nevertheless, the general principle can be stated: BP can be estimated as the steady state ratio of bound to free tracer. BP is also proportional to the available binding sites and inversely proportional to the equilibrium dissociation constant, KD, of the tracer for the binding site. The former concept is diagrammed in Figure 5. We see that there are four species of interest in imaging neuroreceptor targets. First, the receptor, second, the tracer molecule that binds to the target and emits a positron, third, the unlabeled tracer which also binds to the target but emits no positron, and fourth, the endogenous ligand that is also specific for the target but (naturally) emits no positron.

*1.2.6. Changes in endogenous neurotransmitter*

incremental reduction of binding potential.

**Figure 6.** Lower Binding Potential reflects lower receptor density. (Compare to Figure 5).

Another popular use of BP is as a measure of steady state neurotransmitter level. Such measurements are typically made by comparing BP in the same subject at baseline and in a drug or treatment condition. This can be done via two paired bolus injections of tracer or via one bolus plus infusion of tracer (see section 1.2.10 below). Typically, a drug will be given prior to the PET scan. The drug (e.g., cocaine, methylphenidate, amphetamine) will cause elevation of endogenous neurotransmitter, which will in turn occupy more binding sites. As a result, fewer binding sites will remain available for binding by the labeled tracer, and the measured BP will be lower than at baseline. The fractional change in BP is the parameter that is most often reported as an indicator that there has been a prolonged change in neurotransmitter level (Here, "prolonged" simply means on the order of, or longer than, the scan duration). Figure 7 illustrates the principle using the same scheme as in Figures 5 and 6. Because specific binding sites exist in limited number, the approach to full binding will follow a saturation curve. That is, for greater and greater amounts of neurotransmitter release, we expect to see less and less

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**Figure 5.** Binding potential depicted as bound over free tracer (red with star) at steady state. Receptor (or transporter) molecules (blue) may be embedded in a cell membrane. Two other species compete with tracer for limited binding sites: cold tracer (red), endogenous ligand (green).

#### *1.2.5. Changes in receptor number*

As previously stated, BP is proportional to number of available receptor binding sites and typically serves as a convenient surrogate for receptor density, provided the proportionality constant can be taken as a constant across the groups or conditions being compared. When BP is estimated from dynamic data using the arterial plasma concentration of tracer as the input function, the proportionality between BP and Bmax is simply 1/KD. (i.e., BP = Bmax/KD). Perhaps the most common use of BP as an endpoint is to assay receptor density (e.g., dopamine D2R) in two groups of subjects (e.g., healthy controls and cocaine addicts) and compare them (Martinez et al., 2003; Volkow et al., 1997). In such a case, the density of receptors may be believed to have a direct functional role in a disease process. Alternatively, receptor number can be a surrogate marker for number of functioning neurons. Consider Parkinson's disease (PD), which involves loss of nigro-striatal connections. Because functioning nigro-striatal projections contain D2 receptors and dopamine transporters on their striatal terminals, absence of such sites in a PET scan is indicative of disease progression and attendant loss of neurons. Low dopamine receptors and low dopamine transporters have each been demonstrated with either [11C]raclopride or [11C]CFT, respectively, by comparing the BP for healthy controls to that of PD patients (Biju et al., 2009; Brooks et al., 1990). The schematic in Figure 6 represents the case of low BP caused by low receptors (Figure 6 should not be interpreted too literally. e.g., in the case of PD, the entire cell membrane along with the receptors might be missing).

#### *1.2.6. Changes in endogenous neurotransmitter*

BP = B/F at steady state

108 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**unlabeled tracer**

**Figure 5.** Binding potential depicted as bound over free tracer (red with star) at steady state. Receptor (or transporter) molecules (blue) may be embedded in a cell membrane. Two other species compete with tracer for limited binding

As previously stated, BP is proportional to number of available receptor binding sites and typically serves as a convenient surrogate for receptor density, provided the proportionality constant can be taken as a constant across the groups or conditions being compared. When BP is estimated from dynamic data using the arterial plasma concentration of tracer as the input function, the proportionality between BP and Bmax is simply 1/KD. (i.e., BP = Bmax/KD). Perhaps the most common use of BP as an endpoint is to assay receptor density (e.g., dopamine D2R) in two groups of subjects (e.g., healthy controls and cocaine addicts) and compare them (Martinez et al., 2003; Volkow et al., 1997). In such a case, the density of receptors may be believed to have a direct functional role in a disease process. Alternatively, receptor number can be a surrogate marker for number of functioning neurons. Consider Parkinson's disease (PD), which involves loss of nigro-striatal connections. Because functioning nigro-striatal projections contain D2 receptors and dopamine transporters on their striatal terminals, absence of such sites in a PET scan is indicative of disease progression and attendant loss of neurons. Low dopamine receptors and low dopamine transporters have each been demonstrated with either [11C]raclopride or [11C]CFT, respectively, by comparing the BP for healthy controls to that of PD patients (Biju et al., 2009; Brooks et al., 1990). The schematic in Figure 6 represents the case of low BP caused by low receptors (Figure 6 should not be interpreted too literally. e.g., in the case of PD, the entire cell membrane along with the receptors might be missing).

**radiolabeled tracer receptor**

**endogenous NT**

sites: cold tracer (red), endogenous ligand (green).

*1.2.5. Changes in receptor number*

Another popular use of BP is as a measure of steady state neurotransmitter level. Such measurements are typically made by comparing BP in the same subject at baseline and in a drug or treatment condition. This can be done via two paired bolus injections of tracer or via one bolus plus infusion of tracer (see section 1.2.10 below). Typically, a drug will be given prior to the PET scan. The drug (e.g., cocaine, methylphenidate, amphetamine) will cause elevation of endogenous neurotransmitter, which will in turn occupy more binding sites. As a result, fewer binding sites will remain available for binding by the labeled tracer, and the measured BP will be lower than at baseline. The fractional change in BP is the parameter that is most often reported as an indicator that there has been a prolonged change in neurotransmitter level (Here, "prolonged" simply means on the order of, or longer than, the scan duration). Figure 7 illustrates the principle using the same scheme as in Figures 5 and 6. Because specific binding sites exist in limited number, the approach to full binding will follow a saturation curve. That is, for greater and greater amounts of neurotransmitter release, we expect to see less and less incremental reduction of binding potential.

**Figure 6.** Lower Binding Potential reflects lower receptor density. (Compare to Figure 5).

is that there must exist a tracer that binds selectively to the desired drug target. On the other hand, the *drug* need not be selective. The change in binding of the PET tracer will reflect the occupancy of the drug only at the tracer's target. Again, occupancy of specific receptor binding sites is saturable and reduction in BP (i.e., increase in drug occupancy) increases less and less for given increases in drug as the concentration gets higher and higher. We typically define

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For the case of an exogenous drug binding to target sites, it turns out, Occupancy = ΔBP.

**Figure 8.** Effect of exogenous drug on binding potential. Drug (yellow triangles) occupies some receptor sites reduc‐

The flexibility of BP as an endpoint of PET studies with neuroreceptor ligands (as stated, one can measure receptors, transmitters, drugs) is also the source of potential ambiguity in interpretation. How can one tell the difference between lower receptor density under scan condition B vs. A from higher neurotransmitter level in scan condition B vs. A? These ambi‐

change in BP as a percentage change:

ing available binding sites and then reducing BP.

*1.2.8. Ambiguities in interpretation of PET data*

ΔBP = [1 - BP(under a challenge condition) / BP(at baseline) ]\* 100.

**Figure 7.** Elevation of endogenous neurotransmitter (green triangles) blocks available receptors and is detected as a reduction in BP.

#### *1.2.7. Changes in occupancy by an exogenous drug*

A third common usage of PET and BP is for measuring occupancy of receptor sites by exogenous (unlabeled) drugs. This is a popular use of PET by pharmaceutical companies who typical want to know three things: (a) does their candidate drug get into the brain, (b) does the candidate drug hit the intended target, and (c) what is the relationship between dose of the drug and percentage occupancy of the available (target) receptors? When companies are ready for a drug-occupancy study with PET they usually already know the safe dose range of the drug (i.e., the range of doses that cause little to no adverse side-effects). They also have a desired occupancy level in mind that will produce the desired drug effects. The question that PET can answer is: what is the receptor occupancy for each dose level in the allowable range. This relationship is characterized by an ED50 (drug dose at which 50% occupancy is achieved) and an Emax (maximal achievable level of binding if there were no upper limit on dose). Just as with elevation of endogenous neurotransmitter, the presence of cold exogenous drug that binds to the same receptor as the tracer and reduces the concentration of available receptor sites can be imaged. This scenario is diagrammed in Figure 8. An essential element of occupancy studies is that there must exist a tracer that binds selectively to the desired drug target. On the other hand, the *drug* need not be selective. The change in binding of the PET tracer will reflect the occupancy of the drug only at the tracer's target. Again, occupancy of specific receptor binding sites is saturable and reduction in BP (i.e., increase in drug occupancy) increases less and less for given increases in drug as the concentration gets higher and higher. We typically define change in BP as a percentage change:

ΔBP = [1 - BP(under a challenge condition) / BP(at baseline) ]\* 100.

For the case of an exogenous drug binding to target sites, it turns out, Occupancy = ΔBP.

**Figure 8.** Effect of exogenous drug on binding potential. Drug (yellow triangles) occupies some receptor sites reduc‐ ing available binding sites and then reducing BP.

#### *1.2.8. Ambiguities in interpretation of PET data*

**Figure 7.** Elevation of endogenous neurotransmitter (green triangles) blocks available receptors and is detected as a

110 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

A third common usage of PET and BP is for measuring occupancy of receptor sites by exogenous (unlabeled) drugs. This is a popular use of PET by pharmaceutical companies who typical want to know three things: (a) does their candidate drug get into the brain, (b) does the candidate drug hit the intended target, and (c) what is the relationship between dose of the drug and percentage occupancy of the available (target) receptors? When companies are ready for a drug-occupancy study with PET they usually already know the safe dose range of the drug (i.e., the range of doses that cause little to no adverse side-effects). They also have a desired occupancy level in mind that will produce the desired drug effects. The question that PET can answer is: what is the receptor occupancy for each dose level in the allowable range. This relationship is characterized by an ED50 (drug dose at which 50% occupancy is achieved) and an Emax (maximal achievable level of binding if there were no upper limit on dose). Just as with elevation of endogenous neurotransmitter, the presence of cold exogenous drug that binds to the same receptor as the tracer and reduces the concentration of available receptor sites can be imaged. This scenario is diagrammed in Figure 8. An essential element of occupancy studies

reduction in BP.

*1.2.7. Changes in occupancy by an exogenous drug*

The flexibility of BP as an endpoint of PET studies with neuroreceptor ligands (as stated, one can measure receptors, transmitters, drugs) is also the source of potential ambiguity in interpretation. How can one tell the difference between lower receptor density under scan condition B vs. A from higher neurotransmitter level in scan condition B vs. A? These ambi‐ guities are inherent in the compound parameter, BP. Generally, they can be resolved by considering the context of the measurement. If a stimulus was given just before the scan and the BP was lower than at baseline, we interpret this to mean that neurotransmitter levels rose due to the stimulus. We reject receptor up-regulation as the explanation, because it is a slower process than the time-scale of the PET scan (1-2 hours). On the other hand, if baseline scans are repeated on the same individuals after a year of psychotherapy and the average BP value is higher in the latter scan, we interpret this to mean that receptor number is increased by psychotherapy. (We must admit that long-term depression of baseline neurotransmitter level is also a valid interpretation.) Certainly we can say that "available receptor sites" were increased with therapy. In all cases, one must be alert to alternative interpretations of BP and ∆BP and try as best as possible to control for them via appropriate study designs.

*1.2.10. Experimental approaches to estimate binding potential*

the authors.

*1.2.10.1. Bolus plus constant infusion*

might reach equilibrium but another's might not.

There are generally two approaches to estimating BP and by extension, change in BP. Both approaches turn on recognizing that BP represents a steady state quantity: the ratio of bound to free tracer in the tissue at steady state – that is, when the ratio of these quantities is not changing on a macroscopic level. To make such a measurement, one can either perform an experiment that brings the pools of bound and free tracer to steady state or, if that is not possible or not desired, one can predict the steady state from non-steady measurements. If these ideas seem unintuitive, consider the two fun experiments depicted in Figure 9 for predicting the steady state (i.e., adult) height of one's daughters. Steady state approach: one can make a few measurements (greater reliability than a single measurement) once the child reaches her adult height (Figure 9, left). Non-steady approach: one can make periodic measurements throughout childhood and – given a model of growth patterns of women in the United States – *predict* the

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**Figure 9.** Schematic for (left) a type of steady state experiment for *measuring* height of a fully grown female child, as compared to (right) a type of non-steady experiment for *predicting* the adult height of the female children of one of

In PET, the steady state or equilibrium approach to measuring BP consists of administering the tracer as an initial bolus followed by a constant infusion of additional tracer for the duration of the experiment. If the bolus and infusion fractions of the tracer are balanced correctly, the TAC in the region(s) of interest will achieve a steady state in a minimal amount of time (Carson et al., 1993) at which point tracer concentrations in plasma, free and bound compartments will remain in constant proportions to each other. At said point, BP can be measured directly from the levels of the plasma and tissue curves without the need for a model or any curve-fitting. It must be pointed out that infusions are more taxing experimentally. An infusion pump is required. More tracer is required (as compared to a bolus injection), since some of it decays while sitting in the syringe waiting to be infused. Not all tissue regions are the same. Tissue regions with differing kinetics of tracer uptake will reach equilibrium at different times – or not at all. Not all subjects are the same. For a given injection protocol, one subject's tissue curves

adult height of the child based on these non-steady measurements (right).

#### *1.2.9. Common confounding conditions in PET experiments*

Some sources of ambiguity in the interpretation of BP measurements are inherent in the nature of PET data, but others can and should be controlled experimentally.

#### *1.2.9.1. Effect of age*

The densities of many neuroreceptors are known to decline with normal aging and this has been confirmed with PET (E. D. Morris et al., 1999). Thus, BP will be lower in a group of healthy control subjects with a higher mean age than a second group whose mean age is younger. Similarly, there may be no effect of a treatment or condition (e.g., long-term drug abuse) on the numbers of a particular receptor, but it might appear so if the drug abusers have a mean age that is older than the mean age of the healthy subjects to whom they are being compared. Any careful reading of journal articles reporting BP values for different cohorts must include checking to make sure that the ages of the respective groups are not different. Similarly, a longitudinal study examining the effect of long-term treatment on a single group of individuals should correct for aging of the subjects if the length of the study is considerable.

#### *1.2.9.2. Effect of mass*

As we saw above, an exogenous drug that occupies the target receptor reduces available binding sites for the tracer, and BP is reduced. This is the basis for drug occupancy studies. However, if the specific activity of the tracer (ratio of activity to mass) is low enough, then mass of cold tracer acts like any exogenous drug. This poses two problems. First, we normally do not want the tracer species to exert its own drug effects. Second, the mass of cold tracer – as with any exogenous ligand for the target site – will occupy an appreciable number of receptors and the measured BP will be lower than if the mass of tracer were negligible. Unwanted drug effects notwithstanding, poorly controlled mass of tracer has the potential to introduce a confound into an experiment. If a patient group is being compared to a control group but the patients receive a significantly higher mean tracer mass (i.e., lower specific activity for the same amount of radioactivity injected), then the patients will appear to have lower BP due to their disease, when in fact, the difference may be caused solely by a bias introduced by experimenters.

#### *1.2.10. Experimental approaches to estimate binding potential*

guities are inherent in the compound parameter, BP. Generally, they can be resolved by considering the context of the measurement. If a stimulus was given just before the scan and the BP was lower than at baseline, we interpret this to mean that neurotransmitter levels rose due to the stimulus. We reject receptor up-regulation as the explanation, because it is a slower process than the time-scale of the PET scan (1-2 hours). On the other hand, if baseline scans are repeated on the same individuals after a year of psychotherapy and the average BP value is higher in the latter scan, we interpret this to mean that receptor number is increased by psychotherapy. (We must admit that long-term depression of baseline neurotransmitter level is also a valid interpretation.) Certainly we can say that "available receptor sites" were increased with therapy. In all cases, one must be alert to alternative interpretations of BP and

112 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

∆BP and try as best as possible to control for them via appropriate study designs.

should correct for aging of the subjects if the length of the study is considerable.

Some sources of ambiguity in the interpretation of BP measurements are inherent in the nature

The densities of many neuroreceptors are known to decline with normal aging and this has been confirmed with PET (E. D. Morris et al., 1999). Thus, BP will be lower in a group of healthy control subjects with a higher mean age than a second group whose mean age is younger. Similarly, there may be no effect of a treatment or condition (e.g., long-term drug abuse) on the numbers of a particular receptor, but it might appear so if the drug abusers have a mean age that is older than the mean age of the healthy subjects to whom they are being compared. Any careful reading of journal articles reporting BP values for different cohorts must include checking to make sure that the ages of the respective groups are not different. Similarly, a longitudinal study examining the effect of long-term treatment on a single group of individuals

As we saw above, an exogenous drug that occupies the target receptor reduces available binding sites for the tracer, and BP is reduced. This is the basis for drug occupancy studies. However, if the specific activity of the tracer (ratio of activity to mass) is low enough, then mass of cold tracer acts like any exogenous drug. This poses two problems. First, we normally do not want the tracer species to exert its own drug effects. Second, the mass of cold tracer – as with any exogenous ligand for the target site – will occupy an appreciable number of receptors and the measured BP will be lower than if the mass of tracer were negligible. Unwanted drug effects notwithstanding, poorly controlled mass of tracer has the potential to introduce a confound into an experiment. If a patient group is being compared to a control group but the patients receive a significantly higher mean tracer mass (i.e., lower specific activity for the same amount of radioactivity injected), then the patients will appear to have lower BP due to their disease, when in fact, the difference may be caused solely by a bias

*1.2.9. Common confounding conditions in PET experiments*

*1.2.9.1. Effect of age*

*1.2.9.2. Effect of mass*

introduced by experimenters.

of PET data, but others can and should be controlled experimentally.

There are generally two approaches to estimating BP and by extension, change in BP. Both approaches turn on recognizing that BP represents a steady state quantity: the ratio of bound to free tracer in the tissue at steady state – that is, when the ratio of these quantities is not changing on a macroscopic level. To make such a measurement, one can either perform an experiment that brings the pools of bound and free tracer to steady state or, if that is not possible or not desired, one can predict the steady state from non-steady measurements. If these ideas seem unintuitive, consider the two fun experiments depicted in Figure 9 for predicting the steady state (i.e., adult) height of one's daughters. Steady state approach: one can make a few measurements (greater reliability than a single measurement) once the child reaches her adult height (Figure 9, left). Non-steady approach: one can make periodic measurements throughout childhood and – given a model of growth patterns of women in the United States – *predict* the adult height of the child based on these non-steady measurements (right).

**Figure 9.** Schematic for (left) a type of steady state experiment for *measuring* height of a fully grown female child, as compared to (right) a type of non-steady experiment for *predicting* the adult height of the female children of one of the authors.

#### *1.2.10.1. Bolus plus constant infusion*

In PET, the steady state or equilibrium approach to measuring BP consists of administering the tracer as an initial bolus followed by a constant infusion of additional tracer for the duration of the experiment. If the bolus and infusion fractions of the tracer are balanced correctly, the TAC in the region(s) of interest will achieve a steady state in a minimal amount of time (Carson et al., 1993) at which point tracer concentrations in plasma, free and bound compartments will remain in constant proportions to each other. At said point, BP can be measured directly from the levels of the plasma and tissue curves without the need for a model or any curve-fitting. It must be pointed out that infusions are more taxing experimentally. An infusion pump is required. More tracer is required (as compared to a bolus injection), since some of it decays while sitting in the syringe waiting to be infused. Not all tissue regions are the same. Tissue regions with differing kinetics of tracer uptake will reach equilibrium at different times – or not at all. Not all subjects are the same. For a given injection protocol, one subject's tissue curves might reach equilibrium but another's might not.

#### *1.2.10.2. Bolus studies*

Alternatively, if an infusion experiment is impractical, a bolus administration of tracer is used. This approach includes a bolus injection of tracer, a dynamic acquisition of PET data, and a kinetic model to fit the data, estimate parameters, and calculate BP from the estimated model parameters. The parameters of the kinetic model are rate constants (they each have units of time-1), but their ratio is an equilibrium (i.e., steady state) constant (BP is unitless).

Both experimental designs (bolus and bolus/infusion) can be used to measure the change in BP. In the case of the bolus administration, two separate injections are required to measure change in BP (ΔBP) – perhaps in response to a drug challenge. A single bolus plus infusion (B/ I) study can suffice to measure ΔBP provided the drug challenge of interest acts rapidly enough and the tracer is sufficiently displaceable so that the effect can be detected during the duration of the scan. The two different paradigms for measuring ΔBP are diagrammed in Figure 10. Each paradigm has advantages and disadvantages that the investigator must consider carefully when planning a study (Table 1). The order of a paired bolus study (baseline vs. challenge condition) can be randomized; the B/I cannot. Both scans of a paired bolus studies with 18F-labelled tracers cannot both be performed on a single day. This may lead to greater variability in the data or even loss of some subjects who fail to return for a second scan. Equilibrium must be reached before the drug challenge in the B/I design. Unfortunately, there is no way of knowing that equilibrium has been achieved in a subject before giving the drug challenge, since PET data are not reconstructed and analyzed in real time. Finally, on the side of the B/I paradigm, the analysis of the data – provided equilibrium has been reached – is simple and requires no modeling and no curve fitting. For bolus studies, with some rare exceptions, one must use a kinetic model to describe the data in order to estimate BP.

dissected into its constituent parts with the use of a kinetic model that describes the processes of uptake and retention of the tracer, as well as the interconnectedness of the compartments.

**Table 1.** Experimental Design. Some common advantages (blue) and disadvantages (red) of paired bolus and bolus

plus infusion designs for measuring drug-induced changes in the neurotransmitter levels with PET.

at same time.

(high- and low-binding) regions don't all reach equilibrium

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requires that regions of interest reach equilibrium; data may be unusable if equilibrium is not achieved

B/I scan needs more radioactivity than single bolus scan

**Paired Bolus design Bolus plus Infusion design**

scan days; more chance of physiological variability requires computerized injection

challenge requires no model-fitting to estimate BP, ΔBP

requires two successful syntheses requires only one successful synthesis of tracer

order of conditions can be randomized: baseline/

studies with [18F]-labeled tracers require two separate

The process of moving from some knowledge of the system of interest to a tracer kinetic model is diagrammed in Figure 11. One must first identify the organ(s) of interest. In the case of imaging drugs, the organ, naturally, is the brain. Next one must consider the relevant (neu‐ ro)chemistry of the selected organ and how it relates to the tracer to be used. In a simple conception of the brain, we must include the vasculature that delivers the tracer to the tissue. The blood brain barrier – how does the tracer traverse it? Once inside the tissue, are there receptors or transporters to (specifically) bind the tracer? If there are multiple possible specific binding sites, is there one site that is likely to dominate? Inevitably there will be nonspecific (i.e., non-displaceable) binding as well, because there are other entities in the tissue that appear to retain foreign molecules. Due to mathematical limitations (related to the limits of parameter identifiability), most models will treat the nonspecific binding pool as a sub-pool of the free, unbound tracer; nevertheless, we must keep in mind that such a process lurks under the surface even if it is not explicated in the model statement. Next, we must conceptualize the possible fates of the tracer into distinct pools or compartments of the model (all compartments are pools, but not all pools are compartments – see next section for explanation). Every route by which tracer can move from one compartment to another must be assigned a rate constant (designated by an arrow in Figure 11c). Finally, we turn a diagram of connected pools into a series of equations. Because what drives movement of tracer is mass action (diffusion from pools of high concentration to low), we must write mass balance equations for each compartment. Mass balance equations assert that the net accumulation of tracer over time is equal to the amount of tracer coming into the compartment per time, minus the amount of tracer leaving per time, plus tracer generated, minus tracer destroyed. Typically, generation does not apply – our bodies do not create exogenous compounds. These equations take the form of ordinary

*1.2.11.1. The modeling process*

**Figure 10.** Two common schemes for measuring change in BP with PET. General appearance of data from a paired bolus study (left) compared to a single bolus plus infusion study (right). Stars on right indicate that only two static measurements are necessary to get change in BP from an equilibrium study

#### *1.2.11. Modeling basics (to get to binding potential via bolus or bolus + infusion)*

As we discussed in Section 1.2.3 and diagrammed in Figure 4, the PET signal consists of tracer molecules in different pools, only one of which is the specific binding we are most interested in. These pools or compartments differentiate themselves over time. They have different temporal characteristics based on their degree of retention of the tracer. The PET signal can be


**Table 1.** Experimental Design. Some common advantages (blue) and disadvantages (red) of paired bolus and bolus plus infusion designs for measuring drug-induced changes in the neurotransmitter levels with PET.

dissected into its constituent parts with the use of a kinetic model that describes the processes of uptake and retention of the tracer, as well as the interconnectedness of the compartments.

#### *1.2.11.1. The modeling process*

*1.2.10.2. Bolus studies*

Alternatively, if an infusion experiment is impractical, a bolus administration of tracer is used. This approach includes a bolus injection of tracer, a dynamic acquisition of PET data, and a kinetic model to fit the data, estimate parameters, and calculate BP from the estimated model parameters. The parameters of the kinetic model are rate constants (they each have units of

114 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Both experimental designs (bolus and bolus/infusion) can be used to measure the change in BP. In the case of the bolus administration, two separate injections are required to measure change in BP (ΔBP) – perhaps in response to a drug challenge. A single bolus plus infusion (B/ I) study can suffice to measure ΔBP provided the drug challenge of interest acts rapidly enough and the tracer is sufficiently displaceable so that the effect can be detected during the duration of the scan. The two different paradigms for measuring ΔBP are diagrammed in Figure 10. Each paradigm has advantages and disadvantages that the investigator must consider carefully when planning a study (Table 1). The order of a paired bolus study (baseline vs. challenge condition) can be randomized; the B/I cannot. Both scans of a paired bolus studies with 18F-labelled tracers cannot both be performed on a single day. This may lead to greater variability in the data or even loss of some subjects who fail to return for a second scan. Equilibrium must be reached before the drug challenge in the B/I design. Unfortunately, there is no way of knowing that equilibrium has been achieved in a subject before giving the drug challenge, since PET data are not reconstructed and analyzed in real time. Finally, on the side of the B/I paradigm, the analysis of the data – provided equilibrium has been reached – is simple and requires no modeling and no curve fitting. For bolus studies, with some rare

time-1), but their ratio is an equilibrium (i.e., steady state) constant (BP is unitless).

exceptions, one must use a kinetic model to describe the data in order to estimate BP.

**Figure 10.** Two common schemes for measuring change in BP with PET. General appearance of data from a paired bolus study (left) compared to a single bolus plus infusion study (right). Stars on right indicate that only two static

As we discussed in Section 1.2.3 and diagrammed in Figure 4, the PET signal consists of tracer molecules in different pools, only one of which is the specific binding we are most interested in. These pools or compartments differentiate themselves over time. They have different temporal characteristics based on their degree of retention of the tracer. The PET signal can be

measurements are necessary to get change in BP from an equilibrium study

*1.2.11. Modeling basics (to get to binding potential via bolus or bolus + infusion)*

The process of moving from some knowledge of the system of interest to a tracer kinetic model is diagrammed in Figure 11. One must first identify the organ(s) of interest. In the case of imaging drugs, the organ, naturally, is the brain. Next one must consider the relevant (neu‐ ro)chemistry of the selected organ and how it relates to the tracer to be used. In a simple conception of the brain, we must include the vasculature that delivers the tracer to the tissue. The blood brain barrier – how does the tracer traverse it? Once inside the tissue, are there receptors or transporters to (specifically) bind the tracer? If there are multiple possible specific binding sites, is there one site that is likely to dominate? Inevitably there will be nonspecific (i.e., non-displaceable) binding as well, because there are other entities in the tissue that appear to retain foreign molecules. Due to mathematical limitations (related to the limits of parameter identifiability), most models will treat the nonspecific binding pool as a sub-pool of the free, unbound tracer; nevertheless, we must keep in mind that such a process lurks under the surface even if it is not explicated in the model statement. Next, we must conceptualize the possible fates of the tracer into distinct pools or compartments of the model (all compartments are pools, but not all pools are compartments – see next section for explanation). Every route by which tracer can move from one compartment to another must be assigned a rate constant (designated by an arrow in Figure 11c). Finally, we turn a diagram of connected pools into a series of equations. Because what drives movement of tracer is mass action (diffusion from pools of high concentration to low), we must write mass balance equations for each compartment. Mass balance equations assert that the net accumulation of tracer over time is equal to the amount of tracer coming into the compartment per time, minus the amount of tracer leaving per time, plus tracer generated, minus tracer destroyed. Typically, generation does not apply – our bodies do not create exogenous compounds. These equations take the form of ordinary differential equations. The only dependent variable is time. The dependent, or "state", variables are the unknown concentrations in the respective compartments.

Arterial blood taken from the arm is considered a good representation of the tracer concentra‐ tion in arterial blood reaching the brain at each moment in time. For tracers that are known to bind specifically to a target, it would seem natural to model them with the 2T model. Howev‐ er, the 2T model has 4 unknown parameters: K1, k2, k3, k4. By contrast, the 1T model has one

the k2 parameters have different meanings for each of the two models and so in this chapter, we give them different superscripts to distinguish between them (the reader is advised that this is typically not done in the PET literature). While the 2T model would seem the intuitive choice – especially if we know that specific binding of tracer to a target occurs - it is not always support‐ ed by the data. That is, the specific binding may be too fast to allow for reliable estimation of k3 and k4 or it represents only a small fraction of the total uptake or perhaps the signal to noise ratio of the data is poor. Whatever the reason, if we cannot uniquely identify all the parame‐ ters of the 2T model by fitting it to the data, the 1T model can be used and the total volume of

**Figure 12.** Common compartmental models used to analyze PET TACs. 2T model (top) has 2 unknown variables and 4 parameters (rate constants) to be estimated from the data. 1T model has only one variable (the tissue compartment)

To fit TACs with the 1T or 2T models requires an iterative algorithm and some knowledge of numerical methods, parameter estimation, and computer programming. There is a popular

1T, becomes the estimated endpoint. By contrast, Vt as measured with the

2T(1 +BP).IftheVt is estimatedfromparameters ofthe 1Tmodel,

1T implicitly contains effects of the specific binding term, BP.

1T. Note that

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variable, the concentration of tracer in the tissue and only 2 parameters, K1 and k2

distribution, Vt = K1/k2

2TmodelisdefinedasVt =K1/k2

and 2 rate constants to be estimated.

*1.2.11.3. Graphical methods*

but specific binding exists, then k2

**Figure 11.** Schematic of the tracer kinetic modeling process. (a) Identify an organ of interest and a region of interest within it. (b) Consider the relevant physiology or biochemistry. (c) Abstract the tracer pools into connected compart‐ ments. (d) Write the mass balance equations

#### *1.2.11.2. Compartmental models (1T, 2T)*

Compartments represent the unknown variables of a model (free tracer, F, bound tracer, B). These are sometimes referred to as "state" variables. Although in most circumstances plasmaborne tracer can be thought of as a distinct "pool", we typically do not assign it a compart‐ ment, because it is measured directly via an arterial catheter and therefore not an unknown. Rather, the plasma tracer concentration over time is an input to the system. That is the case for the two most common compartmental models used to describe PET tracers: the one-tissue compartment (1T) and the two-tissue compartment (2T) models (see Figure 12). Each of these modelsrequiresmeasurementofthearterialplasmaconcentrationoftracerastheinputfunction. Arterial blood taken from the arm is considered a good representation of the tracer concentra‐ tion in arterial blood reaching the brain at each moment in time. For tracers that are known to bind specifically to a target, it would seem natural to model them with the 2T model. Howev‐ er, the 2T model has 4 unknown parameters: K1, k2, k3, k4. By contrast, the 1T model has one variable, the concentration of tracer in the tissue and only 2 parameters, K1 and k2 1T. Note that the k2 parameters have different meanings for each of the two models and so in this chapter, we give them different superscripts to distinguish between them (the reader is advised that this is typically not done in the PET literature). While the 2T model would seem the intuitive choice – especially if we know that specific binding of tracer to a target occurs - it is not always support‐ ed by the data. That is, the specific binding may be too fast to allow for reliable estimation of k3 and k4 or it represents only a small fraction of the total uptake or perhaps the signal to noise ratio of the data is poor. Whatever the reason, if we cannot uniquely identify all the parame‐ ters of the 2T model by fitting it to the data, the 1T model can be used and the total volume of distribution, Vt = K1/k2 1T, becomes the estimated endpoint. By contrast, Vt as measured with the 2TmodelisdefinedasVt =K1/k2 2T(1 +BP).IftheVt is estimatedfromparameters ofthe 1Tmodel, but specific binding exists, then k2 1T implicitly contains effects of the specific binding term, BP.

**Figure 12.** Common compartmental models used to analyze PET TACs. 2T model (top) has 2 unknown variables and 4 parameters (rate constants) to be estimated from the data. 1T model has only one variable (the tissue compartment) and 2 rate constants to be estimated.

#### *1.2.11.3. Graphical methods*

differential equations. The only dependent variable is time. The dependent, or "state",

116 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**Figure 11.** Schematic of the tracer kinetic modeling process. (a) Identify an organ of interest and a region of interest within it. (b) Consider the relevant physiology or biochemistry. (c) Abstract the tracer pools into connected compart‐

Compartments represent the unknown variables of a model (free tracer, F, bound tracer, B). These are sometimes referred to as "state" variables. Although in most circumstances plasmaborne tracer can be thought of as a distinct "pool", we typically do not assign it a compart‐ ment, because it is measured directly via an arterial catheter and therefore not an unknown. Rather, the plasma tracer concentration over time is an input to the system. That is the case for the two most common compartmental models used to describe PET tracers: the one-tissue compartment (1T) and the two-tissue compartment (2T) models (see Figure 12). Each of these modelsrequiresmeasurementofthearterialplasmaconcentrationoftracerastheinputfunction.

ments. (d) Write the mass balance equations

*1.2.11.2. Compartmental models (1T, 2T)*

variables are the unknown concentrations in the respective compartments.

To fit TACs with the 1T or 2T models requires an iterative algorithm and some knowledge of numerical methods, parameter estimation, and computer programming. There is a popular alternative to iterative curve fitting that can be used in many circumstances. Collectively, these methods are based on rearrangements of the model equations to yield linear relationships between measured quantities (Ichise et al., 2003; Logan et al., 1996; Logan et al., 1990; Patlak et al., 1985; Patlak et al., 1983; Zhou et al., 2006). One can think about these methods as transformations akin to a logarithm that transforms an exponential relationship into a linear one. The Logan plot was the first linearization of the 2T model to be applied widely to reversibly bound tracers (e.g., [11C]raclopride). The slope of the original Logan plot is equivalent to the volume of distribution, Vt , the same parameter that can be estimated directly with either the 1T or 2T model (Logan et al., 1990). An advantage of using the Logan plot is it is possible to perform all the necessary calculations in a spreadsheet. Further, the estimate of Vt via the Logan plot is highly robust. That is, it almost never fails to produce an estimate with high precision. A disadvantage of the Logan plot is that it is not unbiased. It has been shown to underestimate Vt with increasing noise in the PET data (Slifstein et al., 2000). As with proper experimental design, one must be cognizant of potential biases that can be introduced into the analysis by the model or the model transform and guard against misinterpretation.

collimation can be foiled and standard corrections must be applied to the raw data to assure that the emission images are quantitative and proportional to concentration of tracer. Some common artifacts that require correction are diagrammed in Figure 14 (counter-clockwise from

**Figure 13.** (top left) A positron emitter emits a beta particle. (top right) Beta particle annihilates with an electron and two photons are produced which exit the object in opposite directions. (bottom left) The two 511 KeV photons are detected by opposing detectors, leading to signals being recorded. Coincidence logic determines that the events hap‐ pened within a pre-set time window. The time of the coincidence event and its unique angle, Φ, and distance, R, are recorded. (bottom right) Image reconstruction locates the original annihilation event along a line-of-response (within

If either pair of photons emanating from a single annihilation event is deflected from its path but still detected simultaneously with the non-deflected photon, then the positioning of the

If one photon each from two separate annihilation events is lost to attenuation or scatter and the remaining photons (from different events) are detected simultaneously, the apparent

line of response (between the two detectors) will be incorrect.

coincidence event will be located improperly.

Figure 1. (top left) A positron emitter emits a beta particle. (top right) Beta particle annihilates with an electron and two photons are produced which exit the object in opposite directions. (bottom left) The two 511 KeV photons are detected by opposing detectors, leading to signals being recorded. Coincidence logic determines that the events happened within a pre-set time window. The time of the coincidence event and its unique angle, , and distance, R, are recorded. (bottom right) Image reconstruction locates the original annihilation event along a line-of-response (within

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119

top left).

the dotted lines).

*1.2.12.1. Scatter*

*1.2.12.2. Randoms*

**FIGURES**

the dotted lines).

DUMMY TEXT, KOJI NIJE IME KNJIGE

#### *1.2.11.4. Reference region methods*

From the diagrams in Figure 12, it would appear that one always needs a measured plasma input function to drive a kinetic model. On its face, this makes sense, since tracers enter (are inputted) into the system via the plasma. In fact, models designed to describe the data in the tissue can also work with input functions derived from reference regions in the image. A reference region is one that is essentially equivalent to the target region except that it is devoid of specific binding sites. By taking advantage of the fact that the same plasma concentration of tracer supplies both the target and the reference regions, it is possible to eliminate the plasma concentration from the model and describe the concentration in the target region compart‐ ments in terms of the reference region concentration. In effect, the reference region has become the input function. This concept was first applied to PET data by Farde et al. and by Cunning‐ ham et al. (Cunningham et al., 1991; Farde et al., 1989). Subsequent assumptions applied by Lammertsma and Hume reduced the number of parameters in the reference tissue model (thus named the "simplified reference tissue model" (SRTM)) (A. Lammertsma et al., 1996; A. A. Lammertsma et al., 1996). Finally, Gunn et al. devised an implementation of SRTM (using basis functions) that turned it into a linear model and thus almost as easy to use in practice as the Logan plot (Gunn et al., 1997).

#### *1.2.12. Physics basics*

The spatial precision of PET is based on the concept of "electronic collimation". That is, radioactive decays lead to pairs of 511KeV photons being emitted in (nearly) opposite directions. When they are captured simultaneously by detectors in the PET scanner ring, a coincidence is recorded. Because of the co-linearity of the paths of the two photons, the direction from which they came is known and physical collimators (used to filter out photons approaching at various angles to the detector) are not needed. The sequence of coincidence detection is diagrammed in Figure 13. But there are certain common ways that electronic collimation can be foiled and standard corrections must be applied to the raw data to assure that the emission images are quantitative and proportional to concentration of tracer. Some common artifacts that require correction are diagrammed in Figure 14 (counter-clockwise from top left). the dotted lines).

recorded. Coincidence logic determines that the events happened within a pre-set time window. The time of the coincidence event and its unique angle, , and distance, R, are recorded. (bottom right) Image reconstruction locates the original annihilation event along a line-of-response (within

DUMMY TEXT, KOJI NIJE IME KNJIGE

**FIGURES**

**Figure 13.** (top left) A positron emitter emits a beta particle. (top right) Beta particle annihilates with an electron and two photons are produced which exit the object in opposite directions. (bottom left) The two 511 KeV photons are detected by opposing detectors, leading to signals being recorded. Coincidence logic determines that the events hap‐ pened within a pre-set time window. The time of the coincidence event and its unique angle, Φ, and distance, R, are recorded. (bottom right) Image reconstruction locates the original annihilation event along a line-of-response (within the dotted lines).

#### *1.2.12.1. Scatter*

alternative to iterative curve fitting that can be used in many circumstances. Collectively, these methods are based on rearrangements of the model equations to yield linear relationships between measured quantities (Ichise et al., 2003; Logan et al., 1996; Logan et al., 1990; Patlak et al., 1985; Patlak et al., 1983; Zhou et al., 2006). One can think about these methods as transformations akin to a logarithm that transforms an exponential relationship into a linear one. The Logan plot was the first linearization of the 2T model to be applied widely to reversibly bound tracers (e.g., [11C]raclopride). The slope of the original Logan plot is

118 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

with either the 1T or 2T model (Logan et al., 1990). An advantage of using the Logan plot is it is possible to perform all the necessary calculations in a spreadsheet. Further, the estimate of

 via the Logan plot is highly robust. That is, it almost never fails to produce an estimate with high precision. A disadvantage of the Logan plot is that it is not unbiased. It has been shown

experimental design, one must be cognizant of potential biases that can be introduced into the

From the diagrams in Figure 12, it would appear that one always needs a measured plasma input function to drive a kinetic model. On its face, this makes sense, since tracers enter (are inputted) into the system via the plasma. In fact, models designed to describe the data in the tissue can also work with input functions derived from reference regions in the image. A reference region is one that is essentially equivalent to the target region except that it is devoid of specific binding sites. By taking advantage of the fact that the same plasma concentration of tracer supplies both the target and the reference regions, it is possible to eliminate the plasma concentration from the model and describe the concentration in the target region compart‐ ments in terms of the reference region concentration. In effect, the reference region has become the input function. This concept was first applied to PET data by Farde et al. and by Cunning‐ ham et al. (Cunningham et al., 1991; Farde et al., 1989). Subsequent assumptions applied by Lammertsma and Hume reduced the number of parameters in the reference tissue model (thus named the "simplified reference tissue model" (SRTM)) (A. Lammertsma et al., 1996; A. A. Lammertsma et al., 1996). Finally, Gunn et al. devised an implementation of SRTM (using basis functions) that turned it into a linear model and thus almost as easy to use in practice as the

The spatial precision of PET is based on the concept of "electronic collimation". That is, radioactive decays lead to pairs of 511KeV photons being emitted in (nearly) opposite directions. When they are captured simultaneously by detectors in the PET scanner ring, a coincidence is recorded. Because of the co-linearity of the paths of the two photons, the direction from which they came is known and physical collimators (used to filter out photons approaching at various angles to the detector) are not needed. The sequence of coincidence detection is diagrammed in Figure 13. But there are certain common ways that electronic

analysis by the model or the model transform and guard against misinterpretation.

with increasing noise in the PET data (Slifstein et al., 2000). As with proper

, the same parameter that can be estimated directly

equivalent to the volume of distribution, Vt

Vt

to underestimate Vt

*1.2.11.4. Reference region methods*

Logan plot (Gunn et al., 1997).

*1.2.12. Physics basics*

If either pair of photons emanating from a single annihilation event is deflected from its path but still detected simultaneously with the non-deflected photon, then the positioning of the line of response (between the two detectors) will be incorrect.

#### *1.2.12.2. Randoms*

If one photon each from two separate annihilation events is lost to attenuation or scatter and the remaining photons (from different events) are detected simultaneously, the apparent coincidence event will be located improperly.

related to its energy and represents an unavoidable blurring of the image from ideality.

Figure 2. (a) Scatter: A collision of one of the daughter photons with scattering material disrupting the normal co-linearity of the photon paths but not their ultimate detection leads to a mis-placement of the line of response (grey start). (b) Randoms: if single photons are absorbed or otherwise not detected, unrelated pairs of photons can be detected as a coincidence leading to a mis-location of the originating event (grey star). (c) Dead Time: if too much radioactivity is in the object such that detectors cannot keep pace with decay events, then information is lost and radioactivity is no longer proportional to tracer concentration. (d) Positron Range: notice that the relocation along a line of response is never tied to the tracer molecule but rather the annihilation even though, in fact, we seek to locate tracer molecule itself. The positron range of a beta particle is inversely

> thus emitted from a location that is some distance from the location of the tracer molecule that we seek to localize. This distance, called the positron range, is an average distance that is dependent on the energy of the emitted beta (see Table 2). Positron range contributes uncer‐ tainty to the localization of the deposited radiotracer. Because it is not directional (equally likely for beta to travel in any direction), the positron range contributes a blur to the image.

> > **T ½ Photon Positron**

**(keV) (MeV) (mm in H2**

**0)**

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**Nuclide (min) Energy Energy Range**

**15O 2.1 511 1.70 1.5 13N 10.0 511 1.19 1.4 11C 20.3 511 0.96 1.1 18F 109 511 0.64 1.0**

Without attenuation correction, regions of an object near its outer surface would appear hotter than regions deep inside because photons emerging from within a body are more likely to be scattered or absorbed and not detected than those starting on or near the body's surface. Data

A lot of work has gone into improving attenuation correction for whole body images. Consider PET images of the chest. There are large translations of the chest from the beginning to the end of the normal respiratory cycle. Unlike CT imaging which is very fast, we cannot ask subjects to hold their breath for 10 minutes while we acquire an FDG-PET scan of their torso. In fact, the development of PET/CT (two scanners integrated together) was driven in part by the need to have multiple attenuation scans for different phases of the respiratory cycle. Kinahan and colleagues have shown – quite persuasively – that failure to align the transmission scan to data from separate 'gates' (images acquired in different phases of breathing, gated -or triggered by the respiratory signal) causes serious artifacts on images of the chest (Liu et al., 2009). These artifacts can be so serious that they can be mistaken for tumors (Liu et al., 2009) or as serious defects in cardiac perfusion (Alessio et al., 2007). Alessio et al. showed that perfusion was underestimated by 60% if the attenuation map was misaligned due to normal respiration

Generally, a skull does not expand and contract like a chest (due to respiration), so a single transmission scan taken at the beginning or end of a PET scan session is adequate for attenu‐

from a CT scan or model can correct non-uniform attenuation in the brain.

**Table 2.** Beta energies for common PET isotopes and their positron range

*1.2.13. Attenuation correction*

(Alessio et al., 2007).

*1.2.13.1. Attenuation correction artifacts*

**Figure 14.** (a) Scatter: A collision of one of the daughter photons with scattering material disrupting the normal colinearity of the photon paths but not their ultimate detection leads to a mis-placement of the line of response (grey start). (b) Randoms: if single photons are absorbed or otherwise not detected, unrelated pairs of photons can be de‐ tected as a coincidence leading to a mis-location of the originating event (grey star). (c) Dead Time: if too much radio‐ activity is in the object such that detectors cannot keep pace with decay events, then information is lost and radioactivity is no longer proportional to tracer concentration. (d) Positron Range: notice that the relocation along a line of response is never tied to the tracer molecule but rather the annihilation even though, in fact, we seek to locate tracer molecule itself. The positron range of a beta particle is inversely related to its energy and represents an unavoid‐ able blurring of the image from ideality.

#### *1.2.12.3. Deadtime*

If the amount of radioactivity in the object is so great that the rate of annihilation events exceeds the capacity of the detectors to record them, then annihilation events will be lost. This condition threatens the quantitative value of PET. We assume that detected coincidences are proportional to concentration of radiotracer molecules in the object. If the detectors are "maxed out", then this desired linear relationship no longer holds and the images are no longer quantitative.

Commercial PET scanners typically come with reconstruction software that corrects for scatter, randoms, and deadtime.

#### *1.2.12.4. Positron range*

When a beta emitter ejects a beta particle, the particle travels some finite distance before annihilating with an electron. The two 511 KeV photons that result from the annihilation are thus emitted from a location that is some distance from the location of the tracer molecule that we seek to localize. This distance, called the positron range, is an average distance that is dependent on the energy of the emitted beta (see Table 2). Positron range contributes uncer‐ tainty to the localization of the deposited radiotracer. Because it is not directional (equally likely for beta to travel in any direction), the positron range contributes a blur to the image.


**Table 2.** Beta energies for common PET isotopes and their positron range

#### *1.2.13. Attenuation correction*

*1.2.12.3. Deadtime*

able blurring of the image from ideality.

randoms, and deadtime.

*1.2.12.4. Positron range*

If the amount of radioactivity in the object is so great that the rate of annihilation events exceeds the capacity of the detectors to record them, then annihilation events will be lost. This condition threatens the quantitative value of PET. We assume that detected coincidences are proportional to concentration of radiotracer molecules in the object. If the detectors are "maxed out", then this desired linear relationship no longer holds and the images are no longer quantitative. Commercial PET scanners typically come with reconstruction software that corrects for scatter,

**Figure 14.** (a) Scatter: A collision of one of the daughter photons with scattering material disrupting the normal colinearity of the photon paths but not their ultimate detection leads to a mis-placement of the line of response (grey start). (b) Randoms: if single photons are absorbed or otherwise not detected, unrelated pairs of photons can be de‐ tected as a coincidence leading to a mis-location of the originating event (grey star). (c) Dead Time: if too much radio‐ activity is in the object such that detectors cannot keep pace with decay events, then information is lost and radioactivity is no longer proportional to tracer concentration. (d) Positron Range: notice that the relocation along a line of response is never tied to the tracer molecule but rather the annihilation even though, in fact, we seek to locate tracer molecule itself. The positron range of a beta particle is inversely related to its energy and represents an unavoid‐

Figure 2. (a) Scatter: A collision of one of the daughter photons with scattering material disrupting the normal co-linearity of the photon paths but not their ultimate detection leads to a mis-placement of the line of response (grey start). (b) Randoms: if single photons are absorbed or otherwise not detected, unrelated pairs of photons can be detected as a coincidence leading to a mis-location of the originating event (grey star). (c) Dead Time: if too much radioactivity is in the object such that detectors cannot keep pace with decay events, then information is lost and radioactivity is no longer proportional to tracer concentration. (d) Positron Range: notice that the relocation along a line of response is never tied to the tracer molecule but rather the annihilation even though, in fact, we seek to locate tracer molecule itself. The positron range of a beta particle is inversely

related to its energy and represents an unavoidable blurring of the image from ideality.

120 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

When a beta emitter ejects a beta particle, the particle travels some finite distance before annihilating with an electron. The two 511 KeV photons that result from the annihilation are Without attenuation correction, regions of an object near its outer surface would appear hotter than regions deep inside because photons emerging from within a body are more likely to be scattered or absorbed and not detected than those starting on or near the body's surface. Data from a CT scan or model can correct non-uniform attenuation in the brain.

#### *1.2.13.1. Attenuation correction artifacts*

A lot of work has gone into improving attenuation correction for whole body images. Consider PET images of the chest. There are large translations of the chest from the beginning to the end of the normal respiratory cycle. Unlike CT imaging which is very fast, we cannot ask subjects to hold their breath for 10 minutes while we acquire an FDG-PET scan of their torso. In fact, the development of PET/CT (two scanners integrated together) was driven in part by the need to have multiple attenuation scans for different phases of the respiratory cycle. Kinahan and colleagues have shown – quite persuasively – that failure to align the transmission scan to data from separate 'gates' (images acquired in different phases of breathing, gated -or triggered by the respiratory signal) causes serious artifacts on images of the chest (Liu et al., 2009). These artifacts can be so serious that they can be mistaken for tumors (Liu et al., 2009) or as serious defects in cardiac perfusion (Alessio et al., 2007). Alessio et al. showed that perfusion was underestimated by 60% if the attenuation map was misaligned due to normal respiration (Alessio et al., 2007).

Generally, a skull does not expand and contract like a chest (due to respiration), so a single transmission scan taken at the beginning or end of a PET scan session is adequate for attenu‐ ation correction of brain images. However, this may not be the case for certain types of studies of drug taking (reviewed below). In these cases, the act of taking a subject out of the scanner and then re-positioning them following drug administration could potentially lead to a mismatch between the transmission scan (taken at start of session) and the PET images acquired after the re-positioning.

urement. On the other hand, if effects of a drug or other stimulus are short-lived, it is generally

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We can learn from the work of Shultz and colleagues that dopamine neurons not only are activated in the presence of most drugs of abuse but that they are activated even before delivery of a drug, in response to cues and other stimuli that are "conditioned" or a conditioned stimulus (CS) (Schultz et al., 1997). Additionally, the dopamine neurons are sensitive to changes and errors in reward, which can be called prediction error. Dopamine neurons in the nonhuman primate brain fired after presentation of a reward that was not paired with a CS. When the reward and CS were paired, the dopamine neurons fired in response to the presen‐ tation of the CS and not to the subsequent presentation of the reward (Figure 15). That is, the dopamine neurons activated to the CS itself, because it was *predictive* of a reward (Doyon et al., 2005; Doyon et al., 2006). When the CS is presented and then the reward does not occur (negative prediction error), there is the typical activation to the CS, but then a dip in dopamine neuron activation when the expected reward does not occur. This study highlights how sensitive the dopamine system is to cues and expectation of reward, and care needs to be taken

Sex differences are evident in many psychiatric disorders, medical disorders, and also in the normal human brain (Cosgrove, Mazure, et al., 2007). There are sex differences in structure (e.g., total volume of the human brain and some subdivisions), in function (e.g., emotional processing as measured with fMRI), and in chemistry (as measured with PET). These differ‐ ences are important to measure, as they may clarify the clinical literature. It might be helpful, for instance, to know if the higher prevalence of depression in women vs. men can be explained by greater serotonergic dysfunction in women. Unfortunately, sex differences can also cloud the interpretation of data - if they are not carefully recognized and controlled. In one of our own studies, we were at first convinced of differences in nicotinic Acetylcholine receptor (nAChR) availability between healthy men and women when looking at a standard imaging outcome measure, volume of distribution (VT). On further examination, however, we also found significant differences in total parent of the radiotracer (total unmetabolized radiotracer in the blood) and in fp (the fraction of radiotracer free in the blood and not bound to plasma proteins). When these two factors were included in the analysis (by use of the normalized outcome, VT/fp), the apparent sex difference disappeared (Figure 16) (Cosgrove, Mitsis, et al.,

Care must be taken in managing any study with human subjects, especially patients who are not typical healthy controls but may be individuals suffering from psychiatric disorders. There is a balance that must be struck between designing a study to answer every possible experi‐ mental question and keeping the demands on the participants within reason. As described

possible to counter-balance the scans.

**2.4. Sex differences**

2007).

**2.5. Patient management**

**2.3. Expectation and reward-prediction error**

to design PET studies that take this sensitivity into account.

#### **2. PET Imaging of drug challenge studies**

Here, we discuss a series of parameters or conditions that make it challenging to use PET to image receptor changes and drug-induced changes in the human brain. These themes will be repeated throughout the remainder of the chapter as they arise in the discussions of the literature.

#### **2.1. Novelty**

Many different imaging groups measure drug-induced changes in dopamine release in the scanner or during the study day. However, dopamine is released in response not just to drugs of abuse but also to stress and to novelty. As the majority of subjects in these studies will not have been exposed to these experimental situations in their past, the experience will be novel to them. Suffice to say, it would not be helpful to be imaging novelty-induced dopamine release when one is trying to measure the effect of a drug. One way to avoid this common confound is to expose the subject to the study environment before their participation begins. In the case of our smoking-in-the-scanner studies, we have the subjects lie down in the scanner and simulate smoking at a session prior to a real scan session.

#### **2.2. Order effects**

Order effects can occur in any scientific study. In rodent studies of drug treatment when a placebo is compared to an active drug, the conditions are counter-balanced so that some rats receive the drug first and other rats receive the placebo first. This eliminates bias that could occur if the order in which drugs were given were to alter the results. In imaging studies, this can be more challenging. When using radiotracers with short half-lives (carbon-11 has a 20.3 minute half-life), it is possible and sometimes preferable to do baseline and drug-challenge scans on the same day. This can reduce the variation between scans that may occur if scans are conducted far apart in time. It also increases the likelihood that the subject will be able to easily complete the study (e.g., it is usually easier for a subject to commit to one day at the PET center rather than having to take off multiple days from their job or school). However, this also makes it more difficult to randomize the order of scans.

Consider scans of amphetamine-induced dopamine release. Amphetamine's effect on dopa‐ mine (and thus 11C-raclopride binding) is profound and long-lasting. It is not possible to do the drug-challenge scan on the same day before the baseline scan, since the effect of amphet‐ amine would persist for hours (possibly longer) and corrupt a subsequent "baseline" meas‐ urement. On the other hand, if effects of a drug or other stimulus are short-lived, it is generally possible to counter-balance the scans.

#### **2.3. Expectation and reward-prediction error**

We can learn from the work of Shultz and colleagues that dopamine neurons not only are activated in the presence of most drugs of abuse but that they are activated even before delivery of a drug, in response to cues and other stimuli that are "conditioned" or a conditioned stimulus (CS) (Schultz et al., 1997). Additionally, the dopamine neurons are sensitive to changes and errors in reward, which can be called prediction error. Dopamine neurons in the nonhuman primate brain fired after presentation of a reward that was not paired with a CS. When the reward and CS were paired, the dopamine neurons fired in response to the presen‐ tation of the CS and not to the subsequent presentation of the reward (Figure 15). That is, the dopamine neurons activated to the CS itself, because it was *predictive* of a reward (Doyon et al., 2005; Doyon et al., 2006). When the CS is presented and then the reward does not occur (negative prediction error), there is the typical activation to the CS, but then a dip in dopamine neuron activation when the expected reward does not occur. This study highlights how sensitive the dopamine system is to cues and expectation of reward, and care needs to be taken to design PET studies that take this sensitivity into account.

#### **2.4. Sex differences**

ation correction of brain images. However, this may not be the case for certain types of studies of drug taking (reviewed below). In these cases, the act of taking a subject out of the scanner and then re-positioning them following drug administration could potentially lead to a mismatch between the transmission scan (taken at start of session) and the PET images

122 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Here, we discuss a series of parameters or conditions that make it challenging to use PET to image receptor changes and drug-induced changes in the human brain. These themes will be repeated throughout the remainder of the chapter as they arise in the discussions of the

Many different imaging groups measure drug-induced changes in dopamine release in the scanner or during the study day. However, dopamine is released in response not just to drugs of abuse but also to stress and to novelty. As the majority of subjects in these studies will not have been exposed to these experimental situations in their past, the experience will be novel to them. Suffice to say, it would not be helpful to be imaging novelty-induced dopamine release when one is trying to measure the effect of a drug. One way to avoid this common confound is to expose the subject to the study environment before their participation begins. In the case of our smoking-in-the-scanner studies, we have the subjects lie down in the scanner and

Order effects can occur in any scientific study. In rodent studies of drug treatment when a placebo is compared to an active drug, the conditions are counter-balanced so that some rats receive the drug first and other rats receive the placebo first. This eliminates bias that could occur if the order in which drugs were given were to alter the results. In imaging studies, this can be more challenging. When using radiotracers with short half-lives (carbon-11 has a 20.3 minute half-life), it is possible and sometimes preferable to do baseline and drug-challenge scans on the same day. This can reduce the variation between scans that may occur if scans are conducted far apart in time. It also increases the likelihood that the subject will be able to easily complete the study (e.g., it is usually easier for a subject to commit to one day at the PET center rather than having to take off multiple days from their job or school). However, this also makes

Consider scans of amphetamine-induced dopamine release. Amphetamine's effect on dopa‐ mine (and thus 11C-raclopride binding) is profound and long-lasting. It is not possible to do the drug-challenge scan on the same day before the baseline scan, since the effect of amphet‐ amine would persist for hours (possibly longer) and corrupt a subsequent "baseline" meas‐

acquired after the re-positioning.

literature.

**2.1. Novelty**

**2.2. Order effects**

**2. PET Imaging of drug challenge studies**

simulate smoking at a session prior to a real scan session.

it more difficult to randomize the order of scans.

Sex differences are evident in many psychiatric disorders, medical disorders, and also in the normal human brain (Cosgrove, Mazure, et al., 2007). There are sex differences in structure (e.g., total volume of the human brain and some subdivisions), in function (e.g., emotional processing as measured with fMRI), and in chemistry (as measured with PET). These differ‐ ences are important to measure, as they may clarify the clinical literature. It might be helpful, for instance, to know if the higher prevalence of depression in women vs. men can be explained by greater serotonergic dysfunction in women. Unfortunately, sex differences can also cloud the interpretation of data - if they are not carefully recognized and controlled. In one of our own studies, we were at first convinced of differences in nicotinic Acetylcholine receptor (nAChR) availability between healthy men and women when looking at a standard imaging outcome measure, volume of distribution (VT). On further examination, however, we also found significant differences in total parent of the radiotracer (total unmetabolized radiotracer in the blood) and in fp (the fraction of radiotracer free in the blood and not bound to plasma proteins). When these two factors were included in the analysis (by use of the normalized outcome, VT/fp), the apparent sex difference disappeared (Figure 16) (Cosgrove, Mitsis, et al., 2007).

#### **2.5. Patient management**

Care must be taken in managing any study with human subjects, especially patients who are not typical healthy controls but may be individuals suffering from psychiatric disorders. There is a balance that must be struck between designing a study to answer every possible experi‐ mental question and keeping the demands on the participants within reason. As described

below, in many smoking studies we asked our subjects to quit smoking. If this is for a short time, the subjects can manage. When it is for longer, we must implement strategies to help them quit. When we asked *schizophrenic* smokers to quit smoking, we took the additional step

**Figure 16.** Mean parametric images illustrating 1231-5-IA-85380 activity in 10 men and 19 women in VT' (regional ac‐ tivity divided by total plasma parent between 6 and 8 h) and VT (regional activity divided by free plasma parent be‐ tween 6 and 8 h). Across brain regions, the main VT' component was significantly greater in women than in men, but the main VT component did not significantly differ between the sexes. This research was originally published in *JNM*. 123I-5-IA-85380 SPECT Imaging of Nicotinic Acetylcholine Receptor Availability in Nonsmokers: Effects of Sex and

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There is also a huge effort that goes into subject recruitment and screening before individuals are invited to participate in studies. Subjects undergo batteries of psychological tests, thorough medical evaluations including a physical exam, complete blood tests, drug toxicology tests, electrocardiograms to ensure cardiac health, and structural MRs to rule out any obvious brain abnormalities. There is also a lengthy informed consent process that must be conducted with all potential subjects. SPECT and PET studies are complex and may involve a variety of risks including administration of radiotracers, placement of arterial lines, and drug administration. Each facet of the study demands discussion between investigator and subject of the potential risks. All of our studies are carefully evaluated and approved by a local radiation safety and a human subjects investigation committee (the latter is typically referred to as an Institutional

of having them stay in an inpatient facility for the week so they could be monitored.

Menstrual Phase. JNM. 2007;48:1637. © by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Review Board or IRB).

**Figure 15.** (Top) Prior to conditioning, reward without prediction causes a positive error in reward prediction, which increases DA neuron firing. (Middle) Following conditioning, the CS predicts the reward, leading to no prediction er‐ ror. CS but not reward shows increase in DA neuron firing. (Bottom) After conditioning, CS but no reward causes a negative error in reward prediction. The CS causes increase in DA neuron firing, but the lack of reward causes a DE‐ CREASE in DA firing (Schultz et al., 1997).

**Figure 16.** Mean parametric images illustrating 1231-5-IA-85380 activity in 10 men and 19 women in VT' (regional ac‐ tivity divided by total plasma parent between 6 and 8 h) and VT (regional activity divided by free plasma parent be‐ tween 6 and 8 h). Across brain regions, the main VT' component was significantly greater in women than in men, but the main VT component did not significantly differ between the sexes. This research was originally published in *JNM*. 123I-5-IA-85380 SPECT Imaging of Nicotinic Acetylcholine Receptor Availability in Nonsmokers: Effects of Sex and Menstrual Phase. JNM. 2007;48:1637. © by the Society of Nuclear Medicine and Molecular Imaging, Inc.

below, in many smoking studies we asked our subjects to quit smoking. If this is for a short time, the subjects can manage. When it is for longer, we must implement strategies to help them quit. When we asked *schizophrenic* smokers to quit smoking, we took the additional step of having them stay in an inpatient facility for the week so they could be monitored.

There is also a huge effort that goes into subject recruitment and screening before individuals are invited to participate in studies. Subjects undergo batteries of psychological tests, thorough medical evaluations including a physical exam, complete blood tests, drug toxicology tests, electrocardiograms to ensure cardiac health, and structural MRs to rule out any obvious brain abnormalities. There is also a lengthy informed consent process that must be conducted with all potential subjects. SPECT and PET studies are complex and may involve a variety of risks including administration of radiotracers, placement of arterial lines, and drug administration. Each facet of the study demands discussion between investigator and subject of the potential risks. All of our studies are carefully evaluated and approved by a local radiation safety and a human subjects investigation committee (the latter is typically referred to as an Institutional Review Board or IRB).

**Figure 15.** (Top) Prior to conditioning, reward without prediction causes a positive error in reward prediction, which increases DA neuron firing. (Middle) Following conditioning, the CS predicts the reward, leading to no prediction er‐ ror. CS but not reward shows increase in DA neuron firing. (Bottom) After conditioning, CS but no reward causes a negative error in reward prediction. The CS causes increase in DA neuron firing, but the lack of reward causes a DE‐

124 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

CREASE in DA firing (Schultz et al., 1997).

**Brody (2004) Brody (2006) Barrett (2004) Scott (2007)**


• Not all subjects smoked the same number of

• Denicotinized cigarettes possibly causing negative prediction error? • Novel use of Logan graphical analysis to detect change in slope – not published elsewhere.

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11C]raclopride

EXACT HR+ (9 mm FWHM effective res.)

Beer flavor induced DA

49 healthy male drinkers

Non drug/alcohol dependent, except 4 meeting DSM-IV alcohol dependence;

release

12 FH+

• Some subjects reported aversive side effects which would alter hedonic ratings • Large range of ∆BP in smoking group (ventral striatum: -57% to 70%)

11C]raclopride [

scans) Intra-subject (3 scans) Intra-subject (2 scans)

Alcohol & alcohol cues

8 healthy subjects (5 male, 3 female)

Non drug or alcohol dependent; 2 FH+; 5 surpassed hazardous drinking threshold

EXACT HR+ (9 mm

FWHM)

cigarettes

• Only one attenuation scan (following the return to the scanner) was applied to both the pre and post break scans • Some subjects smoked favorite brand, some smoked study standard cigarette • Only 10 controls vs the 35 that

**Basal ganglia** 9.98%

smoked

11C]raclopride [

ECAT HR+ (4.8 x 4.8 x 5.6 mm FWHM)

Alcohol induced DA release

6 healthy male nonalcoholics

Nonalcoholic moderate drinkers

scans)

**Salonen (1997) Boileau (2003) Urban (2010) Yoder (2009) Oberlin (2013)**

ECAT EXACT HR+

Intra-subject (2

Sex differences in DA release post alcohol challenge

21 healthy men and women

Nonalcoholic, 10-15 drinks/wk

Bolus Bolus Bolus + infusion Bolus Bolus

**Tracer dose** 2.89 – 3.51 mCi 10 mCi ~ 7.8 mCi 14.1 ± 0.99 mCi 14.9 ± 0.10 mCi

11C]raclopride [

**Caudate / N Acc**

**Concerns**

• Left -30.5% • Right -25.9%

cue

response.

the effect?

11C]raclopride [

ECAT 931 (6.1 X 6.7

**Design** Intra-subject (2 scans)Intra-subject (2

Acute alcohol effect on DA release in the

Non drug or alcohol dependent

mm)

striatum

handed men

**Subjects** 7 healthy, right-

**Table 3.** Smoking Studies

**Tracer** [

**Injection protocol**

**Scanner (resolution)**

**Phenomenon to test**

**Subject characteristics** • Going outside for nosmoking group can still be a

• Not the first cigarette of the day, perhaps not a strong

• CT only done prior to break, not after return to scannerpossible attenuation issues • Figure 2: 2 subjects driving

• Table 2: baselines are not the same in groups (smoking group higher in all regions, although not significant)



**Table 3.** Smoking Studies

**Brody (2004) Brody (2006) Barrett (2004) Scott (2007)**

11C]raclopride [

10 mCi in 10 ml saline over 120 seconds

DA release due to smoking and hedonic

10 right-handed, nonmedicated smokers (5

Minimum of 2 DSM-IV criteria for nicotine dependence

2 scans, 1 control and 1 smoking; smoked in scanner prior to tracer

Cigarette 15 min pre [11C]raclopride; aimed to smoke 1 cig / 12 min,

delivery

max. 6 cigs

• Anterior 2.9% • Posterior -1.59%

FWHM)

response

male)

11C]carfentanil &

Siemens HR+ (~5.5 x 5.0

μ-opioid and DA D2 receptors and nicotine

6 right-handed, healthy male smokers; 6 ageand sex- matched controls

15-20 cig/day

Tracer infusion (randomized order), smoke 2 denicotinized cigarettes, 45 min, smoke 2 average nicotine cigarettes

90 min scans; smoked each cig for 5 min; smoke denicotinized cig at 2 & 12 min; smoke avg. nicotine cig at 40 &

50 min

Usual brand Denicotinized & average nicotine

11C]raclopride

10-15 mCi

mm FWHM)

[

11C]raclopride [

Slow bolus injection 185 MBq, followed by infusion 111 MBq/h

**Design** Inter-subject (1 scan) Inter-subject (1 scan) Intra-subject (2 scans) Intra-subject (2 scans)

Gene variants of DA pathway & smoking

45 tobacco-dependent

• 15-40 cigarettes per

2 hrs 3 hrs Minimum 12 hrs ~12 hrs

During the scan, subjects had a 10 min break OUTSIDE scanner; 35 smoked 1 cigarette; 10

1 hr scan, 10 min break in outdoor area (smoke/no smoke), 30

• No overlap with previous study group

**Analysis** Equilibrium Equilibrium SRTM Logan Ref

smokers

day

controls

min scan

**Self admin.** Yes, outside scanner Yes, outside scanner Yes, in scanner Yes, in scanner

Either usual brand or standard study cigarette

**Injection protocol** Bolus + infusion Bolus + infusion Bolus Bolus + infusion

126 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**Tracer** [

**Scanner**

**test**

**Subject**

**Protocol**

**Putamen**

**Time from last cigarette**

**Phenomenon to**

11C]raclopride [

followed by infusion 3mCi/hr

DA release in ventral striatum

During the scan, subjects had a 10 min break OUTSIDE scanner; 10 smoked 1 cigarette; 10

due to smoking

**Subjects** 20 nicotine dependent (5 female)

**characteristics** ≥15 cigarettes/day

controls

**Timing** 10 min break (smoking or not)

• Left -36.6% • Right -29.7%

**Cigarette type** Usual brand

50 min post scan initiation

**Ventral striatum** -4.3 ± 1.4% 3.12%

**(resolution)** ECAT 953 (5.6 mm FWHM) GE Advance NXi ECAT HR+ (42 mm

**Tracer dose** Slow bolus injection 5 mCi,


**Weerts (2008) Weerts (2011)**

11C]carfentanil & [11C]methyl naltrindole

18.87 (AD), 17.52 (HC)

male, 6 female) 25 alcohol dependent & 30 healthy control

1x daily for remainder of days; scan day 5 days inpatient protocol; scans on day 5

Avg. mCi: [11C]CFN: 19.30 (AD), 19.99 (HC); [11C]MeNTL:

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**δ**- and μ- opioid receptor availability at baseline

DSM-IV criteria for alcohol dependence; controls <8

2 PET scans in fixed order on the same day: [11C]MeNTL

drinks/wk women, <15 for men

followed by [11C]CFN

• AD = 1.826 ± 0.068 • HC = 1.438 ± 0.061

• AD = 1.272 ± 0.044 • HC = 0.962 ± 0.040

• AD = 1.395 ± 0.057 • HC = 1.113 ± 0.052

11C]carfentanil & [11C]methyl naltrindole [

11C]CAR (19.4 ± 2.1 mCi); [11C]MeNTI (19.2 ± 3.2

**Design** Inter-subject Inter-subject

Naltrexone occupancy of **δ**- and μ- opioid

60+ drinks/month, at least 5 drinks/occasion

N/A N/A

**3. Preclinical imaging of nicotinic acetylcholine receptors**

**3.1. Using nonhuman primate studies to aid in design of human studies**

One key way that nonhuman primate (NHP) studies can help us to inform our clinical studies is to work out basics of experimental design before we inject radiotracers into humans. For imaging studies we conducted with the goal of measuring nicotine-induced "upregulation"

**drink** 15 days prior to naltrexone treatment 5 days

**(resolution)** GE (2 x 2 x 4.25 mm) GE (5.5 x 6.1 mm FWHM)

**Injection protocol** Bolus Bolus

**Tracer** [

**Tracer dose** [

**Phenomenon to**

**Scanner**

**test**

**Subject characteristics**

**Time from last**

**Mode of alcohol administration**

**Ventral striatum**

**Putamen**

**Caudate**

mCi)

receptors

weekly

All ROIs:

**Table 5.** Weerts Studies of Alcohol Dependence

*3.1.1. Wash-out of nicotine in the brain*

**Subjects** 21 alcohol dependent & healthy control (15

**Protocol** 15 days abstinence, followed by 4 days naltrexone

**Timing** 19 days inpatient, 50 mg p.o. 2x on day 15, then

**Alcohol type** N/A N/A

[11C]CAR: 94.9 + 4.9% occupancy

[11C]MeNTI: 21.1 + 14.49% occupancy


**Table 4.** Alcohol Studies


**Table 5.** Weerts Studies of Alcohol Dependence

**Salonen (1997) Boileau (2003) Urban (2010) Yoder (2009) Oberlin (2013)**

3 scans: 1) neutral cues/no alcohol, 2) alcohol cues predict alcohol (but infusion delayed to post scan), 3) neutral cues with unexpected alcohol (infused during scan)

Neutral or alcohol cues start 2 min after bolus, maintained 15 min

Ringer's lactate with or without alcohol

• Cue condition w/ expected intoxication:

• Unexpected alcohol condition: 0.12 ± 0.08

• No conditioning to cues (ala Shultz et al 997). Study assumes that cues are salient.


2 scans,

N/A

2.5%

• R ventral striatum: • FH+: 11.7 ± 4.1% (SE) • FH (ambig.): 3.8 ±

• FH-: 2.7 ± 2.7%

• Only FH+ subjects showed effect of beer flavor on DA • Lack of resting baseline makes definitive

determination of effect direction difficult

counterbalanced: 1) preferred beer flavor, 2) Gatorade® flavor

Beer or Gatorade flavor sprays (~15 ml) start 2 min after bolus, maintained 15 min

~12 hrs 24 hours Since night before ~24 hours ~48 hours

128 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Scan order randomized

Drink for 5-10 min, 5 min prior to bolus + infusion

Self Self Self Investigator (IV infusion) N/A

Cranberry & soda with alcohol (~3 drinks worth) or trace alcohol

• Men: -12.1 ± 8% • Women: -6.2 ±

• Biased to find greater ΔBP: control condition (smelling alcohol but not receiving any) may have caused negative prediction error

8%

Drink BEFORE scan, not told content of drink until this time

Drink for 15 min, 30 min prior to bolus

Orange juice with or without alcohol

16.8 ± 16.3%

5.2 ± 17.5% Ventral 13.7 ± 17.5%

•Alcohol taken long time prior to

• Subjects drank large amount of alcohol – may have been aversive

scan.

**Time from last drink**

> • Drink BEFORE scan • 2 scans: 1) placebo, 2 hr break, 2) ethanol

> 3 separate drinks of placebo (75, 65, 55 min pre bolus), bolus, scan; 2 hr break; same schedule except using ethanol

Orange juice plus either tap water or

**N. acc.** 15.0 ± 15.9%

**Caudate** -0.10 ± 0.12 (P = 0.43)4.0 ± 16.4%

•Alcohol taken long time prior to scan. • Ethanol condition aversive to subjects? (1 subject too nauseous to have > 1

difference:

drink)

**Table 4.** Alcohol Studies

**Putamen** No significant

ethanol

**Protocol**

**Timing**

**Mode of alcohol administration**

**Alcohol type**

**Ventral striatum**

**Concerns**

#### **3. Preclinical imaging of nicotinic acetylcholine receptors**

#### **3.1. Using nonhuman primate studies to aid in design of human studies**

#### *3.1.1. Wash-out of nicotine in the brain*

One key way that nonhuman primate (NHP) studies can help us to inform our clinical studies is to work out basics of experimental design before we inject radiotracers into humans. For imaging studies we conducted with the goal of measuring nicotine-induced "upregulation" of nAChRs in humans, preceding NHP studies played a critical role in experimental design. There is a wealth of literature showing that nicotine and tobacco smoking upregulate nAChRs throughout the brain (Abreu-Villaca et al., 2003; Breese et al., 1997; Kassiou et al., 2001; Marks et al., 1992). Nicotine studies with various doses and routes of administration to rats, mice, and monkeys - as well as postmortem human studies – have all demonstrated that nicotine and tobacco smoke result in significantly more nAChRs throughout the brain compared to saline (animals) or to not smoking (humans). We now know that nicotine itself is responsible for this upregulation. Nicotine acts in the cell to help the receptor subunits assemble and then acts to chaperone the receptors to the cell membrane (Srinivasan et al., 2010). Our goal was to measure this upregulation in living human tobacco smokers (Staley et al., 2006). But first, we needed to work out the proper experimental timing.

binding potential (BP) and can be used as a measure of receptor availability. Because the bolus plus constant infusion paradigm in these studies reliably achieves equilibrium, the analysis is simplified, and there is no need for kinetic modeling. We refer to our outcome measure as receptor "availability", because we are not measuring all receptors. We cannot measure those receptors which, on average, are occupied by the endogenous neurotransmitter, acetylcholine, or by an exogenous ligand such as nicotine (hence the unexpected results at day 1 of with‐

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131

Based on the preclinical monkey studies, our group imaged β2-nAChRs in human tobacco smokers at 7-9 days of smoking abstinence ('withdrawal'). In these studies, the subjects were required to quit smoking and not use any medications or nicotine replacement strategies such as the patch, because all forms of nicotine would bind the β2-nAChR and block the radiotracer from binding. In order to help the subjects quit smoking, we used contingency management (Staley et al., 2006). Put simply, subjects met with a member of the research group one to two times per day and gave evidence that they had not smoked. 'Evidence' is established by carbon monoxide breath readings less than 11 parts per million (the level of a nonsmoker) and urine cotinine levels that are at the level of a nonsmoker or decreased from the day before. *Contin‐ gent* upon successful tests, subjects are paid small sums of money, and they can typically earn up to \$230 for abstaining for up to 9 days. In other words, we used *positive* reinforcement to help the subjects maintain abstinence for the duration of the study. In our first paper, we demonstrated that tobacco smokers at 7-9 days of abstinence have significantly higher β2 nAChR availability in the cortex, striatum, and cerebellum compared to a group of age- and sex-matched nonsmokers (Figure 17). This work confirmed that it is possible to measure the

There is also evidence from preclinical and postmortem studies that the β2-nAchRs do not stay upregulated but return to control levels. A postmortem study indicated that smokers who had quit smoking at least two months prior to their death had β2-nAChR levels similar to controls (Breese et al., 1997). However, smokers in the study had quit anywhere from 2 months to 30 years prior to their death, so the study did not shed light on the acute time course of receptor changes, e.g., during acute withdrawal in the first few months of abstinence. In our next study, we imaged β2-nAChR changes over the first few months of abstinence in tobacco smokers (Cosgrove et al., 2009). As shown in Figure 17, at one day of abstinence, nicotine is still present in the brain blocking the receptor, and there is no difference in β2-nAChR availability com‐ pared to the group of nonsmokers. At one week of abstinence, we again demonstrate there is higher β2-nAchR availability in smokers compared to nonsmokers. Then even at 2 and even 4 weeks of abstinence, receptor availability remains high and does not return to nonsmoker control levels until 6-12 weeks of abstinence. This study demonstrates that upregulation of β2 nAChRs is persistent, and these brain changes during acute abstinence are consistent with the clinical course of smoking cessation in which craving, relapse, and withdrawal symptoms occur over the first few months of abstinence, and relapse may occur months or years after the last cigarette. It is possible that nicotine replacement strategies are effective in some people,

upregulation phenomenon in human smokers, *in vivo* (Staley et al., 2006).

drawal) (Staley et al., 2006).

*3.1.3. Human nAChR scans in tobacco smokers*

Nicotine and our radiotracer, [123I]5-IA-85380, both bind to the same receptor in the brain – the nAChR containing the β2-subunit. When nicotine is present in the brain, it blocks the receptor and prevents the radiotracer from binding. Our preclinical experiment consisted of two monkeys drinking nicotine (diluted in water and sweetened with Tang to make it more appetizing) for 6 weeks. After 6 weeks, the monkeys were taken off nicotine. One monkey was scanned at 1 day into nicotine withdrawal, and the other was scanned at 2 days into nicotine withdrawal. Surprisingly, the data showed a *decrease* in radiotracer binding - suggesting that receptors may have been down-regulated! To probe further, we put the monkeys back on nicotine for two weeks and then scanned them both at 7 days of withdrawal. At that point, we saw the robust increase in radiotracer binding that was suggested by the preclinical literature. Taken together, the early data and the 7-day data suggested that nicotine remains in the brain during early withdrawal, and one must wait about 7 days for it to clear before measuring nicotine-induced upregulation. We also measured urine cotinine (the major metabolite of nicotine) levels in the monkeys over the 7 days of withdrawal. Cotinine progressively declined over the week, not completely clearing or reaching nonsmoker levels until 7 days of abstinence. The cotinine data nicely mirrored the brain closely. Once cotinine had cleared, we knew that we could proceed to measure nicotine-induced upregulation of nAChRs in the brain. In our human studies, discussed below, we routinely use low cotinine levels as an indicator that nicotine has cleared and that smokers can be scanned for nAChR.

#### *3.1.2. Simplifying the analysis of nAChR availability*

As described in the Introduction, a reference region simplifies the estimation of receptor availability. β2-nAChRs are widely distributed throughout the whole brain with highest density in the thalamus, moderate binding in the cerebellum, striatum and brainstem, and low binding throughout the cortex. There is no region in the brain completely devoid of β2 nAChRs, so there is no appropriate reference region. For many of the studies imaging β2 nAChRs with SPECT or PET described herein, a bolus plus constant infusion paradigm was used to achieve equilibrium between the brain and the blood (see Section 1.2.10.1). The outcome measure was volume of distribution, VT, which can be calculated as concentration of radioactivity in brain divided by concentration of radioactivity in blood, provided an equili‐ brium has been achieved between tissue and blood concentrations of tracer. VT is related to binding potential (BP) and can be used as a measure of receptor availability. Because the bolus plus constant infusion paradigm in these studies reliably achieves equilibrium, the analysis is simplified, and there is no need for kinetic modeling. We refer to our outcome measure as receptor "availability", because we are not measuring all receptors. We cannot measure those receptors which, on average, are occupied by the endogenous neurotransmitter, acetylcholine, or by an exogenous ligand such as nicotine (hence the unexpected results at day 1 of with‐ drawal) (Staley et al., 2006).

#### *3.1.3. Human nAChR scans in tobacco smokers*

of nAChRs in humans, preceding NHP studies played a critical role in experimental design. There is a wealth of literature showing that nicotine and tobacco smoking upregulate nAChRs throughout the brain (Abreu-Villaca et al., 2003; Breese et al., 1997; Kassiou et al., 2001; Marks et al., 1992). Nicotine studies with various doses and routes of administration to rats, mice, and monkeys - as well as postmortem human studies – have all demonstrated that nicotine and tobacco smoke result in significantly more nAChRs throughout the brain compared to saline (animals) or to not smoking (humans). We now know that nicotine itself is responsible for this upregulation. Nicotine acts in the cell to help the receptor subunits assemble and then acts to chaperone the receptors to the cell membrane (Srinivasan et al., 2010). Our goal was to measure this upregulation in living human tobacco smokers (Staley et al., 2006). But first, we needed to

130 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Nicotine and our radiotracer, [123I]5-IA-85380, both bind to the same receptor in the brain – the nAChR containing the β2-subunit. When nicotine is present in the brain, it blocks the receptor and prevents the radiotracer from binding. Our preclinical experiment consisted of two monkeys drinking nicotine (diluted in water and sweetened with Tang to make it more appetizing) for 6 weeks. After 6 weeks, the monkeys were taken off nicotine. One monkey was scanned at 1 day into nicotine withdrawal, and the other was scanned at 2 days into nicotine withdrawal. Surprisingly, the data showed a *decrease* in radiotracer binding - suggesting that receptors may have been down-regulated! To probe further, we put the monkeys back on nicotine for two weeks and then scanned them both at 7 days of withdrawal. At that point, we saw the robust increase in radiotracer binding that was suggested by the preclinical literature. Taken together, the early data and the 7-day data suggested that nicotine remains in the brain during early withdrawal, and one must wait about 7 days for it to clear before measuring nicotine-induced upregulation. We also measured urine cotinine (the major metabolite of nicotine) levels in the monkeys over the 7 days of withdrawal. Cotinine progressively declined over the week, not completely clearing or reaching nonsmoker levels until 7 days of abstinence. The cotinine data nicely mirrored the brain closely. Once cotinine had cleared, we knew that we could proceed to measure nicotine-induced upregulation of nAChRs in the brain. In our human studies, discussed below, we routinely use low cotinine levels as an indicator that

As described in the Introduction, a reference region simplifies the estimation of receptor availability. β2-nAChRs are widely distributed throughout the whole brain with highest density in the thalamus, moderate binding in the cerebellum, striatum and brainstem, and low binding throughout the cortex. There is no region in the brain completely devoid of β2 nAChRs, so there is no appropriate reference region. For many of the studies imaging β2 nAChRs with SPECT or PET described herein, a bolus plus constant infusion paradigm was used to achieve equilibrium between the brain and the blood (see Section 1.2.10.1). The outcome measure was volume of distribution, VT, which can be calculated as concentration of radioactivity in brain divided by concentration of radioactivity in blood, provided an equili‐ brium has been achieved between tissue and blood concentrations of tracer. VT is related to

work out the proper experimental timing.

nicotine has cleared and that smokers can be scanned for nAChR.

*3.1.2. Simplifying the analysis of nAChR availability*

Based on the preclinical monkey studies, our group imaged β2-nAChRs in human tobacco smokers at 7-9 days of smoking abstinence ('withdrawal'). In these studies, the subjects were required to quit smoking and not use any medications or nicotine replacement strategies such as the patch, because all forms of nicotine would bind the β2-nAChR and block the radiotracer from binding. In order to help the subjects quit smoking, we used contingency management (Staley et al., 2006). Put simply, subjects met with a member of the research group one to two times per day and gave evidence that they had not smoked. 'Evidence' is established by carbon monoxide breath readings less than 11 parts per million (the level of a nonsmoker) and urine cotinine levels that are at the level of a nonsmoker or decreased from the day before. *Contin‐ gent* upon successful tests, subjects are paid small sums of money, and they can typically earn up to \$230 for abstaining for up to 9 days. In other words, we used *positive* reinforcement to help the subjects maintain abstinence for the duration of the study. In our first paper, we demonstrated that tobacco smokers at 7-9 days of abstinence have significantly higher β2 nAChR availability in the cortex, striatum, and cerebellum compared to a group of age- and sex-matched nonsmokers (Figure 17). This work confirmed that it is possible to measure the upregulation phenomenon in human smokers, *in vivo* (Staley et al., 2006).

There is also evidence from preclinical and postmortem studies that the β2-nAchRs do not stay upregulated but return to control levels. A postmortem study indicated that smokers who had quit smoking at least two months prior to their death had β2-nAChR levels similar to controls (Breese et al., 1997). However, smokers in the study had quit anywhere from 2 months to 30 years prior to their death, so the study did not shed light on the acute time course of receptor changes, e.g., during acute withdrawal in the first few months of abstinence. In our next study, we imaged β2-nAChR changes over the first few months of abstinence in tobacco smokers (Cosgrove et al., 2009). As shown in Figure 17, at one day of abstinence, nicotine is still present in the brain blocking the receptor, and there is no difference in β2-nAChR availability com‐ pared to the group of nonsmokers. At one week of abstinence, we again demonstrate there is higher β2-nAchR availability in smokers compared to nonsmokers. Then even at 2 and even 4 weeks of abstinence, receptor availability remains high and does not return to nonsmoker control levels until 6-12 weeks of abstinence. This study demonstrates that upregulation of β2 nAChRs is persistent, and these brain changes during acute abstinence are consistent with the clinical course of smoking cessation in which craving, relapse, and withdrawal symptoms occur over the first few months of abstinence, and relapse may occur months or years after the last cigarette. It is possible that nicotine replacement strategies are effective in some people,

a biological mechanism that may underlie some of the behaviors. Specifically, men smoke for the nicotine in cigarettes, they are more responsive to nicotine replacement therapy as a cessation strategy, and men's brains are responsive to nicotine, exhibiting upregulation of β2 nAChRs. Women smoke for affect regulation and for reasons other than the nicotine, they do not respond as well to nicotine replacement strategies, and their brains do not respond to nicotine by increasing β2-nAChRs. The bottom line is that novel treatment strategies targeting other receptor systems need to be evaluated to more effectively help women quit smoking. All the current strategies act at the β2-nAChR, and, of course, all nicotine replacement strategies act at that site. Varenicline (Chantix) is a partial agonist at the β2-nAChR, and even bupropion

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In addition to receptor changes, imaging studies have informed our knowledge about what happens in the brain after someone smokes a cigarette. For example, after one puff of a cigarette, approximately 50% of all β2-nAChRs in the brain are occupied by nicotine. After smoking one or two cigarettes, the receptors are saturated, so 100% of β2-nAchRs are occupied by nicotine (Brody, Mandelkern, London, et al., 2006). We know that nicotine doesn't clear the brain right away, so if all the receptors are occupied by nicotine, why do people keep smoking throughout the day? This brings up some important points about tobacco smoking. People smoke for many different reasons, and nicotine reinforcement is only one component. The reinforcement or pleasure derived from nicotine, like many other drugs of abuse, is necessary in driving the initial phases of drug seeking behavior. But as the addiction progresses, many people continue to smoke in order to avoid withdrawal symptoms and due to the many conditioned cues that have become ingrained, which are a part of the repetitive nature of tobacco smoking. Additionally, there are 4000 chemical compounds that are produced when a cigarette burns; all of these compounds are in tobacco smoke and are inhaled. Thus, while nicotine is the primary addictive component of tobacco smoke, there are additional com‐

Other imaging studies have demonstrated that even smoking a denicotinized cigarette, which supposedly has very low nicotine content, still occupies up to 20% of β2-nAChRs in the brain (Brody et al., 2008). This is similar to the level of occupancy produced by second hand smoke. Dr. Arthur Brody and colleagues at UCLA performed an elegant study examining the effect of second hand smoke on β2-nAChRs by having subjects sit in a car (the window was down a few inches) with a person smoking, and they reported up to 20% of β2-nAChRs were occupied by nicotine in the individual who was just sitting in the car, not smoking (Brody et al., 2012). Interestingly, a recent law in California prohibits smoking in the car with children

Before PET made possible indirect measurement of dopamine release, *in vivo*, the only way to measure dopamine levels in a living brain was via microdialysis. Microdialysis is used primarily in rodents. During a surgery, a probe is placed through the skull into the region of interest, e.g., the nucleus accumbens. After recovery, dopamine levels can be sampled in the awake, behaving animal typically in response to a drug or a stimulus. Di Chiara and Imperato

pounds such as MAO-A and MAO-B inhibitors that likely play a role.

(Zyban) is a nicotinic antagonist.

under the age of 18.

*3.1.4. Use of microdialysis measurements*

**Figure 17.** β2-nAChR availability (VT/fP) is shown in individual nonsmokers (open diamonds) and tobacco smokers (fil‐ led circles) at 1 day, 1 week, 2 weeks, 4 weeks, and 6-12 weeks of abstinence in the thalamus, striatum (average of caudate and putamen), cortex (average of cortical regions including parietal, frontal, anterior cingulate, temporoinsu‐ lar, and occipital cortex), and cerebellum. The line in each scatter plot represents the mean value of those subjects. \* indicates significant difference from control nonsmokers after Bonferroni's correction using two-sample t-tests. † indi‐ cates significant difference from 1 week abstinent smokers after Bonferroni's correction using planned post-hoc be‐ tween-group comparisons subsequent to the analysis of repeated measures mixed-effects regression models including the overall effect of abstinent smoker group.

because they continue to activate the pool of upregulated receptors and help "wean" the receptors off of nicotine as the dose of nicotine is decreased over time.

There is a large literature demonstrating sex differences in tobacco smoking behaviors. In general, men tend to smoke for the nicotine reinforcement, or nicotine *per se* in the cigarette, whereas women tend to smoke more for the sensory cues associated with smoking, as well as affect and stress regulation (Perkins, 2009; Perkins et al., 1999; Perkins et al., 2008). There are also two preclinical studies showing that male rats and mice exposed to nicotine exhibited greater nAChR upregulation than female rats and mice exposed to nicotine (Koylu et al., 1997; Mochizuki et al., 1998). We wanted to determine if there were sex differences in β2 nAChR availability between men and women smokers compared to nonsmokers. Consistent with the preclinical literature, we found that male smokers had significantly higher β2 nAChRs compared to male nonsmokers (between 9 and 17%) but that women smokers had similar β2-nAChR availability compared to women nonsmokers (between 1 and 3 %) (Cosgrove et al., 2012). This was a striking finding given all the studies demonstrating that nicotine and tobacco smoking upregulate β2-nAChRs throughout the brain. Considering known behavioral sex differences in tobacco smoking, these findings make sense and provide a biological mechanism that may underlie some of the behaviors. Specifically, men smoke for the nicotine in cigarettes, they are more responsive to nicotine replacement therapy as a cessation strategy, and men's brains are responsive to nicotine, exhibiting upregulation of β2 nAChRs. Women smoke for affect regulation and for reasons other than the nicotine, they do not respond as well to nicotine replacement strategies, and their brains do not respond to nicotine by increasing β2-nAChRs. The bottom line is that novel treatment strategies targeting other receptor systems need to be evaluated to more effectively help women quit smoking. All the current strategies act at the β2-nAChR, and, of course, all nicotine replacement strategies act at that site. Varenicline (Chantix) is a partial agonist at the β2-nAChR, and even bupropion (Zyban) is a nicotinic antagonist.

In addition to receptor changes, imaging studies have informed our knowledge about what happens in the brain after someone smokes a cigarette. For example, after one puff of a cigarette, approximately 50% of all β2-nAChRs in the brain are occupied by nicotine. After smoking one or two cigarettes, the receptors are saturated, so 100% of β2-nAchRs are occupied by nicotine (Brody, Mandelkern, London, et al., 2006). We know that nicotine doesn't clear the brain right away, so if all the receptors are occupied by nicotine, why do people keep smoking throughout the day? This brings up some important points about tobacco smoking. People smoke for many different reasons, and nicotine reinforcement is only one component. The reinforcement or pleasure derived from nicotine, like many other drugs of abuse, is necessary in driving the initial phases of drug seeking behavior. But as the addiction progresses, many people continue to smoke in order to avoid withdrawal symptoms and due to the many conditioned cues that have become ingrained, which are a part of the repetitive nature of tobacco smoking. Additionally, there are 4000 chemical compounds that are produced when a cigarette burns; all of these compounds are in tobacco smoke and are inhaled. Thus, while nicotine is the primary addictive component of tobacco smoke, there are additional com‐ pounds such as MAO-A and MAO-B inhibitors that likely play a role.

Other imaging studies have demonstrated that even smoking a denicotinized cigarette, which supposedly has very low nicotine content, still occupies up to 20% of β2-nAChRs in the brain (Brody et al., 2008). This is similar to the level of occupancy produced by second hand smoke. Dr. Arthur Brody and colleagues at UCLA performed an elegant study examining the effect of second hand smoke on β2-nAChRs by having subjects sit in a car (the window was down a few inches) with a person smoking, and they reported up to 20% of β2-nAChRs were occupied by nicotine in the individual who was just sitting in the car, not smoking (Brody et al., 2012). Interestingly, a recent law in California prohibits smoking in the car with children under the age of 18.

#### *3.1.4. Use of microdialysis measurements*

because they continue to activate the pool of upregulated receptors and help "wean" the

**Figure 17.** β2-nAChR availability (VT/fP) is shown in individual nonsmokers (open diamonds) and tobacco smokers (fil‐ led circles) at 1 day, 1 week, 2 weeks, 4 weeks, and 6-12 weeks of abstinence in the thalamus, striatum (average of caudate and putamen), cortex (average of cortical regions including parietal, frontal, anterior cingulate, temporoinsu‐ lar, and occipital cortex), and cerebellum. The line in each scatter plot represents the mean value of those subjects. \* indicates significant difference from control nonsmokers after Bonferroni's correction using two-sample t-tests. † indi‐ cates significant difference from 1 week abstinent smokers after Bonferroni's correction using planned post-hoc be‐ tween-group comparisons subsequent to the analysis of repeated measures mixed-effects regression models

132 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

There is a large literature demonstrating sex differences in tobacco smoking behaviors. In general, men tend to smoke for the nicotine reinforcement, or nicotine *per se* in the cigarette, whereas women tend to smoke more for the sensory cues associated with smoking, as well as affect and stress regulation (Perkins, 2009; Perkins et al., 1999; Perkins et al., 2008). There are also two preclinical studies showing that male rats and mice exposed to nicotine exhibited greater nAChR upregulation than female rats and mice exposed to nicotine (Koylu et al., 1997; Mochizuki et al., 1998). We wanted to determine if there were sex differences in β2 nAChR availability between men and women smokers compared to nonsmokers. Consistent with the preclinical literature, we found that male smokers had significantly higher β2 nAChRs compared to male nonsmokers (between 9 and 17%) but that women smokers had similar β2-nAChR availability compared to women nonsmokers (between 1 and 3 %) (Cosgrove et al., 2012). This was a striking finding given all the studies demonstrating that nicotine and tobacco smoking upregulate β2-nAChRs throughout the brain. Considering known behavioral sex differences in tobacco smoking, these findings make sense and provide

receptors off of nicotine as the dose of nicotine is decreased over time.

including the overall effect of abstinent smoker group.

Before PET made possible indirect measurement of dopamine release, *in vivo*, the only way to measure dopamine levels in a living brain was via microdialysis. Microdialysis is used primarily in rodents. During a surgery, a probe is placed through the skull into the region of interest, e.g., the nucleus accumbens. After recovery, dopamine levels can be sampled in the awake, behaving animal typically in response to a drug or a stimulus. Di Chiara and Imperato performed the seminal study showing that drugs abused by humans release DA in the nucleus accumbens of the rat brain using this technique (Di Chiara et al., 1988). Amphetamine (1.0 mg/ kg, SC) raised DA levels over 1000% from baseline, whereas ethanol (1.0 g/kg, IP) and nicotine (0.6 mg/kg, SC) raised DA levels to 200% over baseline levels. This illustrates how powerful DA release can be when it is directly stimulated as with amphetamine, which is both a direct DA releaser and DA reuptake inhibitor. Put into context, a similar dose of amphetamine given to a monkey or a human in a PET experiment, which is an indirect measure of change in DA, would result in a 15-30% change in BP as measured with [11C]raclopride or another D2/3 ligand.

to [ ] smoking" (n=5) were broken out from the complete cohort, the authors found a 21%

There were some notable innovations in the Barrett et al. study as well as some reasons for caution in interpretation. On the plus side, the smokers smoked in the scanner - thus any DA release detected could be attributed to the entire smoking behavior – something not possible with animals but highly relevant for medications development. The smokers were asked to smoke their own brand - another way of assuring that behavior in the scanner approximated subjects' smoking behavior. The authors recognized that, strictly speaking, the comparison of a baseline BP to one measured under a drug condition requires that a new level of DA be *constant* and maintained throughout the latter scan (we will return to this later). Because smoking probably causes only brief elevation of DA (Di Chiara et al., 1988), the investigators required repeated cigarettes – starting 15 minutes prior to tracer - in an attempt to achieve a constant elevated DA during the drug scan. Subjects were also asked to rate the "hedonic value" of their experience and their craving every 15 minutes during the smoking session. The investigators probed their data in creative and innovative ways. Across subjects (i.e., one data point per subject), they looked for correlations at every voxel in the striatum between change

thresholded at p < 0.05. They found a relationship between craving and ΔBP in dorsal and

On the downside, the extreme variability in BP values suggests the possibility of motion artifact and/or resolution limitations that would preferentially mar the measurement of activity in very small regions, such as the ventral striatum. Subject motion during smoking is unavoidable and could easily explain the wild variability between subjects. The protocol of six cigarettes in an hour is overly demanding and was very likely aversive to some of the subjects. Four subjects were unable to complete the prescribed regimen of cigarettes. Needless to say, imaging of aversive stimuli was not the intended aim of the study and would have constituted a confound. In our own experience, smokers move their heads when they smoke, and they are none too

Scott et al. took an entirely different approach to both the experimental paradigm and the analysis (Scott et al., 2007). Their experiment contained only one scan per subject, and yet it involved a bolus of tracer rather than the more standard single-scan design with a bolus plus constant infusion. Two denicotinized cigarettes were smoked in succession early in the scan at 2 and 12 minutes post injection, and two regular nicotine-containing cigarettes were smoked at minutes 40 and 50 post-tracer injection. By virtue of this design, the investigators are asking a slightly different question than in other studies, namely, what role does the nicotine in cigarettes play in DA release? The cohort was extremely small (n=6 right-handed male smokers). There was also a nonsmoker group scanned at baseline and compared to smokers under denicotinized cigarettes. The value of this comparison is questionable at best. For smokers, there was no statistically significant decrease in raclopride binding from denicoti‐ nized to nicotine-containing cigarettes in any subregion of the striatum across the six smokers. In many of the regions, the reported standard deviations of the BP estimates were quite high, and the authors would have been well served simply to scan more subjects. As in the case of

happy to be asked to smoke a second cigarette *even 25 minutes after* a first.

values were then converted to t-scores, which were

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decrease in BP from baseline (i.e., increase in DA) in the caudate.

in BP from baseline and craving. R2

posterior areas of striatum.

#### **4. Imaging dopamine release in response to nicotine, tobacco smoking, and alcohol in humans**

As we have recounted, one natural strategy for using PET and SPECT to study smoking has been to image nAChR directly with a nicotinic ligand. Such studies have led to greater understanding of nicotine's persistence in the brain, sex differences in nAChR levels, and the role of nicotine in up-regulation of those levels. There is a second way that molecular imaging techniques can shed light on the neurochemistry of smoking (and drinking). As suggested by microdialysis studies, the mesolimibic DA system is important as the common pathway through which all drugs of abuse – and other rewarding inputs - are processed. With PET and a dopaminergic ligand that competes with DA for binding to a receptor, one could, in theory, image the effects of reward processing in the brain in response to an addictive substance or behavior. In practice, such studies have proved quite challenging and the reader must take care to consider the strengths and weaknesses of each attempt. One challenge is that neither alcohol nor nicotine causes large elevations of DA levels above baseline – probably only a doubling or tripling of baseline. And, the effects of both drugs are short-lived. A third challenge is that self-administration of the substances by a volunteer (smoking a cigarette, drinking a beer) is not easily performed within the confines of the PET scanner.

#### **4.1. Nicotine and tobacco smoking**

Most of the PET studies of the dopaminergic response to cigarette smoking and/or nicotine are summarized in Table 2. Barrett et al. did one of the earliest studies of smoking with PET; the first study with smokers actually smoking in the scanner (Barrett et al., 2004). The tracer was [11C]raclopride, a D2 antagonist that has been found to be sensitive to changes in endogenous DA (Dewey et al., 1993; Seeman et al., 1989). Barrett et al. used the paired-bolus design described in Figure 10 (left). But instead of administering the stimulus (i.e., smoking a cigarette) prior to the tracer, subjects were asked to smoke repeatedly (six times!) while in the scanner for the one-hour smoking scan. No task was performed during the baseline scan. The authors did not find any significant change in raclopride binding potential from baseline in any areas of the striatum when they looked at the results of all 10 smokers together. The study was, however, characterized by very large variation in ΔBP across smokers (range in ventral striatum: [-57%, 70%]). When the subjects who experienced "mood elevating effects in response to [ ] smoking" (n=5) were broken out from the complete cohort, the authors found a 21% decrease in BP from baseline (i.e., increase in DA) in the caudate.

performed the seminal study showing that drugs abused by humans release DA in the nucleus accumbens of the rat brain using this technique (Di Chiara et al., 1988). Amphetamine (1.0 mg/ kg, SC) raised DA levels over 1000% from baseline, whereas ethanol (1.0 g/kg, IP) and nicotine (0.6 mg/kg, SC) raised DA levels to 200% over baseline levels. This illustrates how powerful DA release can be when it is directly stimulated as with amphetamine, which is both a direct DA releaser and DA reuptake inhibitor. Put into context, a similar dose of amphetamine given to a monkey or a human in a PET experiment, which is an indirect measure of change in DA, would result in a 15-30% change in BP as measured with [11C]raclopride or another D2/3 ligand.

134 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**4. Imaging dopamine release in response to nicotine, tobacco smoking, and**

As we have recounted, one natural strategy for using PET and SPECT to study smoking has been to image nAChR directly with a nicotinic ligand. Such studies have led to greater understanding of nicotine's persistence in the brain, sex differences in nAChR levels, and the role of nicotine in up-regulation of those levels. There is a second way that molecular imaging techniques can shed light on the neurochemistry of smoking (and drinking). As suggested by microdialysis studies, the mesolimibic DA system is important as the common pathway through which all drugs of abuse – and other rewarding inputs - are processed. With PET and a dopaminergic ligand that competes with DA for binding to a receptor, one could, in theory, image the effects of reward processing in the brain in response to an addictive substance or behavior. In practice, such studies have proved quite challenging and the reader must take care to consider the strengths and weaknesses of each attempt. One challenge is that neither alcohol nor nicotine causes large elevations of DA levels above baseline – probably only a doubling or tripling of baseline. And, the effects of both drugs are short-lived. A third challenge is that self-administration of the substances by a volunteer (smoking a cigarette, drinking a

Most of the PET studies of the dopaminergic response to cigarette smoking and/or nicotine are summarized in Table 2. Barrett et al. did one of the earliest studies of smoking with PET; the first study with smokers actually smoking in the scanner (Barrett et al., 2004). The tracer was [11C]raclopride, a D2 antagonist that has been found to be sensitive to changes in endogenous DA (Dewey et al., 1993; Seeman et al., 1989). Barrett et al. used the paired-bolus design described in Figure 10 (left). But instead of administering the stimulus (i.e., smoking a cigarette) prior to the tracer, subjects were asked to smoke repeatedly (six times!) while in the scanner for the one-hour smoking scan. No task was performed during the baseline scan. The authors did not find any significant change in raclopride binding potential from baseline in any areas of the striatum when they looked at the results of all 10 smokers together. The study was, however, characterized by very large variation in ΔBP across smokers (range in ventral striatum: [-57%, 70%]). When the subjects who experienced "mood elevating effects in response

beer) is not easily performed within the confines of the PET scanner.

**alcohol in humans**

**4.1. Nicotine and tobacco smoking**

There were some notable innovations in the Barrett et al. study as well as some reasons for caution in interpretation. On the plus side, the smokers smoked in the scanner - thus any DA release detected could be attributed to the entire smoking behavior – something not possible with animals but highly relevant for medications development. The smokers were asked to smoke their own brand - another way of assuring that behavior in the scanner approximated subjects' smoking behavior. The authors recognized that, strictly speaking, the comparison of a baseline BP to one measured under a drug condition requires that a new level of DA be *constant* and maintained throughout the latter scan (we will return to this later). Because smoking probably causes only brief elevation of DA (Di Chiara et al., 1988), the investigators required repeated cigarettes – starting 15 minutes prior to tracer - in an attempt to achieve a constant elevated DA during the drug scan. Subjects were also asked to rate the "hedonic value" of their experience and their craving every 15 minutes during the smoking session. The investigators probed their data in creative and innovative ways. Across subjects (i.e., one data point per subject), they looked for correlations at every voxel in the striatum between change in BP from baseline and craving. R2 values were then converted to t-scores, which were thresholded at p < 0.05. They found a relationship between craving and ΔBP in dorsal and posterior areas of striatum.

On the downside, the extreme variability in BP values suggests the possibility of motion artifact and/or resolution limitations that would preferentially mar the measurement of activity in very small regions, such as the ventral striatum. Subject motion during smoking is unavoidable and could easily explain the wild variability between subjects. The protocol of six cigarettes in an hour is overly demanding and was very likely aversive to some of the subjects. Four subjects were unable to complete the prescribed regimen of cigarettes. Needless to say, imaging of aversive stimuli was not the intended aim of the study and would have constituted a confound. In our own experience, smokers move their heads when they smoke, and they are none too happy to be asked to smoke a second cigarette *even 25 minutes after* a first.

Scott et al. took an entirely different approach to both the experimental paradigm and the analysis (Scott et al., 2007). Their experiment contained only one scan per subject, and yet it involved a bolus of tracer rather than the more standard single-scan design with a bolus plus constant infusion. Two denicotinized cigarettes were smoked in succession early in the scan at 2 and 12 minutes post injection, and two regular nicotine-containing cigarettes were smoked at minutes 40 and 50 post-tracer injection. By virtue of this design, the investigators are asking a slightly different question than in other studies, namely, what role does the nicotine in cigarettes play in DA release? The cohort was extremely small (n=6 right-handed male smokers). There was also a nonsmoker group scanned at baseline and compared to smokers under denicotinized cigarettes. The value of this comparison is questionable at best. For smokers, there was no statistically significant decrease in raclopride binding from denicoti‐ nized to nicotine-containing cigarettes in any subregion of the striatum across the six smokers. In many of the regions, the reported standard deviations of the BP estimates were quite high, and the authors would have been well served simply to scan more subjects. As in the case of Barrett et al., the investigators looked for and found a correlation between change in BP and a behavioral (or demographic) measure (Barrett et al., 2004). In the case of Scott, the significant relationship discovered was between greater decrease in BP (so presumed greater increase in DA) from denicotinized to nicotine-containing vs. degree of dependence on nicotine (as measured by the Fagerström score) (Scott et al., 2007). In contrast to Barrett, the Scott finding was in the ventral striatum. To their credit, Scott et al. corrected their statistical tests for multiple comparisons.

minutes. The data were analyzed with an equilibrium analysis (see Figure 10) comparing BP at baseline (period just preceding smoke break) with BP after smoking (period just following smoke break). The major finding was a large (but variable) amount of DA release in ventral caudate, ventral putamen, which was statistically greater in the smokers who smoked than in those who did not. In a follow up study, the same group used the same protocol two years later, and while they replicated the direction of the findings, the effect size was quite a bit smaller (Brody, Mandelkern, Olmstead, et al., 2006). In both studies, they found that the greater the reduction of craving for a cigarette from pre- to post-break, the greater the reduction in raclopride binding potential in the ventral caudate-nucleus accumbens region. The 2006 paper introduces genetic variation and its possible role in smoking. Subjects were typed for mutations in the genes that encode for dopamine receptors, dopamine transporter or catechol-Omethyltransferase (an enzyme that breaks down catecholamines) proteins. Their results suggest that differences in amount of DA released (change in tracer binding) could be related to mutation status, and this in turn helps to explain some of the inherent variability in the BP

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There are some real strengths to the UCLA design. There is also some reason for concern. First, there is no smoking in the scanner, so there is no reason to worry about smoking-related head motion. On the other hand, repositioning the smokers without taking a new transmission scan could lead to reconstruction artifacts in the post-smoke-break images (transmission and emission data not aligned). In the investigators' defense, they also scanned a control group of smokers who take their break but do not smoke. There is no reason to expect that emissiontransmission misalignment would be more likely in the smokers than in the controls, so it is probably not the driver of their results. The second – and more subtle – reason for caution in interpreting the Brody et al. data requires that we first compare their findings in 2004 with

In the equilibrium analysis, investigators must choose a data window at the end of the prebreak data to use for a baseline measurement. In both cases, the last 10 minutes of data – from 40-50 minutes – was used. In the 2004 paper, they used 10 minutes of data post-break; in 2006, they used 30 minutes. The investigators correctly asserted in their second paper that a key assumption of their analysis is that DA must remain elevated throughout the 30 minutes postbreak (this is why Barrett et al. asked subjects to smoke multiple cigarettes) (Brody, Mandel‐ kern, Olmstead, et al., 2006). Unfortunately, this assumption must be incorrect. If it were true, then both studies should have found exactly the same change in BP. But in 2006, they found less of an effect: only 8.4% change as compared to ~30% change in 2004. The explanations offered by the authors were not persuasive: motion-induced DA release in controls, reposi‐ tioning error. None of these were any more likely to have occurred in the smoking group as opposed to the control. Rather, the discrepancy between 2006 and 2004 is entirely consistent with a change in the analysis procedure that, in essence, washed out the effect by averaging over a period that contains smoking induced DA release and a subsequent period in which DA levels are returning (have returned) to baseline. In other words, they used too wide a data window in their second paper. To be sure, we recently did a simulation study of smokinginduced DA release as measured by raclopride-PET and its dependence on the selection of the

numbers in both studies.

those in 2006.

As with the Barrett paper, the Scott paper involved smoking in the scanner, so motion artifacts must be considered a real possibility. Although the paper mentions motion-correction, the state of the art in 2007 would have allowed correction of misalignment between reconstructed frames acquired over minutes. Nothing could have been done about motion of the subject that happened within the duration of a single time-frame (we note that with the advent of list-mode data, high frequency motion monitoring, and interative image reconstruction algorithms, within-frame motion correction is now possible). The investigators were able to carry out a bolus design rather than a bolus plus constant infusion because of their innovative analysis technique. They employed the Logan plot, mentioned above, to linearize the time-activity curves. Their claim was that they could find two separate slopes (two measures of the ratio of Vt in the striatum to Vt in the reference region) within the plot. The first slope would reflect binding of tracer in the early phase of the scan (corresponding to the denicotinized cigarettes), and the second slope would reflect the later phase (nicotine-containing). In our hands, this technique is extremely sensitive to the choice of data-range for each slope (Sullivan et al., 2013), and we have not seen any papers in the literature subsequent to Scott either using or evaluating said technique.

Two other studies should be mentioned. Like Scott et al., they were both focused on measuring the nicotine (as opposed to cigarette) effect on DA release in humans. Montgomery et al. administered nicotine to subjects via nasal spray (Montgomery et al., 2007); Takahashi et al. had subjects chew nicotine gum (Takahashi et al., 2008). Neither group found any significant change in BP with nicotine in any individual striatal region. Takahashi showed a significant decline in [11C]raclopride binding with nicotine administration in the striatum overall. The former seems like the best design; the latter would seem to be susceptible to motion from chewing - despite express instructions to subjects to chew with their lower jaw only. Following up on Scott et al. and Barrett et al., both newer studies looked for correlations between ΔBP and behavior. Montgomery found a correlation between "happiness" and ΔBP in associative striatum. In apparent agreement with Scott et al., Takahashi found voxels in the "ventral putamen" that showed a significant correlation between raclopride ΔBP and Fagerström score.

Finally, the most oft-cited smoking studies were performed by Brody et al. This is the same group at UCLA that did the study of second-hand smoke's ability to occupy nAChR, described above. Brody and colleagues employed yet a different experimental paradigm. Smokers were scanned with an [11C]raclopride bolus plus constant infusion for 90 minutes (Brody et al., 2004). From 50 to 60 minutes, the subjects went outside for a "smoke break". All the while, they were being infused with [11C]raclopride. Ten smokers smoked a cigarette while outside; ten did not. All returned and were repositioned in the scanner and scanned for a further 30 minutes. The data were analyzed with an equilibrium analysis (see Figure 10) comparing BP at baseline (period just preceding smoke break) with BP after smoking (period just following smoke break). The major finding was a large (but variable) amount of DA release in ventral caudate, ventral putamen, which was statistically greater in the smokers who smoked than in those who did not. In a follow up study, the same group used the same protocol two years later, and while they replicated the direction of the findings, the effect size was quite a bit smaller (Brody, Mandelkern, Olmstead, et al., 2006). In both studies, they found that the greater the reduction of craving for a cigarette from pre- to post-break, the greater the reduction in raclopride binding potential in the ventral caudate-nucleus accumbens region. The 2006 paper introduces genetic variation and its possible role in smoking. Subjects were typed for mutations in the genes that encode for dopamine receptors, dopamine transporter or catechol-Omethyltransferase (an enzyme that breaks down catecholamines) proteins. Their results suggest that differences in amount of DA released (change in tracer binding) could be related to mutation status, and this in turn helps to explain some of the inherent variability in the BP numbers in both studies.

Barrett et al., the investigators looked for and found a correlation between change in BP and a behavioral (or demographic) measure (Barrett et al., 2004). In the case of Scott, the significant relationship discovered was between greater decrease in BP (so presumed greater increase in DA) from denicotinized to nicotine-containing vs. degree of dependence on nicotine (as measured by the Fagerström score) (Scott et al., 2007). In contrast to Barrett, the Scott finding was in the ventral striatum. To their credit, Scott et al. corrected their statistical tests for

136 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

As with the Barrett paper, the Scott paper involved smoking in the scanner, so motion artifacts must be considered a real possibility. Although the paper mentions motion-correction, the state of the art in 2007 would have allowed correction of misalignment between reconstructed frames acquired over minutes. Nothing could have been done about motion of the subject that happened within the duration of a single time-frame (we note that with the advent of list-mode data, high frequency motion monitoring, and interative image reconstruction algorithms, within-frame motion correction is now possible). The investigators were able to carry out a bolus design rather than a bolus plus constant infusion because of their innovative analysis technique. They employed the Logan plot, mentioned above, to linearize the time-activity curves. Their claim was that they could find two separate slopes (two measures of the ratio of Vt in the striatum to Vt in the reference region) within the plot. The first slope would reflect binding of tracer in the early phase of the scan (corresponding to the denicotinized cigarettes), and the second slope would reflect the later phase (nicotine-containing). In our hands, this technique is extremely sensitive to the choice of data-range for each slope (Sullivan et al., 2013), and we have not seen any papers in the literature subsequent to Scott either using or

Two other studies should be mentioned. Like Scott et al., they were both focused on measuring the nicotine (as opposed to cigarette) effect on DA release in humans. Montgomery et al. administered nicotine to subjects via nasal spray (Montgomery et al., 2007); Takahashi et al. had subjects chew nicotine gum (Takahashi et al., 2008). Neither group found any significant change in BP with nicotine in any individual striatal region. Takahashi showed a significant decline in [11C]raclopride binding with nicotine administration in the striatum overall. The former seems like the best design; the latter would seem to be susceptible to motion from chewing - despite express instructions to subjects to chew with their lower jaw only. Following up on Scott et al. and Barrett et al., both newer studies looked for correlations between ΔBP and behavior. Montgomery found a correlation between "happiness" and ΔBP in associative striatum. In apparent agreement with Scott et al., Takahashi found voxels in the "ventral putamen" that showed a significant correlation between raclopride ΔBP and Fagerström score.

Finally, the most oft-cited smoking studies were performed by Brody et al. This is the same group at UCLA that did the study of second-hand smoke's ability to occupy nAChR, described above. Brody and colleagues employed yet a different experimental paradigm. Smokers were scanned with an [11C]raclopride bolus plus constant infusion for 90 minutes (Brody et al., 2004). From 50 to 60 minutes, the subjects went outside for a "smoke break". All the while, they were being infused with [11C]raclopride. Ten smokers smoked a cigarette while outside; ten did not. All returned and were repositioned in the scanner and scanned for a further 30

multiple comparisons.

evaluating said technique.

There are some real strengths to the UCLA design. There is also some reason for concern. First, there is no smoking in the scanner, so there is no reason to worry about smoking-related head motion. On the other hand, repositioning the smokers without taking a new transmission scan could lead to reconstruction artifacts in the post-smoke-break images (transmission and emission data not aligned). In the investigators' defense, they also scanned a control group of smokers who take their break but do not smoke. There is no reason to expect that emissiontransmission misalignment would be more likely in the smokers than in the controls, so it is probably not the driver of their results. The second – and more subtle – reason for caution in interpreting the Brody et al. data requires that we first compare their findings in 2004 with those in 2006.

In the equilibrium analysis, investigators must choose a data window at the end of the prebreak data to use for a baseline measurement. In both cases, the last 10 minutes of data – from 40-50 minutes – was used. In the 2004 paper, they used 10 minutes of data post-break; in 2006, they used 30 minutes. The investigators correctly asserted in their second paper that a key assumption of their analysis is that DA must remain elevated throughout the 30 minutes postbreak (this is why Barrett et al. asked subjects to smoke multiple cigarettes) (Brody, Mandel‐ kern, Olmstead, et al., 2006). Unfortunately, this assumption must be incorrect. If it were true, then both studies should have found exactly the same change in BP. But in 2006, they found less of an effect: only 8.4% change as compared to ~30% change in 2004. The explanations offered by the authors were not persuasive: motion-induced DA release in controls, reposi‐ tioning error. None of these were any more likely to have occurred in the smoking group as opposed to the control. Rather, the discrepancy between 2006 and 2004 is entirely consistent with a change in the analysis procedure that, in essence, washed out the effect by averaging over a period that contains smoking induced DA release and a subsequent period in which DA levels are returning (have returned) to baseline. In other words, they used too wide a data window in their second paper. To be sure, we recently did a simulation study of smokinginduced DA release as measured by raclopride-PET and its dependence on the selection of the data window (Sullivan et al., 2013). While the simulations confirmed what we suspected, they raise an even more troubling concern about all previous attempts to image smoking effects on DA. That is, how can we compare across studies if people use even slightly different analysis techniques? How can we compare across groups if the time-period of response of dopamine to any drug stimulus is short and different between groups? And more generally, how can we apply standard models that assume "that DA concentration will remain elevated" to PET data when the assumption is not true? We address this important technical question in the final section of the chapter following our discussion of drinking studies.

not aversion. In the Salonen study, the alcohol was taken a lengthy time before the tracer (from 75 – 55 min before). Although the authors were careful to document considerably elevated blood alcohol at both the beginning and end of the (1 hour) scanning period, one should not confuse elevated alcohol level with elevated DA. In fact, it is likely that DA responds early to drinking – possibly to the cues or the rapid rise in brain alcohol and then returns to baseline more quickly than alcohol level itself. In fact, it appears that Oberlin et al. have demonstrated that DA responds to the cues for alcohol rather than the alcohol itself (Oberlin et al., 2013). Consider nicotine. Nicotine remains in the brain for days, but the discrepancy (discussed above) between the 2004 and 2006 Brody papers (and microdialysis data) certainly suggests that nicotine-induced DA elevation is rather brief (Brody, Mandelkern, Olmstead, et al., 2006; Brody et al., 2004). All three alcohol-drinking designs suffer from lack of a baseline condition. Juice alone is used as a placebo, but if the taste of juice is rewarding then perhaps DA was released in this condition. There is always a difficulty interpreting any study that contains only placebo and drug. The difference could be due to changes during drug or changes during placebo. Consider the Urban design (Urban et al., 2010). In order to control expectation across conditions, the juice-only glass was rimmed with alcohol. But what if the smell of alcohol actually set up an expectation of alcohol? In that case, the juice condition was scanned while the subject experienced disappointment over not receiving the reward. This is called "reward prediction error" and in monkeys, it has been shown to be the cause of decreased dopaminergic firing rates as discussed previously (Schultz et al., 1997). Is there any evidence that reward prediction error leads to alteration of dopamine levels in humans? We must consider one last

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Yoder et al. took a different experimental approach to the study of alcohol-induced DA release (Yoder et al., 2009). Wary of the variability in alcohol absorption among people, they chose to administer the alcohol intravenously. The technique, called the "alcohol clamp", was devel‐ oped by O'Connor et al. and is based on pharmacokinetic modeling of a variable-rate infusion of alcohol to maintain a constant blood alcohol level in each subject based on their height, weight, and gender (O'Connor et al., 1998). Second, expectation was controlled through visual and olfactory cues, which preceded – and predicted - the delivery of alcohol or saline, IV. There were three conditions scanned in three separate sessions – each scanned with a bolus of [11C]raclopride. The conditions were as follows: #1: neutral cues signaling IV saline, #2: alcohol cues signifying alcohol, and #3: neutral cues coupled with unexpected alcohol. This design was constructed to decouple expectation from consumption of alcohol. The alcohol in condition #2 was delivered *after* the data acquisition was complete, so the condition can be thought of "expectation of alcohol but no alcohol consumption" whereas condition #3 – thanks to a little trickery – can be thought of as "alcohol consumption with no expectation of alcohol". Subjects' answers to questionnaires during the scan confirmed that expectations were controlled as intended. The results were quite provocative: in left ventral striatum, BP of "alcohol con‐ sumption without expectation" went down relative to condition #1. That is, this comparison signifies increase in DA. But, in the contralateral ventral striatum, BP of "expectation of alcohol without alcohol consumption" was *higher* than condition #1. The authors explained this combination of results as follows. Expectation of reward without reward is equivalent to negative reward prediction error. Reward without expectation of reward is positive prediction

raclopride-PET paper to answer that question.

#### **4.2. Imaging dopamine release in response to alcohol**

If smoking is difficult for subjects lying in the scanner, it is nevertheless possible. Drinking while lying in the scanner is not. Researchers have taken two approaches to this problem. The most obvious study design for measuring alcohol-induced DA release is for the subject to drink an alcoholic beverage shortly before being scanned and compare raclopride BP in this condition to either baseline or placebo. This is the approach that was employed by the three studies to look at drinking-induced DA release, per se. Salonen et al., Boileau et al., and Urban et al. each used two-scan designs (Boileau et al., 2003; Salonen, 1997; Urban et al., 2010). In each case, the conditions were either juice or alcohol plus juice. The conditions were randomized in the latter two studies. The Boileau and Salonen studies each consisted of 6 subjects; Urban scanned 11 men and 10 women. The subjects were social drinkers. The dose of alcohol was approximately 1 ml/kg in Boileau and Urban but about 1.3 ml/kg in Salonen. The blood alcohol levels in each study were consistent and generally reflected the respective doses (measure‐ ments were not taken at the same times, so direct comparisons are difficult). In any case, Urban claims that the dose in her study was equivalent to 3 standard drinks. Where the paradigms begin to diverge is the relative timing of alcohol and tracer. The alcohol was taken either 60 minutes, 30 minutes or 5 minutes prior to tracer injection in Salonen, Boileau and Urban, respectively. A second difference was that in the Urban study, the rim of the juice glass for the juice-only condition was coated with alcohol to minimize any difference in the subjects' expectation between conditions. A final noteworthy difference is that the Urban study used paired bolus plus infusion scans, whereas the other studies both used the more standard paired-bolus design.

The Salonen and Urban studies were essentially negative. No statistically significant decrease in [11C]raclopride binding was found in any region of the striatum in the alcohol condition compared to juice. Boileau reported decreases of 14-15% in raclopride BP in regions that they termed Nucleus Accumbens and Ventral Putamen. Despite finding no statistically significant drop in BP in any individual region, Urban reported a sex difference in decrease in BP in all regions taken together (see paper for further explanation). What is clear from these studies is that imaging effects of oral alcohol on DA in the striatum is not easy and that we may be at the limits of detectability for raclopride-PET. Perhaps if we scrutinize elements of each design, we may find something worth tweaking. In all studies, the amount of alcohol was quite large. Some subjects – even social drinkers – may have found it aversive. Each study reported at least one subject who dropped out. As with the smoking studies, the idea is to image drug-taking, not aversion. In the Salonen study, the alcohol was taken a lengthy time before the tracer (from 75 – 55 min before). Although the authors were careful to document considerably elevated blood alcohol at both the beginning and end of the (1 hour) scanning period, one should not confuse elevated alcohol level with elevated DA. In fact, it is likely that DA responds early to drinking – possibly to the cues or the rapid rise in brain alcohol and then returns to baseline more quickly than alcohol level itself. In fact, it appears that Oberlin et al. have demonstrated that DA responds to the cues for alcohol rather than the alcohol itself (Oberlin et al., 2013). Consider nicotine. Nicotine remains in the brain for days, but the discrepancy (discussed above) between the 2004 and 2006 Brody papers (and microdialysis data) certainly suggests that nicotine-induced DA elevation is rather brief (Brody, Mandelkern, Olmstead, et al., 2006; Brody et al., 2004). All three alcohol-drinking designs suffer from lack of a baseline condition. Juice alone is used as a placebo, but if the taste of juice is rewarding then perhaps DA was released in this condition. There is always a difficulty interpreting any study that contains only placebo and drug. The difference could be due to changes during drug or changes during placebo. Consider the Urban design (Urban et al., 2010). In order to control expectation across conditions, the juice-only glass was rimmed with alcohol. But what if the smell of alcohol actually set up an expectation of alcohol? In that case, the juice condition was scanned while the subject experienced disappointment over not receiving the reward. This is called "reward prediction error" and in monkeys, it has been shown to be the cause of decreased dopaminergic firing rates as discussed previously (Schultz et al., 1997). Is there any evidence that reward prediction error leads to alteration of dopamine levels in humans? We must consider one last raclopride-PET paper to answer that question.

data window (Sullivan et al., 2013). While the simulations confirmed what we suspected, they raise an even more troubling concern about all previous attempts to image smoking effects on DA. That is, how can we compare across studies if people use even slightly different analysis techniques? How can we compare across groups if the time-period of response of dopamine to any drug stimulus is short and different between groups? And more generally, how can we apply standard models that assume "that DA concentration will remain elevated" to PET data when the assumption is not true? We address this important technical question in the final

138 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

If smoking is difficult for subjects lying in the scanner, it is nevertheless possible. Drinking while lying in the scanner is not. Researchers have taken two approaches to this problem. The most obvious study design for measuring alcohol-induced DA release is for the subject to drink an alcoholic beverage shortly before being scanned and compare raclopride BP in this condition to either baseline or placebo. This is the approach that was employed by the three studies to look at drinking-induced DA release, per se. Salonen et al., Boileau et al., and Urban et al. each used two-scan designs (Boileau et al., 2003; Salonen, 1997; Urban et al., 2010). In each case, the conditions were either juice or alcohol plus juice. The conditions were randomized in the latter two studies. The Boileau and Salonen studies each consisted of 6 subjects; Urban scanned 11 men and 10 women. The subjects were social drinkers. The dose of alcohol was approximately 1 ml/kg in Boileau and Urban but about 1.3 ml/kg in Salonen. The blood alcohol levels in each study were consistent and generally reflected the respective doses (measure‐ ments were not taken at the same times, so direct comparisons are difficult). In any case, Urban claims that the dose in her study was equivalent to 3 standard drinks. Where the paradigms begin to diverge is the relative timing of alcohol and tracer. The alcohol was taken either 60 minutes, 30 minutes or 5 minutes prior to tracer injection in Salonen, Boileau and Urban, respectively. A second difference was that in the Urban study, the rim of the juice glass for the juice-only condition was coated with alcohol to minimize any difference in the subjects' expectation between conditions. A final noteworthy difference is that the Urban study used paired bolus plus infusion scans, whereas the other studies both used the more standard

The Salonen and Urban studies were essentially negative. No statistically significant decrease in [11C]raclopride binding was found in any region of the striatum in the alcohol condition compared to juice. Boileau reported decreases of 14-15% in raclopride BP in regions that they termed Nucleus Accumbens and Ventral Putamen. Despite finding no statistically significant drop in BP in any individual region, Urban reported a sex difference in decrease in BP in all regions taken together (see paper for further explanation). What is clear from these studies is that imaging effects of oral alcohol on DA in the striatum is not easy and that we may be at the limits of detectability for raclopride-PET. Perhaps if we scrutinize elements of each design, we may find something worth tweaking. In all studies, the amount of alcohol was quite large. Some subjects – even social drinkers – may have found it aversive. Each study reported at least one subject who dropped out. As with the smoking studies, the idea is to image drug-taking,

section of the chapter following our discussion of drinking studies.

**4.2. Imaging dopamine release in response to alcohol**

paired-bolus design.

Yoder et al. took a different experimental approach to the study of alcohol-induced DA release (Yoder et al., 2009). Wary of the variability in alcohol absorption among people, they chose to administer the alcohol intravenously. The technique, called the "alcohol clamp", was devel‐ oped by O'Connor et al. and is based on pharmacokinetic modeling of a variable-rate infusion of alcohol to maintain a constant blood alcohol level in each subject based on their height, weight, and gender (O'Connor et al., 1998). Second, expectation was controlled through visual and olfactory cues, which preceded – and predicted - the delivery of alcohol or saline, IV. There were three conditions scanned in three separate sessions – each scanned with a bolus of [11C]raclopride. The conditions were as follows: #1: neutral cues signaling IV saline, #2: alcohol cues signifying alcohol, and #3: neutral cues coupled with unexpected alcohol. This design was constructed to decouple expectation from consumption of alcohol. The alcohol in condition #2 was delivered *after* the data acquisition was complete, so the condition can be thought of "expectation of alcohol but no alcohol consumption" whereas condition #3 – thanks to a little trickery – can be thought of as "alcohol consumption with no expectation of alcohol". Subjects' answers to questionnaires during the scan confirmed that expectations were controlled as intended. The results were quite provocative: in left ventral striatum, BP of "alcohol con‐ sumption without expectation" went down relative to condition #1. That is, this comparison signifies increase in DA. But, in the contralateral ventral striatum, BP of "expectation of alcohol without alcohol consumption" was *higher* than condition #1. The authors explained this combination of results as follows. Expectation of reward without reward is equivalent to negative reward prediction error. Reward without expectation of reward is positive prediction error. The caveat in this interpretation is that the subjects (heavy drinkers) must be considered to have been "conditioned" by their drinking history to respond with appropriate expectation to the cues. Accepting the author's interpretation, this paper highlights the importance of controlling expectation in the study of drugs of abuse. To return to the Urban design (Urban et al., 2010), if the initial smell of alcohol on the rim of the juice-only glass was a cue for imminent alcohol reward, then we might expect DA to decrease during this scan. When compared to a second condition (i.e., alcohol drink), any apparent increase in DA with alcohol could, in fact, be the result of decrease in the juice-only condition.

models. As such, they asked subjects to smoke cigarettes every 15 minutes repeatedly (Barrett et al., 2004), or they were careful to assay blood alcohol level at start and end of scan and show that it was the same (Salonen, 1997). Nevertheless, no one can assure that DA remains constant throughout the PET scan. In fact, in the case of drinking or smoking, it almost certainly does not. Recall that if smoking-induced DA levels were constant in the Brody experiments, there would have been no discrepancy between the analyses of the 2004 and 2006 data sets (Brody, Mandelkern, Olmstead, et al., 2006; Brody et al., 2004). If alcohol drinking-induced DA levels were constant, there would be no discrepancy between the Boileau finding of change in BP and the Salonen negative result even though one gave alcohol 30 minutes before the scan, and the other gave it an hour before (Boileau et al., 2003; Salonen, 1997). What's more, if the timing of DA release is different across groups then – as Yoder et al. showed – the mere difference in timing could result in differences in BP and thus be interpreted as differences in magnitude of

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We have been working over the last ten years to develop kinetic models of tracer uptake and binding in the presence of transient neurotransmitter release (Constantinescu et al., 2007; Constantinescu et al., 2008; E. Morris et al., 1995; E. D. Morris et al., 2010; E. D. Morris et al., 2013; E. D. Morris et al., 2005; M. D. Normandin et al., 2008; M. D. Normandin et al., 2012; Sullivan et al., 2013). The earlier versions of the model were based on the idea that dopamine (or any other transmitter that competes with tracer) can exist in the free or bound states in addition to the various states of the tracer (refer back to Figures 4 and 11). New species in the model required new "boxes" which, in turn, meant more differential equations (E. Morris et al., 1995; E. D. Morris et al., 2005). The model described the data well (E. Morris et al., 1995; E. D. Morris et al., 2008) but was cumbersome to use. Subsequent work by Constantinescu and by Normandin et al. developed linearized versions of the model that could be solved quickly (and hence at each voxel) while retaining time-varying terms to describe brief changes in neurotransmitter level (M. Normandin et al., 2009). Validation of these models was carried out either (a) by configuring experiments in which a predictable pattern of DA change could be provoked in human subjects (Constantinescu et al., 2008; E. D. Morris et al., 2010), or (b) a comparison could be made between model predictions and microdialysis measurements made in the (rat) subjects at the same time as PET (E. D. Morris et al., 2008; M. D. Normandin et al., 2008; M. D. Normandin et al., 2012). Most recently, we have adapted the Normandin approach to the voxel level so that we can estimate time-courses of dopamine at each voxel in the striatum where "activation" is occurring due to drug stimulus. A critical step in such a process is some sort of statistical test to determine that change in DA really occurred at that location (voxel) in question. Finally, the outcome is a collection of curves in time at many voxels in the brain. The visualization technique that we have invented to display such 4-dimensional results is a "dopamine movie", wherein dopamine level is color-coded and the color in the activated voxels is displayed overlaid on MRI as a series of frames. The methods are described and demonstrated in a new publication in the Journal of Visualized Experiments (E. D. Morris et al., 2013). Validation and testing of these new dopamine movies is ongoing. We hope that they are a more sensitive probe of DA changes in the brain as a consequence of smoking and drinking behavior and that the increased sensitivity of the method will allow us to tease out

patterns of response that are either "addictive" or "non-addictive".

DA release (Yoder et al., 2004).

Finally, in this section we should point out that there are many other important lines of investigation of alcohol abuse using PET other than examining DA release. Some have looked at receptor number (Martinez et al., 2005; Volkow et al., 1996), and others have looked at change in BP due to drugs for treatment of alcohol. We highlight two studies, briefly. Both studies are by Weerts et al. (Weerts et al., 2008; Weerts et al., 2011). Both studies looked at the Mu opioid receptor (MOR) and the Delta opioid receptor (DOR) thanks to the use of two selective tracers, [11C]carfentail and [11C]methyl-naltrindol. Collectively, the two studies looked at baseline level of MOR and DOR, as well as occupancy of the receptors due to four days of treatment with naltrexone, a non-selective opioid receptor antagonist that is prescribed for alcohol abuse. Baseline receptors in alcoholics were compared to healthy controls, and occupancy of naltrex‐ one was measured in alcoholics only. The main findings were that clinical doses of naltrexone occupied 95% of MOR but only 75% of DOR. Second, MOR and DOR levels in high binding regions of the brain were higher in alcoholics than in controls (MOR was significant; DOR was not). The first finding suggests that any variability on efficacy of naltrexone is probably not mediated by binding to MOR, since all alcoholics were uniformly blocked. The second finding suggests that years of drinking may lead to upregulation of MOR and DOR, which is more like nAChR (Cosgrove et al., 2009) and less like D2 (Martinez et al., 2005).

#### **5. Limitations of conventional modeling methods — Need for new ones**

As previously stated, the "conventional" kinetic models used in all of the work discussed to this point treat BP as a surrogate for number of receptors (because BP = Bmax/KD where Bmax is available, unoccupied receptors and KD is the affinity of the tracer for the receptor.) Depending on the circumstance, investigators treat ∆BP as change in available receptors due to altered number of receptors or altered level of endogenous transmitter occupying sites. Whether the analysis method is a full fitting of dynamic data or fitting of linearized data via the Logan plot or measurement of equilibrium levels, the underlying kinetic model is the same. In all cases, however, a fundamental assumption of the model(s) is that BP is not changing over the course of the study, because BP is a constant. Mathematically, we say that the kinetic model is timeinvariant in parameters. The inadequacies of all three common methods of analysis in the face of transient DA release have been thoroughly studied in the recent paper by Sullivan et al (Sullivan et al., 2013). The reader is directed to that paper for more details. Any violation of the time-invariant parameters assumption could lead to misinterpretation of data. Many if not all of the investigators whose work is profiled herein appreciate this limitation of the kinetic models. As such, they asked subjects to smoke cigarettes every 15 minutes repeatedly (Barrett et al., 2004), or they were careful to assay blood alcohol level at start and end of scan and show that it was the same (Salonen, 1997). Nevertheless, no one can assure that DA remains constant throughout the PET scan. In fact, in the case of drinking or smoking, it almost certainly does not. Recall that if smoking-induced DA levels were constant in the Brody experiments, there would have been no discrepancy between the analyses of the 2004 and 2006 data sets (Brody, Mandelkern, Olmstead, et al., 2006; Brody et al., 2004). If alcohol drinking-induced DA levels were constant, there would be no discrepancy between the Boileau finding of change in BP and the Salonen negative result even though one gave alcohol 30 minutes before the scan, and the other gave it an hour before (Boileau et al., 2003; Salonen, 1997). What's more, if the timing of DA release is different across groups then – as Yoder et al. showed – the mere difference in timing could result in differences in BP and thus be interpreted as differences in magnitude of DA release (Yoder et al., 2004).

error. The caveat in this interpretation is that the subjects (heavy drinkers) must be considered to have been "conditioned" by their drinking history to respond with appropriate expectation to the cues. Accepting the author's interpretation, this paper highlights the importance of controlling expectation in the study of drugs of abuse. To return to the Urban design (Urban et al., 2010), if the initial smell of alcohol on the rim of the juice-only glass was a cue for imminent alcohol reward, then we might expect DA to decrease during this scan. When compared to a second condition (i.e., alcohol drink), any apparent increase in DA with alcohol

140 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Finally, in this section we should point out that there are many other important lines of investigation of alcohol abuse using PET other than examining DA release. Some have looked at receptor number (Martinez et al., 2005; Volkow et al., 1996), and others have looked at change in BP due to drugs for treatment of alcohol. We highlight two studies, briefly. Both studies are by Weerts et al. (Weerts et al., 2008; Weerts et al., 2011). Both studies looked at the Mu opioid receptor (MOR) and the Delta opioid receptor (DOR) thanks to the use of two selective tracers, [11C]carfentail and [11C]methyl-naltrindol. Collectively, the two studies looked at baseline level of MOR and DOR, as well as occupancy of the receptors due to four days of treatment with naltrexone, a non-selective opioid receptor antagonist that is prescribed for alcohol abuse. Baseline receptors in alcoholics were compared to healthy controls, and occupancy of naltrex‐ one was measured in alcoholics only. The main findings were that clinical doses of naltrexone occupied 95% of MOR but only 75% of DOR. Second, MOR and DOR levels in high binding regions of the brain were higher in alcoholics than in controls (MOR was significant; DOR was not). The first finding suggests that any variability on efficacy of naltrexone is probably not mediated by binding to MOR, since all alcoholics were uniformly blocked. The second finding suggests that years of drinking may lead to upregulation of MOR and DOR, which is more

could, in fact, be the result of decrease in the juice-only condition.

like nAChR (Cosgrove et al., 2009) and less like D2 (Martinez et al., 2005).

**5. Limitations of conventional modeling methods — Need for new ones**

As previously stated, the "conventional" kinetic models used in all of the work discussed to this point treat BP as a surrogate for number of receptors (because BP = Bmax/KD where Bmax is available, unoccupied receptors and KD is the affinity of the tracer for the receptor.) Depending on the circumstance, investigators treat ∆BP as change in available receptors due to altered number of receptors or altered level of endogenous transmitter occupying sites. Whether the analysis method is a full fitting of dynamic data or fitting of linearized data via the Logan plot or measurement of equilibrium levels, the underlying kinetic model is the same. In all cases, however, a fundamental assumption of the model(s) is that BP is not changing over the course of the study, because BP is a constant. Mathematically, we say that the kinetic model is timeinvariant in parameters. The inadequacies of all three common methods of analysis in the face of transient DA release have been thoroughly studied in the recent paper by Sullivan et al (Sullivan et al., 2013). The reader is directed to that paper for more details. Any violation of the time-invariant parameters assumption could lead to misinterpretation of data. Many if not all of the investigators whose work is profiled herein appreciate this limitation of the kinetic

We have been working over the last ten years to develop kinetic models of tracer uptake and binding in the presence of transient neurotransmitter release (Constantinescu et al., 2007; Constantinescu et al., 2008; E. Morris et al., 1995; E. D. Morris et al., 2010; E. D. Morris et al., 2013; E. D. Morris et al., 2005; M. D. Normandin et al., 2008; M. D. Normandin et al., 2012; Sullivan et al., 2013). The earlier versions of the model were based on the idea that dopamine (or any other transmitter that competes with tracer) can exist in the free or bound states in addition to the various states of the tracer (refer back to Figures 4 and 11). New species in the model required new "boxes" which, in turn, meant more differential equations (E. Morris et al., 1995; E. D. Morris et al., 2005). The model described the data well (E. Morris et al., 1995; E. D. Morris et al., 2008) but was cumbersome to use. Subsequent work by Constantinescu and by Normandin et al. developed linearized versions of the model that could be solved quickly (and hence at each voxel) while retaining time-varying terms to describe brief changes in neurotransmitter level (M. Normandin et al., 2009). Validation of these models was carried out either (a) by configuring experiments in which a predictable pattern of DA change could be provoked in human subjects (Constantinescu et al., 2008; E. D. Morris et al., 2010), or (b) a comparison could be made between model predictions and microdialysis measurements made in the (rat) subjects at the same time as PET (E. D. Morris et al., 2008; M. D. Normandin et al., 2008; M. D. Normandin et al., 2012). Most recently, we have adapted the Normandin approach to the voxel level so that we can estimate time-courses of dopamine at each voxel in the striatum where "activation" is occurring due to drug stimulus. A critical step in such a process is some sort of statistical test to determine that change in DA really occurred at that location (voxel) in question. Finally, the outcome is a collection of curves in time at many voxels in the brain. The visualization technique that we have invented to display such 4-dimensional results is a "dopamine movie", wherein dopamine level is color-coded and the color in the activated voxels is displayed overlaid on MRI as a series of frames. The methods are described and demonstrated in a new publication in the Journal of Visualized Experiments (E. D. Morris et al., 2013). Validation and testing of these new dopamine movies is ongoing. We hope that they are a more sensitive probe of DA changes in the brain as a consequence of smoking and drinking behavior and that the increased sensitivity of the method will allow us to tease out patterns of response that are either "addictive" or "non-addictive".

rette smoking saturates brain alpha 4 beta 2 nicotinic acetylcholine receptors. *Arch*

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#### **Author details**

Evan D. Morris, Molly V. Lucas and Kelly P. Cosgrove

\*Address all correspondence to: evan.morris@yale.edu

Yale PET Center, Yale University, USA

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**Chapter 6**

**PET Imaging of the Serotoninergic 5-HT1A System**

Serotonin (5-hydroxytryptophan, 5-HT) is a modulating neurotransmitter of the central nervous system involved in a large spectrum of emotional and cognitive processes and physiological activities [1, 2], including sleep, locomotion, eating, memory, endocrine modu‐ lation, and sexual behaviour. The serotoninergic system is modulated in humans by both genetic and environmental factors. Furthermore, the central serotoninergic system is altered in multiple diseases such as depression [3, 4], migraine [5, 6], epilepsy [7-9], Alzheimer's disease [10, 11], eating disorders [12], anxiety [13], schizophrenia [14] and autism [15, 16]. Various radioligands are currently available for *in vivo* brain imaging of the serotoninergic system in humans, including antagonists for the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 receptors,

5-HT exerts its multiplicity of actions though seven classes of 5-HT receptors (17 subtypes identified to date), involving different signal transduction pathways [18, 19, 2]. The 5-HT1A receptors were the first to be cloned in humans and are probably the best-characterized subtype of 5-HT receptors [20]. These receptors are G protein coupled receptors (GPCRs); 5-HT binding to 5-HT1A receptors causes neuronal hyperpolarization through the G-protein-coupled opening of K+ channels [21, 22]. The 5-HT1A receptors are mostly expressed in neurons, either as heteroreceptors when located in target regions of 5-HT neurons with a particularly high concentration in limbic areas, such as cingulate cortex and hippocampus, or as autoreceptors on the soma and dendrites of 5-HT neurons in raphe nuclei, where they exert negative feedback on the serotoninergic neuron firing rate and 5-HT release [23, 24]. Thus, serotoninergic

Several PET tracers have been developed for imaging 5-HT1A receptors [25]. The most com‐ monly used radioligands are [11C]WAY-100635 (N- [2-[4-(2-methoxyphenyl)-1-piperazin‐

> © 2013 Lothe et al.; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Amélie Lothe, Sandrine Bouvard and Philippe Ryvlin

Additional information is available at the end of the chapter

and for the serotonin transporter (SERT) [17].

neurotransmission is strongly modulated by 5-HT1A receptors.

http://dx.doi.org/10.5772/57122

**1. Introduction**

### **PET Imaging of the Serotoninergic 5-HT1A System**

Amélie Lothe, Sandrine Bouvard and Philippe Ryvlin

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57122

#### **1. Introduction**

Serotonin (5-hydroxytryptophan, 5-HT) is a modulating neurotransmitter of the central nervous system involved in a large spectrum of emotional and cognitive processes and physiological activities [1, 2], including sleep, locomotion, eating, memory, endocrine modu‐ lation, and sexual behaviour. The serotoninergic system is modulated in humans by both genetic and environmental factors. Furthermore, the central serotoninergic system is altered in multiple diseases such as depression [3, 4], migraine [5, 6], epilepsy [7-9], Alzheimer's disease [10, 11], eating disorders [12], anxiety [13], schizophrenia [14] and autism [15, 16]. Various radioligands are currently available for *in vivo* brain imaging of the serotoninergic system in humans, including antagonists for the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 receptors, and for the serotonin transporter (SERT) [17].

5-HT exerts its multiplicity of actions though seven classes of 5-HT receptors (17 subtypes identified to date), involving different signal transduction pathways [18, 19, 2]. The 5-HT1A receptors were the first to be cloned in humans and are probably the best-characterized subtype of 5-HT receptors [20]. These receptors are G protein coupled receptors (GPCRs); 5-HT binding to 5-HT1A receptors causes neuronal hyperpolarization through the G-protein-coupled opening of K+ channels [21, 22]. The 5-HT1A receptors are mostly expressed in neurons, either as heteroreceptors when located in target regions of 5-HT neurons with a particularly high concentration in limbic areas, such as cingulate cortex and hippocampus, or as autoreceptors on the soma and dendrites of 5-HT neurons in raphe nuclei, where they exert negative feedback on the serotoninergic neuron firing rate and 5-HT release [23, 24]. Thus, serotoninergic neurotransmission is strongly modulated by 5-HT1A receptors.

Several PET tracers have been developed for imaging 5-HT1A receptors [25]. The most com‐ monly used radioligands are [11C]WAY-100635 (N- [2-[4-(2-methoxyphenyl)-1-piperazin‐

© 2013 Lothe et al.; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

yl]ethyl]-N-(2-pyridinyl)cyclohexane carboxamide) and [18F]MPPF (4-(2′-methoxyphenyl)-1- [2′-(N-2-pirydynyl)-p-fluorobenzamido]-ethyl-piperazine) (see figure 1).

were confirmed with simulated [18F]MPPF PET data [34]. Moreover, an original PET study using [18F]MPPF and alpha-[11C]Methyl-L-Tryptophan (AMT), a precursor of 5-HT, reported a significant negative correlation between 5-HT synthesis and 5-HT1A binding potential (BP) bilaterally in hippocampus and anterior insula and in the left anterior cingulate gyrus in

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153

Accordingly, in contrast to [11C]WAY-100635, a decreased [18F]MPPF binding could either reflect lower 5-HT1A receptor density or a higher extracellular concentration of 5-HT that could

Secondly, [18F]MPPF binds to externalized 5-HT1A receptors only, while [11C]WAY-100635 also binds to internalized receptors [36]. As a result of this property, [18F]MPPF may allow indirect

Using β-sensitive microprobes in rats, a significant decrease of [18F]MPPF binding was observed in the dorsal raphe nucleus (autoreceptors), but not in the hippocampus (heterore‐ ceptors), after acute treatment with 8-OH-DPAT, a 5-HT1A receptor agonist, or with fluoxetine, a selective serotonin reuptake inhibitor (SSRI) [37, 38]. This reduction is associated with the internalization of 5-HT1A autoreceptors of dorsal raphe nucleus observed in parallel using quantitative electron microscopic immunocytochemistry [38]. Similarly, a [18F]MPPF PET study conducted in cats reported a decreased BP in the dorsal raphe nucleus after acute fluoxetine administration [39]. Finally, an interesting [18F]MPPF PET study has examined this property by investigating healthy subjects five hours after the randomized, double-blind administration of a single oral dose of fluoxetine [40]. As expected, [18F]MPPF binding in raphe

Thirdly, the 5-HT1A binding of both ligand was found to be differentially influenced by several

Several genetic factors, including the triallelic 5-HT transporter gene-linked polymorphic region (5-HTTLPR) and 5-HT1A promoter polymorphism, have a significant impact on

Two [11C]WAY-100635 PET studies showed a significant impact of the 5-HTTLPR polymor‐ phism on the 5-HT1A receptor binding, but in different directions [41-42]. One of the two studies reported lower [11C]WAY-100635 BP in various limbic and neocortical brain regions in healthy subjects (predominantly men) with S/S or S/L genotypes compared to those with L/L genotype [41], whereas the other series found greater BP in the cingulate gyri in healthy women with S/ S and S/L genotypes compared to those with L/L genotype [42]. Similarly, we observed a greater [18F]MPPF non displaceable BPND (BPND = fND.Bavail/KD where fND is the fraction of radioligands free and non specifically bound, Bavail is the total number of available receptors for binding and 1/KD is the affinity of the radioligand) [48] in homozygote women carriers of the S allele of 5-HTTLPR compared with carriers of at least one LA allele over large brain regions including temporal and parietal lobes as well as the insula, cingulate gyri and left orbitofrontal cortex [43]. In contrast, a recent PET study failed to show a significant effect of the 5-HTTLPR polymorphism on the [11C]WAY-100635 BP in a large population of 54 healthy volunteers, but

be associated with various changes in the number of 5-HT1A receptors.

nuclei is decreased in response to fluoxetine in each healthy subject [40].

factors, including genetic factors, age and gender.

18F]MPPF and [11C]WAY-100635 binding [41-47].

that included men predominantly [47].

assessment of the internalization of 5-HT1A autoreceptors [37].

healthy subjects [35].

[

**Figure 1.** Chemical structure of antagonist PET tracers of 5-HT1A receptors

In this chapter, we will start by reviewing the different binding properties of [<sup>18</sup>F]MPPF versus [ <sup>11</sup>C]WAY-100635. We will then discuss in more detail PET data obtained with [18F]MPPF in comparison with those obtained with [<sup>11</sup>C]WAY-100635 in various pathological conditions, including major depressive disorder, depressive comorbidity in temporal lobe epilepsy, and schizophrenia.

### **2. Binding properties of [18F]MPPF versus [11C]WAY-100635**

[ 18F]MPPF and [11C]WAY-100635 are both selective and potent antagonists at 5-HT1A autore‐ ceptors and heteroreceptors, but differ in their binding properties at 5-HT1A receptors.

Firstly, [<sup>18</sup>F]MPPF is characterized by a lower affinity for 5-HT1A receptors (Ki=3.3 nM in rat hippocampal membrane homogenates) than [<sup>11</sup>C]WAY-100635 (Ki=0.8 nM) [26] and [ <sup>18</sup>F]FCWAY (Ki=0.25 nM) [27].

The high affinity of [<sup>11</sup>C]WAY-100635 for 5-HT1A receptors would make it relatively insensitive to changes in endogenous 5-HT concentration. Indeed, the binding of [11C]WAY-100635 remained unchanged after injection of fenfluramine or after depletion of 5-HT by treatment with p-chlorophenylalanine (p-CPA) or with reserpine in rodents [28, 29]. In this regard, a decreased [<sup>11</sup>C]WAY-100635 binding will be interpreted as reflecting a reduction in the density of 5-HT1A receptors.

Conversely, the affinity of [<sup>18</sup>F]MPPF is closer to that of endogenous 5-HT for 5-HT1A receptors (Ki=4.2 nM in rat frontal cortex homogenates) [30]. Thus, [<sup>18</sup>F]MPPF appears to be sensitive to the extra-cellular concentration of endogenous 5-HT [31, 32, 33]. Several studies using β-sensitive microprobes and microdialysis in the brain of rats demonstrated decreases in [<sup>18</sup>F]MPPF binding after pharmacologically or electrical stimulation induced increases in the concentration of extracellular 5-HT [31, 32], while the binding of [18F]MPPF is increased in the hippocampus following a reduction in the extracellular 5-HT concentra‐ tion in rats treated with p-EPA, an inhibitor of tryptophan hydroxylase [33]. These findings were confirmed with simulated [18F]MPPF PET data [34]. Moreover, an original PET study using [18F]MPPF and alpha-[11C]Methyl-L-Tryptophan (AMT), a precursor of 5-HT, reported a significant negative correlation between 5-HT synthesis and 5-HT1A binding potential (BP) bilaterally in hippocampus and anterior insula and in the left anterior cingulate gyrus in healthy subjects [35].

yl]ethyl]-N-(2-pyridinyl)cyclohexane carboxamide) and [18F]MPPF (4-(2′-methoxyphenyl)-1-

152 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

In this chapter, we will start by reviewing the different binding properties of [<sup>18</sup>F]MPPF versus

<sup>11</sup>C]WAY-100635. We will then discuss in more detail PET data obtained with [18F]MPPF in comparison with those obtained with [<sup>11</sup>C]WAY-100635 in various pathological conditions, including major depressive disorder, depressive comorbidity in temporal lobe epilepsy, and

18F]MPPF and [11C]WAY-100635 are both selective and potent antagonists at 5-HT1A autore‐

Firstly, [<sup>18</sup>F]MPPF is characterized by a lower affinity for 5-HT1A receptors (Ki=3.3 nM in rat hippocampal membrane homogenates) than [<sup>11</sup>C]WAY-100635 (Ki=0.8 nM) [26] and

The high affinity of [<sup>11</sup>C]WAY-100635 for 5-HT1A receptors would make it relatively insensitive to changes in endogenous 5-HT concentration. Indeed, the binding of [11C]WAY-100635 remained unchanged after injection of fenfluramine or after depletion of 5-HT by treatment with p-chlorophenylalanine (p-CPA) or with reserpine in rodents [28, 29]. In this regard, a decreased [<sup>11</sup>C]WAY-100635 binding will be interpreted as reflecting a reduction in the density

Conversely, the affinity of [<sup>18</sup>F]MPPF is closer to that of endogenous 5-HT for 5-HT1A receptors (Ki=4.2 nM in rat frontal cortex homogenates) [30]. Thus, [<sup>18</sup>F]MPPF appears to be sensitive to the extra-cellular concentration of endogenous 5-HT [31, 32, 33]. Several studies using β-sensitive microprobes and microdialysis in the brain of rats demonstrated decreases in [<sup>18</sup>F]MPPF binding after pharmacologically or electrical stimulation induced increases in the concentration of extracellular 5-HT [31, 32], while the binding of [18F]MPPF is increased in the hippocampus following a reduction in the extracellular 5-HT concentra‐ tion in rats treated with p-EPA, an inhibitor of tryptophan hydroxylase [33]. These findings

ceptors and heteroreceptors, but differ in their binding properties at 5-HT1A receptors.

[2′-(N-2-pirydynyl)-p-fluorobenzamido]-ethyl-piperazine) (see figure 1).

**2. Binding properties of [18F]MPPF versus [11C]WAY-100635**

**Figure 1.** Chemical structure of antagonist PET tracers of 5-HT1A receptors

[

[

[

schizophrenia.

<sup>18</sup>F]FCWAY (Ki=0.25 nM) [27].

of 5-HT1A receptors.

Accordingly, in contrast to [11C]WAY-100635, a decreased [18F]MPPF binding could either reflect lower 5-HT1A receptor density or a higher extracellular concentration of 5-HT that could be associated with various changes in the number of 5-HT1A receptors.

Secondly, [18F]MPPF binds to externalized 5-HT1A receptors only, while [11C]WAY-100635 also binds to internalized receptors [36]. As a result of this property, [18F]MPPF may allow indirect assessment of the internalization of 5-HT1A autoreceptors [37].

Using β-sensitive microprobes in rats, a significant decrease of [18F]MPPF binding was observed in the dorsal raphe nucleus (autoreceptors), but not in the hippocampus (heterore‐ ceptors), after acute treatment with 8-OH-DPAT, a 5-HT1A receptor agonist, or with fluoxetine, a selective serotonin reuptake inhibitor (SSRI) [37, 38]. This reduction is associated with the internalization of 5-HT1A autoreceptors of dorsal raphe nucleus observed in parallel using quantitative electron microscopic immunocytochemistry [38]. Similarly, a [18F]MPPF PET study conducted in cats reported a decreased BP in the dorsal raphe nucleus after acute fluoxetine administration [39]. Finally, an interesting [18F]MPPF PET study has examined this property by investigating healthy subjects five hours after the randomized, double-blind administration of a single oral dose of fluoxetine [40]. As expected, [18F]MPPF binding in raphe nuclei is decreased in response to fluoxetine in each healthy subject [40].

Thirdly, the 5-HT1A binding of both ligand was found to be differentially influenced by several factors, including genetic factors, age and gender.

Several genetic factors, including the triallelic 5-HT transporter gene-linked polymorphic region (5-HTTLPR) and 5-HT1A promoter polymorphism, have a significant impact on [ 18F]MPPF and [11C]WAY-100635 binding [41-47].

Two [11C]WAY-100635 PET studies showed a significant impact of the 5-HTTLPR polymor‐ phism on the 5-HT1A receptor binding, but in different directions [41-42]. One of the two studies reported lower [11C]WAY-100635 BP in various limbic and neocortical brain regions in healthy subjects (predominantly men) with S/S or S/L genotypes compared to those with L/L genotype [41], whereas the other series found greater BP in the cingulate gyri in healthy women with S/ S and S/L genotypes compared to those with L/L genotype [42]. Similarly, we observed a greater [18F]MPPF non displaceable BPND (BPND = fND.Bavail/KD where fND is the fraction of radioligands free and non specifically bound, Bavail is the total number of available receptors for binding and 1/KD is the affinity of the radioligand) [48] in homozygote women carriers of the S allele of 5-HTTLPR compared with carriers of at least one LA allele over large brain regions including temporal and parietal lobes as well as the insula, cingulate gyri and left orbitofrontal cortex [43]. In contrast, a recent PET study failed to show a significant effect of the 5-HTTLPR polymorphism on the [11C]WAY-100635 BP in a large population of 54 healthy volunteers, but that included men predominantly [47].

The association of C(-1019)G 5-HT1A promoter polymorphism and 5-HT1A receptor binding has also been evaluated in humans in three [11C]WAY-100635 PET studies and one [18F]MPPF study [41, 44-46]. One of these [11C]WAY-100635 studies reported no association between C(-1019)G 5-HT1A promoter polymorphism and 5-HT1A receptor BP in a homogenous group of healthy subjects [41]. We also failed to detect a significant relationship between C(-1019)G 5-HT1A promoter polymorphism and [18F]MPPF binding in healthy subjects. However our data suggest that women homozygote for the G allele have greater [18F]MPPF BPND compared to other individuals primarily over the frontal and temporal neocortex. The other two [ 11C]WAY-100635 PET studies, performed in a mixed population of depressed and healthy individuals, demonstrated greater BP in limbic regions and the raphe nuclei, in carriers with at least one G allele compared to the C/C genotype [45, 46].

or a markedly diminished interest or pleasure in all or almost all activities most of the day during the same 2-week period. In addition, three or more of the following symptoms must be present: gain or loss of weight, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, feelings of worthlessness or guilt, diminished ability to concentrate, and

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155

MDD is associated with diminished role functioning, poor health-related quality of life, medical comorbidity, such as cardiovascular disease [58], and increased risk of mortality [59]. Since roughly the 1970s, 5-HT has been involved in the pathophysiology of MDD [60, 61]. Numerous studies reported a reduction of 5-HT plasma concentrations and 5-HT metabolite levels in the cerebro-spinal fluid of patients with MDD [62, 63]. In addition, pharmacological agents that reduce brain 5-HT levels (e.g. reserpine) can induce depressive symptoms in healthy subjects as well as in recovered depressed patients [4, 64-66]. More recently, PET studies using alpha-[11C]Methyl-L-Tryptophan (AMT) showed a reduction of this tracer uptake in the anterior cingulate gyrus and left mesial temporal cortex in MDD patients, supporting the possibility of reduced extracellular 5-HT concentration in depression [67, 68]. The involvement of 5-HT1A receptors in depression is well recognized; however the nature of their modifications is still controversial (see for review [69, 70]). A large number of PET studies have investigated 5-HT1A receptors in patients with MDD using [11C]WAY-100635 [3, 69, 71-81]. Most previous [11C]WAY-100635 PET studies showed a reduction of 5-HT1A receptor BPND in various limbic and neocortical brain regions, as well as in the raphe nuclei, of untreated, treated, remitted MDD patients as well as in drug-naïve primary-care patients with MDD [3, 71, 73, 74-76, 79]. Interestingly, a [18F]MPPF PET study performed in a monkey model of depression also reported a reduced BP in limbic regions and raphe nuclei [82]. It is in agreement with the majority of post-mortem data demonstrating decreased 5-HT1A receptor density in depressed suicide victims in different brain regions including the raphe nuclei, the hippocam‐ pus, and the frontal cortex [83-89]. The reduction of 5-HT1A receptor binding could be partly the consequence of a possible hypersecretion of endogenous corticosteroids (see for review

However, other PET studies using [11C]WAY-100635 reported an increased ratio of specifically bound ligand over free ligand (BPF) in the same regions in MDD patients never or not recently exposed to antidepressants, compared with controls [77-79]. Similarly, an increased 5-HT1A BPF has been shown in patients with MDD during sustained remission and not having taken antidepressant medications for at least six months, compared with healthy controls [81]. These authors suggest that higher 5-HT1A autoreceptor binding in the raphe nuclei could lead to greater inhibition of 5-HT neuron firing rate and decreased 5-HT release in the target regions of 5-HT neurons, possibly leading to compensatory up-regulation of 5-HT1A receptors in the

These discordant PET findings might partly reflect differences in the modeling methods used to calculate BP (BPND versus BPF) [48], the choice of the reference region (e.g. inclusion of cerebellar vermis and gray matter in the reference region or use of white matter) [91], MDD severity, treatment status, and genetic polymorphism status (e.g. for the C-1019G 5-HT1A

recurrent thoughts of death or suicidal ideation.

[69, 90]).

same regions [78].

5-HT1A receptor binding measured by either [18F]MPPF and [11C]WAY-100635 significantly declines with age [49-52]. However, this effect was especially observed on [18F]MPPF binding in women [50] and, conversely, on [11C]WAY-100635 binding in men [52]. Note that one [ 11C]WAY-100635 PET study failed to show any significant correlation between age and 5- HT1A receptor binding [53].

With regard to the gender factor, greater [18F]MPPF BPND values independent of age were demonstrated in women compared to men, in limbic and paralimbic regions, predominantly in the right hemisphere [50]. Furthermore, after controlling for age and 5-HTTLPR polymor‐ phism, a higher [18F]MPPF BPND to 5-HT1A receptors was also observed in women than in men over a very restricted set of brain regions, including the left temporal pole and parahippo‐ campal gyrus [43]. Thus, we might speculate that the larger gender difference could partly reflect unbalanced 5-HTTLPR polymorphism between men and women.

A few PET studies have also examined the effects of gender on [11C]WAY-100635 binding to 5-HT1A receptors, reporting contradictory findings. Two previous studies found no effect of gender on [11C]WAY-100635 binding [51, 54], whereas other series reported higher binding in women compared to men [47, 53, 55].

Overall, [18F]MPPF and [11C]WAY-100635 are likely to yield different and complementary PET findings in different pathological conditions.

#### **3. Major depressive disorder**

Depression is a common mental disorder, affecting about 121 million people worldwide. By the year 2020, depression is projected to become the second most important cause of disease burden, as measured by Disability-Adjusted Life Years (DALYs) (World Health Organization). The average lifetime prevalence of Major Depressive Disorder (MDD) is 14.6% in high-income countries [56], with the typically reported rates of 5% to 12% for men and 10% to 26% for women.

According to the Diagnostic Statistical Manual of Mental Disorders [57], Fourth edition, Text revision (DSM-IV-R), a Major Depressive Episode is characterized by a depressed mood and/ or a markedly diminished interest or pleasure in all or almost all activities most of the day during the same 2-week period. In addition, three or more of the following symptoms must be present: gain or loss of weight, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, feelings of worthlessness or guilt, diminished ability to concentrate, and recurrent thoughts of death or suicidal ideation.

The association of C(-1019)G 5-HT1A promoter polymorphism and 5-HT1A receptor binding has also been evaluated in humans in three [11C]WAY-100635 PET studies and one [18F]MPPF study [41, 44-46]. One of these [11C]WAY-100635 studies reported no association between C(-1019)G 5-HT1A promoter polymorphism and 5-HT1A receptor BP in a homogenous group of healthy subjects [41]. We also failed to detect a significant relationship between C(-1019)G 5-HT1A promoter polymorphism and [18F]MPPF binding in healthy subjects. However our data suggest that women homozygote for the G allele have greater [18F]MPPF BPND compared to other individuals primarily over the frontal and temporal neocortex. The other two

154 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

11C]WAY-100635 PET studies, performed in a mixed population of depressed and healthy individuals, demonstrated greater BP in limbic regions and the raphe nuclei, in carriers with

5-HT1A receptor binding measured by either [18F]MPPF and [11C]WAY-100635 significantly declines with age [49-52]. However, this effect was especially observed on [18F]MPPF binding in women [50] and, conversely, on [11C]WAY-100635 binding in men [52]. Note that one

11C]WAY-100635 PET study failed to show any significant correlation between age and 5-

With regard to the gender factor, greater [18F]MPPF BPND values independent of age were demonstrated in women compared to men, in limbic and paralimbic regions, predominantly in the right hemisphere [50]. Furthermore, after controlling for age and 5-HTTLPR polymor‐ phism, a higher [18F]MPPF BPND to 5-HT1A receptors was also observed in women than in men over a very restricted set of brain regions, including the left temporal pole and parahippo‐ campal gyrus [43]. Thus, we might speculate that the larger gender difference could partly

A few PET studies have also examined the effects of gender on [11C]WAY-100635 binding to 5-HT1A receptors, reporting contradictory findings. Two previous studies found no effect of gender on [11C]WAY-100635 binding [51, 54], whereas other series reported higher binding in

Overall, [18F]MPPF and [11C]WAY-100635 are likely to yield different and complementary PET

Depression is a common mental disorder, affecting about 121 million people worldwide. By the year 2020, depression is projected to become the second most important cause of disease burden, as measured by Disability-Adjusted Life Years (DALYs) (World Health Organization). The average lifetime prevalence of Major Depressive Disorder (MDD) is 14.6% in high-income countries [56], with the typically reported rates of 5% to 12% for men and 10% to 26% for

According to the Diagnostic Statistical Manual of Mental Disorders [57], Fourth edition, Text revision (DSM-IV-R), a Major Depressive Episode is characterized by a depressed mood and/

reflect unbalanced 5-HTTLPR polymorphism between men and women.

at least one G allele compared to the C/C genotype [45, 46].

[

[

HT1A receptor binding [53].

women compared to men [47, 53, 55].

**3. Major depressive disorder**

women.

findings in different pathological conditions.

MDD is associated with diminished role functioning, poor health-related quality of life, medical comorbidity, such as cardiovascular disease [58], and increased risk of mortality [59].

Since roughly the 1970s, 5-HT has been involved in the pathophysiology of MDD [60, 61]. Numerous studies reported a reduction of 5-HT plasma concentrations and 5-HT metabolite levels in the cerebro-spinal fluid of patients with MDD [62, 63]. In addition, pharmacological agents that reduce brain 5-HT levels (e.g. reserpine) can induce depressive symptoms in healthy subjects as well as in recovered depressed patients [4, 64-66]. More recently, PET studies using alpha-[11C]Methyl-L-Tryptophan (AMT) showed a reduction of this tracer uptake in the anterior cingulate gyrus and left mesial temporal cortex in MDD patients, supporting the possibility of reduced extracellular 5-HT concentration in depression [67, 68].

The involvement of 5-HT1A receptors in depression is well recognized; however the nature of their modifications is still controversial (see for review [69, 70]). A large number of PET studies have investigated 5-HT1A receptors in patients with MDD using [11C]WAY-100635 [3, 69, 71-81].

Most previous [11C]WAY-100635 PET studies showed a reduction of 5-HT1A receptor BPND in various limbic and neocortical brain regions, as well as in the raphe nuclei, of untreated, treated, remitted MDD patients as well as in drug-naïve primary-care patients with MDD [3, 71, 73, 74-76, 79]. Interestingly, a [18F]MPPF PET study performed in a monkey model of depression also reported a reduced BP in limbic regions and raphe nuclei [82]. It is in agreement with the majority of post-mortem data demonstrating decreased 5-HT1A receptor density in depressed suicide victims in different brain regions including the raphe nuclei, the hippocam‐ pus, and the frontal cortex [83-89]. The reduction of 5-HT1A receptor binding could be partly the consequence of a possible hypersecretion of endogenous corticosteroids (see for review [69, 90]).

However, other PET studies using [11C]WAY-100635 reported an increased ratio of specifically bound ligand over free ligand (BPF) in the same regions in MDD patients never or not recently exposed to antidepressants, compared with controls [77-79]. Similarly, an increased 5-HT1A BPF has been shown in patients with MDD during sustained remission and not having taken antidepressant medications for at least six months, compared with healthy controls [81]. These authors suggest that higher 5-HT1A autoreceptor binding in the raphe nuclei could lead to greater inhibition of 5-HT neuron firing rate and decreased 5-HT release in the target regions of 5-HT neurons, possibly leading to compensatory up-regulation of 5-HT1A receptors in the same regions [78].

These discordant PET findings might partly reflect differences in the modeling methods used to calculate BP (BPND versus BPF) [48], the choice of the reference region (e.g. inclusion of cerebellar vermis and gray matter in the reference region or use of white matter) [91], MDD severity, treatment status, and genetic polymorphism status (e.g. for the C-1019G 5-HT1A receptor and 5-HTTLPR polymorphisms) of the patients selected [79] (see for review [70]). Thus, regarding the choice of the reference region, scans from the same patient population, analysed with SRTM and a cerebellar reference region, could either demonstrate reduced 5- HT1A BPND when using cerebellar gray matter, or increased or unchanged BPND when using cerebellar white matter [79, 81]. Indeed, the grey matter of cerebellum contains limited but significant amount of 5-HT1A receptors, while its white matter does not and thus represents a more appropriate reference. Furthermore, as already mentioned, [18F]MPPF and [ 11C]WAY-100635 BPND were reported to be influenced by the triallelic 5-HTTLPR polymor‐ phism, which S allele is associated with depressive disorder [92, 93].

95]. Firstly, one of these [11C]WAY-100635 studies did not evaluate specifically the medial orbital region and the anterior cingulate gyrus [94]. Moreover, the treatment response, the treatment duration, the polymorphism status for serotoninergic genes as well as the cortisol plasma levels [69] of the patients selected could partly explain these discrepancies. For instance, in one of the [11C]WAY-100635 studies, only half of the patients studied were

PET Imaging of the Serotoninergic 5-HT1A System

http://dx.doi.org/10.5772/57122

157

Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures, due to an abnormal, excessive, and synchronous neuronal discharges, affecting about 50 million people worldwide. Depressive disorders are the most frequent psychiatric comor‐ bidity in epilepsy but often remain under-recognized and untreated [100-103]. The lifetime prevalence of major depression ranged from 11 and 60% in patients with recurrent seizures [103] and increased in patients with temporal lobe epilepsy (TLE), particularly in those with left TLE and possibly hippocampal sclerosis (for review see [101, 104-108]). The rate of suicide in patients with epilepsy is about two to five times that of the general population, and this rate rises to six to seven times in the case of TLE [109, 110]. In addition, comorbid depression is a strong predictor of poor quality of life in patients with epilepsy [111]. This higher incidence of depressive disorders in patients with epilepsy, in particular in those with TLE, may reflect the existence of common pathogenic mechanisms between mood disorders and epilepsy [112]. In this paragraph, we are referring to the presence of depressive symptoms in interictal period. Indeed, depressive symptoms may also occur transiently during ictal or post-ictal [103].

A large body of evidence from preclinical studies indicates an anticonvulsant and antiepileptic effect of 5-HT mediated by 5-HT1A receptors [113]. The activation of 5-HT1A receptors retards the development of the kindling process in rats [114] and in cats [115, 116] and inhibits epileptiform activity in various cellular models of epilepsy [117, 118]. In addition, agents that raise endogenous 5-HT levels (e.g. SSRI) have an anticonvulsant effect, mediated by 5-HT1A receptors [119], in genetically epilepsy-prone rats [120], in partial seizures generated by lowfrequency electrical stimulation in rats [121], as well as in kindled rats [116]. Finally, given their multiple cellular localizations, the 5-HT1A receptors may mediate inhibition of excitatory neurons, but also of inhibitory neurons, leading to opposite effects on the neural network [122]. Accordingly, a possible mechanism of neuronal hyperexcitability in epilepsy could be an

Abnormalities of the 5-HT1A receptors were reported in TLE using various radioligands, including [11C]WAY-100635, [18F]FCWAY and [18F]MPPF. All showed a BP reduction that predominated over the epileptogenic temporo-limbic structures [123-130] (see figure 2).

This reduction of 5-HT1A binding on the side of the epileptogenic zone support the hypothesis of a decrease in 5-HT1A receptors density in TLE. In line with these imaging studies, a decrease

HT1A receptors was reported in the hippocampus of genetically epilepsy-prone rats [131].

H]8-OH-DPAT (8-hydroxy-2-(di-n-propylamino) tetralin) to 5-

excitatory/inhibitory shift mediated by changes in serotoninergic transmission.

of binding of the agonist [3

responders [75], whereas in our [18F]MPPF study all patients were responders.

**4. Depressive comorbidity in temporal lobe epilepsy**

#### **3.1. Effects of antidepressants**

A small number of PET studies have examined the potential impact of chronic antidepressant medication on 5-HT1A receptor binding.

Three test-retest [11C]WAY-100635 studies reported no change of BPND after selective serotonin recapture inhibitor (SSRI) treatment in MDD patients [75, 94, 95]. Contrary to these findings, a reduction of [11C]WAY-100635 BPF was found in MDD patients previously treated by antidepressants (most of the antidepressant exposure ended between 21 and 14 days prior to PET scans) when compared with medication naïve MDD patients, but not when compared with healthy controls [77]. In line with this result, a decreased 5-HT1A BPND was observed following at least 12 weeks of SSRI treatment in patients suffering from social phobia or panic disorder [96]. These data suggest that chronic antidepressant treatment could induce a downregulation of 5-HT1A receptors.

In a recent test-retest [18F]MPPF PET study, we explored the potential dynamic changes in [ 18F]MPPF BPND in six patients with untreated MDD, before, and after five and 30 days of SSRI treatment [97]. No change of [18F]MPPF BPND after SSRI medication was observed within the raphe nuclei and a significant increase of [18F]MPPF BPND from baseline to 30 days of SSRI treatment was reported primarily in the medial orbital region and the anterior cingulate gyrus. These findings are in contradiction with the three previous test-retest [11C]WAY-100635 studies which have addressed this issue [75, 94, 95].

After 30 days of SSRI treatment, no more significant modification of [18F]MPPF BPND was found in MDD patients compared with healthy subjects in the medial orbital region and the anterior cingulate gyrus. Thus effective SSRI treatment is associated with a trend toward normalisation of the serotoninergic function. In agreement with these human PET imaging data, no change in the in vivo [18F]MPPF binding was found in the dorsal raphe nucleus, frontal cortex and hippocampus of rats undergoing chronic SSRI treatment, as measured with β-microprobes or with the small animal PET scanner YAP-(S)PET system [98, 99].

Overall these preliminary [18F]MPPF data suggest the existence of SSRI-mediated serotoni‐ nergic adaptative mechanisms in patients with MDD. However, due to the small sample size, it is necessary to confirm these findings in a larger population.

Apart from the discrepancy of the used radioligands, several points of difference between our [18F]MPPF study and the three previous [11C]WAY-100635 studies should be noted [75, 94, 95]. Firstly, one of these [11C]WAY-100635 studies did not evaluate specifically the medial orbital region and the anterior cingulate gyrus [94]. Moreover, the treatment response, the treatment duration, the polymorphism status for serotoninergic genes as well as the cortisol plasma levels [69] of the patients selected could partly explain these discrepancies. For instance, in one of the [11C]WAY-100635 studies, only half of the patients studied were responders [75], whereas in our [18F]MPPF study all patients were responders.

#### **4. Depressive comorbidity in temporal lobe epilepsy**

receptor and 5-HTTLPR polymorphisms) of the patients selected [79] (see for review [70]). Thus, regarding the choice of the reference region, scans from the same patient population, analysed with SRTM and a cerebellar reference region, could either demonstrate reduced 5- HT1A BPND when using cerebellar gray matter, or increased or unchanged BPND when using cerebellar white matter [79, 81]. Indeed, the grey matter of cerebellum contains limited but significant amount of 5-HT1A receptors, while its white matter does not and thus represents a more appropriate reference. Furthermore, as already mentioned, [18F]MPPF and

156 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

11C]WAY-100635 BPND were reported to be influenced by the triallelic 5-HTTLPR polymor‐

A small number of PET studies have examined the potential impact of chronic antidepressant

Three test-retest [11C]WAY-100635 studies reported no change of BPND after selective serotonin recapture inhibitor (SSRI) treatment in MDD patients [75, 94, 95]. Contrary to these findings, a reduction of [11C]WAY-100635 BPF was found in MDD patients previously treated by antidepressants (most of the antidepressant exposure ended between 21 and 14 days prior to PET scans) when compared with medication naïve MDD patients, but not when compared with healthy controls [77]. In line with this result, a decreased 5-HT1A BPND was observed following at least 12 weeks of SSRI treatment in patients suffering from social phobia or panic disorder [96]. These data suggest that chronic antidepressant treatment could induce a down-

In a recent test-retest [18F]MPPF PET study, we explored the potential dynamic changes in

18F]MPPF BPND in six patients with untreated MDD, before, and after five and 30 days of SSRI treatment [97]. No change of [18F]MPPF BPND after SSRI medication was observed within the raphe nuclei and a significant increase of [18F]MPPF BPND from baseline to 30 days of SSRI treatment was reported primarily in the medial orbital region and the anterior cingulate gyrus. These findings are in contradiction with the three previous test-retest [11C]WAY-100635 studies

After 30 days of SSRI treatment, no more significant modification of [18F]MPPF BPND was found in MDD patients compared with healthy subjects in the medial orbital region and the anterior cingulate gyrus. Thus effective SSRI treatment is associated with a trend toward normalisation of the serotoninergic function. In agreement with these human PET imaging data, no change in the in vivo [18F]MPPF binding was found in the dorsal raphe nucleus, frontal cortex and hippocampus of rats undergoing chronic SSRI treatment, as measured with β-microprobes or

Overall these preliminary [18F]MPPF data suggest the existence of SSRI-mediated serotoni‐ nergic adaptative mechanisms in patients with MDD. However, due to the small sample size,

Apart from the discrepancy of the used radioligands, several points of difference between our [18F]MPPF study and the three previous [11C]WAY-100635 studies should be noted [75, 94,

phism, which S allele is associated with depressive disorder [92, 93].

[

[

**3.1. Effects of antidepressants**

regulation of 5-HT1A receptors.

which have addressed this issue [75, 94, 95].

with the small animal PET scanner YAP-(S)PET system [98, 99].

it is necessary to confirm these findings in a larger population.

medication on 5-HT1A receptor binding.

Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures, due to an abnormal, excessive, and synchronous neuronal discharges, affecting about 50 million people worldwide. Depressive disorders are the most frequent psychiatric comor‐ bidity in epilepsy but often remain under-recognized and untreated [100-103]. The lifetime prevalence of major depression ranged from 11 and 60% in patients with recurrent seizures [103] and increased in patients with temporal lobe epilepsy (TLE), particularly in those with left TLE and possibly hippocampal sclerosis (for review see [101, 104-108]). The rate of suicide in patients with epilepsy is about two to five times that of the general population, and this rate rises to six to seven times in the case of TLE [109, 110]. In addition, comorbid depression is a strong predictor of poor quality of life in patients with epilepsy [111]. This higher incidence of depressive disorders in patients with epilepsy, in particular in those with TLE, may reflect the existence of common pathogenic mechanisms between mood disorders and epilepsy [112]. In this paragraph, we are referring to the presence of depressive symptoms in interictal period. Indeed, depressive symptoms may also occur transiently during ictal or post-ictal [103].

A large body of evidence from preclinical studies indicates an anticonvulsant and antiepileptic effect of 5-HT mediated by 5-HT1A receptors [113]. The activation of 5-HT1A receptors retards the development of the kindling process in rats [114] and in cats [115, 116] and inhibits epileptiform activity in various cellular models of epilepsy [117, 118]. In addition, agents that raise endogenous 5-HT levels (e.g. SSRI) have an anticonvulsant effect, mediated by 5-HT1A receptors [119], in genetically epilepsy-prone rats [120], in partial seizures generated by lowfrequency electrical stimulation in rats [121], as well as in kindled rats [116]. Finally, given their multiple cellular localizations, the 5-HT1A receptors may mediate inhibition of excitatory neurons, but also of inhibitory neurons, leading to opposite effects on the neural network [122]. Accordingly, a possible mechanism of neuronal hyperexcitability in epilepsy could be an excitatory/inhibitory shift mediated by changes in serotoninergic transmission.

Abnormalities of the 5-HT1A receptors were reported in TLE using various radioligands, including [11C]WAY-100635, [18F]FCWAY and [18F]MPPF. All showed a BP reduction that predominated over the epileptogenic temporo-limbic structures [123-130] (see figure 2).

This reduction of 5-HT1A binding on the side of the epileptogenic zone support the hypothesis of a decrease in 5-HT1A receptors density in TLE. In line with these imaging studies, a decrease of binding of the agonist [3 H]8-OH-DPAT (8-hydroxy-2-(di-n-propylamino) tetralin) to 5- HT1A receptors was reported in the hippocampus of genetically epilepsy-prone rats [131].

toms of psychomotor anhedonia and negative cognition, whereas somatic symptoms corre‐ lated with [18F]MPPF BPND in the anterior cingulate gyrus and hippocampus ipsilateral to seizure onset. Considering the sensitivity of [18F]MPPF to the extra-cellular concentration of endogenous 5-HT, the greater [18F]MPPF BPND observed in the more depressed patients suggests a combination of an underlying depletion in the extra-celllular concentration of 5-HT

PET Imaging of the Serotoninergic 5-HT1A System

http://dx.doi.org/10.5772/57122

159

As previously mentioned, discordance between PET studies of 5-HT1A receptors in patients with epilepsy and depression might also reflect a difference in the modeling methods used to calculate BP [79], the choice of the reference region, as well as the studied patient samples. Indeed, in our [18F]MPPF PET study, we have selected a more homogeneous group of patients than those of previous [11C]WAY-100635 studies; all patients were naïve to previous antide‐ pressant exposure and showed MRI signs of hippocampal sclerosis. Conversely, the propor‐ tion of patients with hippocampal sclerosis varied in other series [126, 127, 133, 134]. The pathophysiology of epilepsy-related depression might differ between TLE patients with and without hippocampal sclerosis [136, 137]. Furthermore, the brain distribution of 5-HT1A receptors would be influenced by previous antidepressant treatment [77]. Finally, it should be noted that antiepileptic drugs, such as carbamazepine [138], could modify the intracerebral concentration of 5-HT. Thus, differences in the proportion of patients with and without depressive symptoms receiving carbamazepine could also play a role in the discordances

Schizophrenia is a severely disabling and complex psychiatric disorder with a lifetime prevalence of approximately 1% in the general population [139]. The diagnosis of schizophre‐ nia encompasses the presence of positive (delusions, hallucinations, thought disorder) and negative (emotional blunting, paucity of speech, loss of motivation, self neglect, and social withdrawal) symptoms, and cognitive deficits (deficits in attention, executive function, and memory). According to DSM-IV-TR, two or more positive symptoms have occurred for at least one month, unless hallucinations or delusions are especially bizarre, in which case one alone suffices for diagnosis. The onset of symptoms typically occurs during adolescence and young adulthood, with men having an earlier age of onset than women. Medical and psychiatric comorbidities, such as substance abuse, anxiety and depressive disorders, are frequent in patients with schizophrenia [140]. Furthermore patients with schizophrenia have higher rates

Schizophrenia has a multifactorial etiology, involving a combination of genetic and environ‐ mental risk factors. Several neurotransmitters systems (dopamine, glutamate, acetylcholine, GABA, serotonin) are altered in schizophrenia. Until recently, the predominant focus of research in the pathophysiology of schizophrenia was the dopaminergic neurotransmission. The current dopamine hypothesis postulates that dopaminergic systems in schizophrenia might be characterized by a cortical/subcortical imbalance. Subcortical mesolimbic dopami‐

and a decreased density in 5-HT1A receptors.

**5. Schizophrenia**

observed between [18F]MPPF and [11C]WAY-100635 PET findings.

of mortality in comparison to the general population [141].

**Figure 2.** Typical pattern of [18F]MPPF BPND in patients with TLE.

Nevertheless, it should be stressed that the P-glycoprotein (PGP) expression could compro‐ mise this interpretation of PET findings. PGP is an ATP-driven transmembrane efflux pump, which is located at the blood-brain barrier and transports a wide variety of substrates from the brain to blood and cerebrospinal fluid. [18F]MPPF being a substrate for PGP, its brain uptake is modulated. An overexpression of PGP is reported in epileptic foci, probably leading to drug resistance in epilepsy [132]. Thus, the reduction of [18F]MPPF BPND observed in patients with TLE could reflect a combination between decreased number of 5-HT1A receptors and a more active PGP pump.

In epilepsy and depression, PET studies of the serotoninergic system focused on 5-HT1A receptors in patients with TLE. Previous PET investigations of 5-HT1A receptors using [ 11C]WAY-100635 and [18F]FC-WAY observed greater BP reduction in the more depressed patients with TLE, suggesting decreased expression of 5-HT1A receptors [126, 127, 133, 134]. This abnormality was primarily reported ipsilateral to the epileptogenic temporal lobe, and more specifically over the anterior cingulate gyrus [126] and the hippocampus [127, 133]. Recently this finding was confirmed in a larger sample of TLE patients, reporting a significant inverse relation between Beck depression inventory (BDI) scores and [18F]FC-WAY 5HT1A receptor plasma free-fraction corrected volume of distribution (V/f1) in the hippocampus ipsilateral to the patient's epileptic focus [134]. In 37 TLE patients with or without hippocampal sclerosis, Hasler et al. [135] also showed lower [18F]FCWAY binding in patients with a history of MDD compared with those without such a history, in hippocampus, temporal neocortex, anterior insula, anterior cingulate and raphe nuclei. However, a recent [11C]WAY-100635 PET study performed in a small population of 13 TLE patients with or without hippocampal sclerosis failed to report any correlation between binding potential and depression [130].

In contrast with these findings, we observed greater BPND of [18F]MPPF in the more depressed TLE patients with hippocampal sclerosis and no previous antidepressant exposure, particu‐ larly within the insula contralateral to seizure onset as well as in the raphe nuclei [8]. Inter‐ estingly, a different set of brain regions was associated with each of the main dimensions explored by the BDI-2, with the insula and raphe abnormalities being associated with symp‐ toms of psychomotor anhedonia and negative cognition, whereas somatic symptoms corre‐ lated with [18F]MPPF BPND in the anterior cingulate gyrus and hippocampus ipsilateral to seizure onset. Considering the sensitivity of [18F]MPPF to the extra-cellular concentration of endogenous 5-HT, the greater [18F]MPPF BPND observed in the more depressed patients suggests a combination of an underlying depletion in the extra-celllular concentration of 5-HT and a decreased density in 5-HT1A receptors.

As previously mentioned, discordance between PET studies of 5-HT1A receptors in patients with epilepsy and depression might also reflect a difference in the modeling methods used to calculate BP [79], the choice of the reference region, as well as the studied patient samples. Indeed, in our [18F]MPPF PET study, we have selected a more homogeneous group of patients than those of previous [11C]WAY-100635 studies; all patients were naïve to previous antide‐ pressant exposure and showed MRI signs of hippocampal sclerosis. Conversely, the propor‐ tion of patients with hippocampal sclerosis varied in other series [126, 127, 133, 134]. The pathophysiology of epilepsy-related depression might differ between TLE patients with and without hippocampal sclerosis [136, 137]. Furthermore, the brain distribution of 5-HT1A receptors would be influenced by previous antidepressant treatment [77]. Finally, it should be noted that antiepileptic drugs, such as carbamazepine [138], could modify the intracerebral concentration of 5-HT. Thus, differences in the proportion of patients with and without depressive symptoms receiving carbamazepine could also play a role in the discordances observed between [18F]MPPF and [11C]WAY-100635 PET findings.

#### **5. Schizophrenia**

Nevertheless, it should be stressed that the P-glycoprotein (PGP) expression could compro‐ mise this interpretation of PET findings. PGP is an ATP-driven transmembrane efflux pump, which is located at the blood-brain barrier and transports a wide variety of substrates from the brain to blood and cerebrospinal fluid. [18F]MPPF being a substrate for PGP, its brain uptake is modulated. An overexpression of PGP is reported in epileptic foci, probably leading to drug resistance in epilepsy [132]. Thus, the reduction of [18F]MPPF BPND observed in patients with TLE could reflect a combination between decreased number of 5-HT1A receptors and a more

158 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

In epilepsy and depression, PET studies of the serotoninergic system focused on 5-HT1A receptors in patients with TLE. Previous PET investigations of 5-HT1A receptors using

11C]WAY-100635 and [18F]FC-WAY observed greater BP reduction in the more depressed patients with TLE, suggesting decreased expression of 5-HT1A receptors [126, 127, 133, 134]. This abnormality was primarily reported ipsilateral to the epileptogenic temporal lobe, and more specifically over the anterior cingulate gyrus [126] and the hippocampus [127, 133]. Recently this finding was confirmed in a larger sample of TLE patients, reporting a significant inverse relation between Beck depression inventory (BDI) scores and [18F]FC-WAY 5HT1A receptor plasma free-fraction corrected volume of distribution (V/f1) in the hippocampus ipsilateral to the patient's epileptic focus [134]. In 37 TLE patients with or without hippocampal sclerosis, Hasler et al. [135] also showed lower [18F]FCWAY binding in patients with a history of MDD compared with those without such a history, in hippocampus, temporal neocortex, anterior insula, anterior cingulate and raphe nuclei. However, a recent [11C]WAY-100635 PET study performed in a small population of 13 TLE patients with or without hippocampal sclerosis failed to report any correlation between binding potential and depression [130].

In contrast with these findings, we observed greater BPND of [18F]MPPF in the more depressed TLE patients with hippocampal sclerosis and no previous antidepressant exposure, particu‐ larly within the insula contralateral to seizure onset as well as in the raphe nuclei [8]. Inter‐ estingly, a different set of brain regions was associated with each of the main dimensions explored by the BDI-2, with the insula and raphe abnormalities being associated with symp‐

active PGP pump.

**Figure 2.** Typical pattern of [18F]MPPF BPND in patients with TLE.

[

Schizophrenia is a severely disabling and complex psychiatric disorder with a lifetime prevalence of approximately 1% in the general population [139]. The diagnosis of schizophre‐ nia encompasses the presence of positive (delusions, hallucinations, thought disorder) and negative (emotional blunting, paucity of speech, loss of motivation, self neglect, and social withdrawal) symptoms, and cognitive deficits (deficits in attention, executive function, and memory). According to DSM-IV-TR, two or more positive symptoms have occurred for at least one month, unless hallucinations or delusions are especially bizarre, in which case one alone suffices for diagnosis. The onset of symptoms typically occurs during adolescence and young adulthood, with men having an earlier age of onset than women. Medical and psychiatric comorbidities, such as substance abuse, anxiety and depressive disorders, are frequent in patients with schizophrenia [140]. Furthermore patients with schizophrenia have higher rates of mortality in comparison to the general population [141].

Schizophrenia has a multifactorial etiology, involving a combination of genetic and environ‐ mental risk factors. Several neurotransmitters systems (dopamine, glutamate, acetylcholine, GABA, serotonin) are altered in schizophrenia. Until recently, the predominant focus of research in the pathophysiology of schizophrenia was the dopaminergic neurotransmission. The current dopamine hypothesis postulates that dopaminergic systems in schizophrenia might be characterized by a cortical/subcortical imbalance. Subcortical mesolimbic dopami‐ nergic projections might be hyperactive (underlying positive symptoms), while mesocortical dopaminergic projections to the prefrontal cortex might be hypoactive (underlying negative symptoms and cognitive impairments) [142]. However, despite over 100 years of research, the precise pathophysiologic mechanisms of schizophrenia still remain unclear.

in the medial prefrontal cortex through the activation of 5-HT1A receptors [159]. Furthermore, aripiprazole does not induce extrapyramidal symptoms in patients with schizophrenia or

The effects of different APDs on 5-HT1A receptors have been evaluated using PET and

11C]WAY-100635 or [18F]MPPF as radioligand, but these series reported conflicting results [151, 161-163]. Two [11C]WAY-100635 PET studies showed contradictory findings in treated schizophrenic patients, reporting either no difference between patients taking clozapine or second generation antipsychotics and age-matched controls [151] or a reduction in BPND obtained after treatment with aripiprazole in comparison to age-matched controls [163]. In addition a recent test-retest study failed to observe a significant effect of chronic treatment of

To investigate the impact of various APDs on the serotoninergic system, we performed a

18F]MPPF PET study in 19 schizophrenic patients treated with either aripiprazole or second

and orbitofrontal cortex, in treated schizophrenic patients compared to age- and gendermatched healthy subjects. These findings may reflect either the pathophysiology of schizophrenia or medication effects. Furthermore, the schizophrenic patients treated with

and schizophrenic patients with second generation antipsychotic treatment. In addition, in

in the schizophrenic patients treated with aripiprazole in comparison to those receiving second generation antipsychotic treatment. These abnormalities were localized in larger clusters encompassing the right and left frontal and orbitofrontal cortex, precunei and cingulate regions, the left temporal region as well as the raphe nuclei. These findings could be due to either occupancy by aripiprazole at 5-HT1A receptors or a decreased 5-HT1A receptor density. These findings may possibly reflect the partial agonist of aripiprazole activity at 5-HT1A receptors. However, no modifications of 5-HT1A receptor density and mRNA expression were found in limbic regions in rats after 12 weeks of aripiprazole

activity of aripiprazole at 5-HT1A receptors. Importantly, in contrast with previous [11C]WAY-100635 PET studies, we take into account cortical atrophy as a confounding factor, by excluding the affected clusters in the right temporal gyrus and insula from our [18F]MPPF PET analyses. These contradictory 5-HT1A receptors PET findings could be attributable to differences in the used radioligands, the choice of the reference region, in sample popula‐ tions, including duration of illness, as well as the in vivo agonist properties at the 5-HT1A

Discordance between [18F]MPPF and [11C]WAY-100635 PET studies of 5-HT1A receptors might reflect their differential sensitivity to extracellular concentration of endogenous 5-HT and to

18F]MPPF BPND mainly in the frontal

PET Imaging of the Serotoninergic 5-HT1A System

http://dx.doi.org/10.5772/57122

161

18F]MPPF BPND was more marked

18F]MPPF BPND in comparison to healthy subjects

18F]MPPF PET data most likely reflect the partial agonist

ziprasidone on the 5-HT1A binding in six schizophrenic patients [162].

generation antipsychotics [161]. We reported a reduced [

comparison to matched controls, the reduction of regional [

aripiprazole showed a reduction of global [

treatment [164]. In our opinion, our [

receptors of studied APDs.

**6. Conclusion**

schizoaffective disorder [160].

[

[

Over the years, there is increasing evidence that the serotonergic 5-HT1A system is involved in the pathophysiology of schizophrenia and its treatment [143]. Abnormalities of 5-HT1A receptors were reported in patients suffering from schizophrenia or schizoaffective disorder. Firstly, most post-mortem studies observed an increased 5-HT1A receptor density (between 17% and 79%) in different brain regions of patients with schizophrenia, including the dorso‐ lateral prefrontal cortex [144-148]. It should be noted that the majority of patients included in post-mortem studies had generally lengthy histories of psychiatric illness and of antipsychotic chronic treatment and/or other medications that could have an impact on the 5-HT1A receptor distribution.

Only few [11C]WAY-100635 PET studies were performed in patients with schizophrenia or schizoaffective disorder and have reported inconsistent results. The first [11C]WAY-100635 PET study showed an increased BPND in the left medial temporal cortex in patients with schizophrenia who were untreated and never previously exposed to antipsychotic drug (APD) compared to healthy subjects [149]. However, other PET series demonstrated a decreased [11C]WAY-100635 BP in the amygdala in drug-free and drug-naïve patients with schizophrenia or schizophreniform disorder (predominantly drug-naïve) [150] or failed to show BP altera‐ tions in various populations of APD-treated, untreated or never exposed to APDs patients with schizophrenia or schizoaffective disorder [151, 152]. There are several possible explanations for these discrepancies including differences in the brain regional distribution of PET changes, in the modeling methods used to calculate BP, in the selected patient samples as well as in their antipsychotic treatment.

Antipsychotic medications are used to treat schizophrenia. Since mid-1950's, numerous APDs with different pharmacological profiles were developed. In agreement with the dopamine hypothesis of schizophrenia, the first generation antipsychotics, such as haloperidol, are dopamine D2 antagonists and are effective for reducing positive symptoms of schizophrenia. However, they are ineffective against negative symptoms and have high propensity for induction of extrapyramidal symptoms. The second generation antipsychotics, such as clozapine, olanzapine or risperidone, present enhanced efficacy in treating positive and negative symptoms and lower rates of extrapyramidal side effects [153]. The latter are potent 5-HT2A/2C receptor antagonists and relatively weak dopamine D2 antagonists.

To date, the development of new APDs focuses on agonist properties at 5-HT1A receptors, pharmacologic profile involved in the treatment of negative symptoms and cognitive deficits of schizophrenia and in the reduction of extrapyramidal side effects [154]. Indeed, preclinical studies reported that 5-HT1A agonists reduced D2-antagonist-induced catalepsy and increased the outflow of dopamine in the striatum [155] and in the medial prefrontal cortex [156, 157]. Aripiprazole is the first APDs with a unique pharmacologic profile combining a partial agonist activity at dopamine D2 receptors, an antagonism at 5-HT2 receptors and a partial agonism at 5-HT1A receptors [158]. In rats, aripiprazole modulates the in-vivo 5-HT and dopamine release in the medial prefrontal cortex through the activation of 5-HT1A receptors [159]. Furthermore, aripiprazole does not induce extrapyramidal symptoms in patients with schizophrenia or schizoaffective disorder [160].

The effects of different APDs on 5-HT1A receptors have been evaluated using PET and [ 11C]WAY-100635 or [18F]MPPF as radioligand, but these series reported conflicting results [151, 161-163]. Two [11C]WAY-100635 PET studies showed contradictory findings in treated schizophrenic patients, reporting either no difference between patients taking clozapine or second generation antipsychotics and age-matched controls [151] or a reduction in BPND obtained after treatment with aripiprazole in comparison to age-matched controls [163]. In addition a recent test-retest study failed to observe a significant effect of chronic treatment of ziprasidone on the 5-HT1A binding in six schizophrenic patients [162].

To investigate the impact of various APDs on the serotoninergic system, we performed a [ 18F]MPPF PET study in 19 schizophrenic patients treated with either aripiprazole or second generation antipsychotics [161]. We reported a reduced [ 18F]MPPF BPND mainly in the frontal and orbitofrontal cortex, in treated schizophrenic patients compared to age- and gendermatched healthy subjects. These findings may reflect either the pathophysiology of schizophrenia or medication effects. Furthermore, the schizophrenic patients treated with aripiprazole showed a reduction of global [ 18F]MPPF BPND in comparison to healthy subjects and schizophrenic patients with second generation antipsychotic treatment. In addition, in comparison to matched controls, the reduction of regional [ 18F]MPPF BPND was more marked in the schizophrenic patients treated with aripiprazole in comparison to those receiving second generation antipsychotic treatment. These abnormalities were localized in larger clusters encompassing the right and left frontal and orbitofrontal cortex, precunei and cingulate regions, the left temporal region as well as the raphe nuclei. These findings could be due to either occupancy by aripiprazole at 5-HT1A receptors or a decreased 5-HT1A receptor density. These findings may possibly reflect the partial agonist of aripiprazole activity at 5-HT1A receptors. However, no modifications of 5-HT1A receptor density and mRNA expression were found in limbic regions in rats after 12 weeks of aripiprazole treatment [164]. In our opinion, our [ 18F]MPPF PET data most likely reflect the partial agonist activity of aripiprazole at 5-HT1A receptors. Importantly, in contrast with previous [11C]WAY-100635 PET studies, we take into account cortical atrophy as a confounding factor, by excluding the affected clusters in the right temporal gyrus and insula from our [18F]MPPF PET analyses. These contradictory 5-HT1A receptors PET findings could be attributable to differences in the used radioligands, the choice of the reference region, in sample popula‐ tions, including duration of illness, as well as the in vivo agonist properties at the 5-HT1A receptors of studied APDs.

#### **6. Conclusion**

nergic projections might be hyperactive (underlying positive symptoms), while mesocortical dopaminergic projections to the prefrontal cortex might be hypoactive (underlying negative symptoms and cognitive impairments) [142]. However, despite over 100 years of research, the

160 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Over the years, there is increasing evidence that the serotonergic 5-HT1A system is involved in the pathophysiology of schizophrenia and its treatment [143]. Abnormalities of 5-HT1A receptors were reported in patients suffering from schizophrenia or schizoaffective disorder. Firstly, most post-mortem studies observed an increased 5-HT1A receptor density (between 17% and 79%) in different brain regions of patients with schizophrenia, including the dorso‐ lateral prefrontal cortex [144-148]. It should be noted that the majority of patients included in post-mortem studies had generally lengthy histories of psychiatric illness and of antipsychotic chronic treatment and/or other medications that could have an impact on the 5-HT1A receptor

Only few [11C]WAY-100635 PET studies were performed in patients with schizophrenia or schizoaffective disorder and have reported inconsistent results. The first [11C]WAY-100635 PET study showed an increased BPND in the left medial temporal cortex in patients with schizophrenia who were untreated and never previously exposed to antipsychotic drug (APD) compared to healthy subjects [149]. However, other PET series demonstrated a decreased [11C]WAY-100635 BP in the amygdala in drug-free and drug-naïve patients with schizophrenia or schizophreniform disorder (predominantly drug-naïve) [150] or failed to show BP altera‐ tions in various populations of APD-treated, untreated or never exposed to APDs patients with schizophrenia or schizoaffective disorder [151, 152]. There are several possible explanations for these discrepancies including differences in the brain regional distribution of PET changes, in the modeling methods used to calculate BP, in the selected patient samples as well as in

Antipsychotic medications are used to treat schizophrenia. Since mid-1950's, numerous APDs with different pharmacological profiles were developed. In agreement with the dopamine hypothesis of schizophrenia, the first generation antipsychotics, such as haloperidol, are dopamine D2 antagonists and are effective for reducing positive symptoms of schizophrenia. However, they are ineffective against negative symptoms and have high propensity for induction of extrapyramidal symptoms. The second generation antipsychotics, such as clozapine, olanzapine or risperidone, present enhanced efficacy in treating positive and negative symptoms and lower rates of extrapyramidal side effects [153]. The latter are potent

To date, the development of new APDs focuses on agonist properties at 5-HT1A receptors, pharmacologic profile involved in the treatment of negative symptoms and cognitive deficits of schizophrenia and in the reduction of extrapyramidal side effects [154]. Indeed, preclinical studies reported that 5-HT1A agonists reduced D2-antagonist-induced catalepsy and increased the outflow of dopamine in the striatum [155] and in the medial prefrontal cortex [156, 157]. Aripiprazole is the first APDs with a unique pharmacologic profile combining a partial agonist activity at dopamine D2 receptors, an antagonism at 5-HT2 receptors and a partial agonism at 5-HT1A receptors [158]. In rats, aripiprazole modulates the in-vivo 5-HT and dopamine release

5-HT2A/2C receptor antagonists and relatively weak dopamine D2 antagonists.

precise pathophysiologic mechanisms of schizophrenia still remain unclear.

distribution.

their antipsychotic treatment.

Discordance between [18F]MPPF and [11C]WAY-100635 PET studies of 5-HT1A receptors might reflect their differential sensitivity to extracellular concentration of endogenous 5-HT and to the internalization of 5-HT1A autoreceptors, but also differences in the data modeling strategies used to calculate BP, including the choice of the reference region (inclusion of cerebellar vermis and gray matter in the reference region)[79], and the population studied. We should also bear in mind that the genetic background for each subject and the gene-by-environment interaction can have a significant influence in different directions on [18F]MPPF and [11C]WAY-100635 PET findings, which is difficult to control for in the small samples of patients and healthy subjects included in PET studies [41-46].

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In future PET studies of 5-HT1A receptors, a more detailed clinical description of studied patients would improve the understanding of discrepancies between studies. Furthermore, particular attention should be paid to the constitution of a group of healthy subjects matched for confounding factors, such as age and sex. For instance, a PET study reported a lower cortical trapping of the alpha-[11C]Methyl-L-Tryptophan (AMT) in women compared to men [165].

Future studies should aim at disentangling these issues by using a traditional multi-injection [ <sup>18</sup>F]MPPF protocol that enables a precise quantification of binding parameters (B′MAX; Kd) and the estimation of extracellular 5-HT concentration [166] or by coupling [18F]MPPF and [ 11C]WAY-100635 PET studies in the same individuals taking advantage of their different affinities for 5-HT1A receptors. Another future challenge will be to image endogenous 5HT release in humans [167].

#### **Acknowledgements**

We thank Didier Le Bars for [18F]MPPF radiosynthesis and the medical team of the CERMEP – Imagerie du vivant. We are indebted to Nicolas Costes and Jérôme Redouté.

The Article Processing Charge was funded by the Translational and Integrative Group in Epilepsy Research (TIGER) (CRNL).

#### **Author details**

Amélie Lothe1\*, Sandrine Bouvard1 and Philippe Ryvlin1,2

\*Address all correspondence to: amelie.lothe@cermep.fr

1 INSERM U1028, CNRS UMR5292, and University Claude Bernard Lyon 1, Lyon Neuro‐ science Research Center, Translational and Integrative Group in Epilepsy Research (TIGER), Lyon, France

2 Department of Functional Neurology and Epileptology and Institute for Children and Adolescents with Epilepsy (IDEE), Hospices Civils de Lyon, Lyon, France

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162 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

In future PET studies of 5-HT1A receptors, a more detailed clinical description of studied patients would improve the understanding of discrepancies between studies. Furthermore, particular attention should be paid to the constitution of a group of healthy subjects matched for confounding factors, such as age and sex. For instance, a PET study reported a lower cortical trapping of the alpha-[11C]Methyl-L-Tryptophan (AMT) in women compared to men [165].

Future studies should aim at disentangling these issues by using a traditional multi-injection

<sup>18</sup>F]MPPF protocol that enables a precise quantification of binding parameters (B′MAX; Kd) and the estimation of extracellular 5-HT concentration [166] or by coupling [18F]MPPF and

11C]WAY-100635 PET studies in the same individuals taking advantage of their different affinities for 5-HT1A receptors. Another future challenge will be to image endogenous 5HT

We thank Didier Le Bars for [18F]MPPF radiosynthesis and the medical team of the CERMEP

The Article Processing Charge was funded by the Translational and Integrative Group in

and Philippe Ryvlin1,2

1 INSERM U1028, CNRS UMR5292, and University Claude Bernard Lyon 1, Lyon Neuro‐ science Research Center, Translational and Integrative Group in Epilepsy Research (TIGER),

2 Department of Functional Neurology and Epileptology and Institute for Children and

Adolescents with Epilepsy (IDEE), Hospices Civils de Lyon, Lyon, France

– Imagerie du vivant. We are indebted to Nicolas Costes and Jérôme Redouté.

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**Acknowledgements**

**Author details**

Lyon, France

Epilepsy Research (TIGER) (CRNL).

Amélie Lothe1\*, Sandrine Bouvard1

\*Address all correspondence to: amelie.lothe@cermep.fr

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[163] Mamo D, Graff A, Mizrahi R, Shammi CM, Romeyer F, Kapur S. Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A) receptor occupancy in patients with schizophrenia: a triple tracer PET study. Am J Psychiatry 2007;164(9):1411-1417.

[164] Han M, Huang XF, du Bois TM, Deng C. The effects of antipsychotic drugs adminis‐ tration on 5-HT1A receptor expression in the limbic system of the rat brain. Neuro‐

[165] Sakai Y, Nishikawa M, Leyton M, Benkelfat C, Young SN, Diksic M. Cortical trap‐ ping of alpha-[(11)C]methyl-l-tryptophan, an index of serotonin synthesis, is lower in

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tipsychotics. Arch Gen Psychiatry 2003;60:553–564

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[153] Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation an‐ tipsychotics. Arch Gen Psychiatry 2003;60:553–564

[140] Buckley PF, Miller BJ, Lehrer DS, Castle DJ. Psychiatric comorbidities and schizo‐

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[141] Saha S, Chant D, McGrath J. Meta-analyses of the incidence and prevalence of schizo‐ phrenia: conceptual and methodological issues. Int J Methods Psychiatr Res.

[142] Abi-Dargham A. Do we still believe in the dopamine hypothesis? New data bring

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[144] Hashimoto T, Nishino N, Nakai H and Tanaka C. Increase in serotonin 5-HT1A re‐ ceptors in prefrontal and temporal cortices of brains from patients with chronic

[145] Joyce JN, Shane A, Lexow N, Winokur A, Casanova MF and Kleinman JE. Serotonin uptake sites and serotonin receptors are altered in the limbic system of schizophren‐

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[166] Costes N, Benkelfat C, Zimmer L, Dagher A, Le Bars D. Toward a quantification of extra-cellular brain endogenous serotonin concentration with [18F]MPPF in PET and a multi-injection protocol. NeuroReceptor Mapping 08, Pittsburg. Neuroimage 2008;T149.

**Chapter 7**

**Pathological Gambling: PET Studies**

Daniela Santoro and Stefano Pallanti

more about pathophysiology of this disorder.

function of these structures both in the pathological gambling.

**2. Brain areas involved**

http://dx.doi.org/10.5772/57125

**1. Introduction**

Additional information is available at the end of the chapter

Pathological gambling(PG) affects 1–3% of the adult population, and has high comorbidity [1].

PG is a persistent or maladaptive gambling behavior characterized by excessive time con‐ sumed to gambling or thinking about gambling, needing togamble with increasing amounts of money,chasingone's losses,unsuccessfulefforts tostopgamblingandfinancial/socialproblems due to gambling. Hence, PG can also be considered as a behavioral addiction since the charac‐ teristics and diagnostic criteria share many common features with substance addictions [2].

PGcanbeclassifiedasanimpulsecontroldisorder,thatcanbedescribedasa"chain"ofsubjective states including arousal, craving and acting, accompanied by a feeling of elation and followed

It is widely suggested that gambling excitement is central to the disorder, and that it is associated with physiological measures of arousal, that are increased during the gambling [4].

It's become a common opinion among researchers that the use of imaging studies as Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) can be a way to learn

Functional imaging studies of the prefrontal and orbitofrontal cortex have implicated dys‐

A recently published functional magnetic resonance imaging (fMRI) study reported that the healthy controls activated their ventromedial and subgenual prefrontal cortex during a 'loss-

> © 2013 Santoro and Pallanti; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

by disphoria, all of which are supposed related to an underpinning neurobiology [3].

[167] Paterson LM, Tyacke RJ, Nutt DJ, Knudsen GM. Measuring endogenous 5-HT release by emission tomography: promises and pitfalls. J Cereb Blood Flow Metab. 2010;30(10):1682-706.

#### **Chapter 7**

### **Pathological Gambling: PET Studies**

#### Daniela Santoro and Stefano Pallanti

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57125

#### **1. Introduction**

[166] Costes N, Benkelfat C, Zimmer L, Dagher A, Le Bars D. Toward a quantification of extra-cellular brain endogenous serotonin concentration with [18F]MPPF in PET and a multi-injection protocol. NeuroReceptor Mapping 08, Pittsburg. Neuroimage

176 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

[167] Paterson LM, Tyacke RJ, Nutt DJ, Knudsen GM. Measuring endogenous 5-HT release by emission tomography: promises and pitfalls. J Cereb Blood Flow Metab.

2008;T149.

2010;30(10):1682-706.

Pathological gambling(PG) affects 1–3% of the adult population, and has high comorbidity [1].

PG is a persistent or maladaptive gambling behavior characterized by excessive time con‐ sumed to gambling or thinking about gambling, needing togamble with increasing amounts of money,chasingone's losses,unsuccessfulefforts tostopgamblingandfinancial/socialproblems due to gambling. Hence, PG can also be considered as a behavioral addiction since the charac‐ teristics and diagnostic criteria share many common features with substance addictions [2].

PGcanbeclassifiedasanimpulsecontroldisorder,thatcanbedescribedasa"chain"ofsubjective states including arousal, craving and acting, accompanied by a feeling of elation and followed by disphoria, all of which are supposed related to an underpinning neurobiology [3].

It is widely suggested that gambling excitement is central to the disorder, and that it is associated with physiological measures of arousal, that are increased during the gambling [4].

It's become a common opinion among researchers that the use of imaging studies as Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) can be a way to learn more about pathophysiology of this disorder.

#### **2. Brain areas involved**

Functional imaging studies of the prefrontal and orbitofrontal cortex have implicated dys‐ function of these structures both in the pathological gambling.

A recently published functional magnetic resonance imaging (fMRI) study reported that the healthy controls activated their ventromedial and subgenual prefrontal cortex during a 'loss-

chasing game' more then during decisions to quit. The authors suggested that PG patients may have a neural substrate involving these areas, as loss-chasing is one of the cardinal symptoms of the disorder [1]. Compared to controls, patients with PG had greater activation of the prefrontal cortex Brodmann Areas (BA) 9 and 44 while watching gambling-related images [5], lending evidence to the hypothesis that prefrontal cortex areas were also involved in craving aspects of pathological gambling.

RDoC classification rests on three assumptions. First, the RDoC framework conceptualizes mental illnesses as brain disorders. In contrast to neurological disorders with identifiable lesions, mental disorders can be addressed as disorders of brain circuits. Second, RDoC classification assumes that the dysfunction in neural circuits can be identified with the tools of clinical neuroscience, including electrophysiology, functional neuroimaging, and new methods for quantifying connections in vivo. Third, the RDoC framework assumes that data from genetics and clinical neuroscience will yield biosignatures that will augment clinical

Pathological Gambling: PET Studies http://dx.doi.org/10.5772/57125 179

Examples where clinically relevant models of circuitry-behavior relationships augur future clinical use include fear/extinction, reward, executive function, and impulse control. The practitioner of the future could supplement a clinical evaluation of mental disorders with data from functional or structural imaging, genomic sequencing, and laboratory-based evaluations of fear conditioning and extinction to determine prognosis and appropriate treatment,

The RDoC focuses on neural circuitry, with levels of analysis progressing in one of two directions: upwards from measures of circuitry function to clinically relevant variation, or downwards to the genetic and molecular/cellular factors that ultimately influence such function. [9] Fear circuitry and executive functioning are examples of two functional domains where the relevant circuitry and behaviors seem relatively clear, and these have been selected as the initial areas to be developed; other examples might include reward circuitry and frontostriatal circuits. So, we could begin to create neurobiological circuit maps of behavioral and cognitive functioning and explicate the ways in which activity in these circuits becomes

Patient subjects with relevant presenting psychopathology might be grouped on the basis of a genetic polymorphism or a particular response to a neuroimaging task rather than a DSM/ICD diagnosis; in this manner, investigators can query relevant mechanisms as they cut

The rationale for the RDoC approach is to facilitate translation of modern molecular biology, neuroscience, and behavioral approaches toward explicating the pathophysiology of disor‐ ders. By targeting circuit functioning and relevant behaviors, one particular goal is that this

RDoC's integrative approach includes cognition along with social processes, arousal/ regulatory systems, and negative and positive valence systems as the major domains, because these neurobehavioral systems have all evolved to serve the motivational and adaptive needs of the organism. With its focus on neural circuits informed by the grow‐ ing evidence of the neurodevelopmental nature of many disorders and its capacity to capture the patterns of co-occurrence of behaviors and symptoms, the RDoC approach holds

Based on RDoC approach, we could identify some neural circuits supposed involved in PG: Nucleos Accumbes (NA) - Orbital Frontal Cortex (OFC) relatively to craving; OFC - Caudates Nucleus (NC) respect to inhibition failure; Limbic system – OFC concerning to affective

process will direct the search for treatment targets in various domains. [11]

promise to advance our understanding of the nature of mental disorders. [12]

analogous to what is done routinely today in many other areas of medicine.

symptoms and signs for clinical management.

dysregulated in mental disorders.

across traditional categories. [10]

Hollander et al. in a previous study [6], in an entirely different cohort of PG patients assessed with FDG-PET, found that monetary-rewarded blackjack was associated with a significantly higher relative metabolic rate in the primary visual cortex (BA 17), the cingulate gyrus (BA 24), the putamen, and prefrontal BA areas 47 and 10 compared to playing blackjack for points only.

An fMRI study of the Iowa Gambling Task (IGT) confirmed medial frontal/cingulated activation during decision-making and greater activation in gamblers than controls in ventral medial frontal areas [7]. This pattern suggests heightened limbic and sensory activation in gambling for monetary reward with increased emotional valence, and confirms the salience of monetary reward in PG.

Other MRI studies on healthy volunteers responding to monetary consequences reported an activation in prefrontal and premotor cortices. This has been interpreted as related to the integration of reward choice salience and preparatory behaviors for obtaining rewards. The basal ganglia and the caudate nucleus in particular are fundamental structures for liking behavior to rewarding and aversive outcome, and they are also involved in modulation decision-making and risk-taking behaviours. These structures have a key role in learning and reasoning processes, and this is reflected in basal ganglia dysfunction.

Some studies have proposed that the salience of monetary reward would be correlated to caudate and nucleus accumbens activation [3]

#### **3. Investigations on neural circuits involved**

Over the past 2 decades, National Institute of Mental Health (NIMH) has supported research to understand mental disorders as brain disorders. NIMH has therefore launched the Research Domain Criteria (RDoC) project.

RDoC is an experimental approach to the classification of mental disorders that incorporates multiple dimensions: behavior, thought patterns, neurobiological measures, and genetics. RDoC uses genetics, imaging, and cognitive science for understanding deficits in social behavior. The RDoC project has a primary focus on neural circuits. While genes cut across the current diagnostic labels, neuroimaging often helps us to sub-divide current groups. This is particularly interesting when we consider the PG and signs of behavioral alterations related.

The RDoC framework is a heuristic to facilitate the incorporation of behavioral neuroscience in the study of psychopathology. RDoC first aims to identify reliable and valid psychological and biological mechanisms and their disruptions, with an eventual goal of understanding how anomalies in these mechanisms drive psychiatric symptoms [8].

RDoC classification rests on three assumptions. First, the RDoC framework conceptualizes mental illnesses as brain disorders. In contrast to neurological disorders with identifiable lesions, mental disorders can be addressed as disorders of brain circuits. Second, RDoC classification assumes that the dysfunction in neural circuits can be identified with the tools of clinical neuroscience, including electrophysiology, functional neuroimaging, and new methods for quantifying connections in vivo. Third, the RDoC framework assumes that data from genetics and clinical neuroscience will yield biosignatures that will augment clinical symptoms and signs for clinical management.

chasing game' more then during decisions to quit. The authors suggested that PG patients may have a neural substrate involving these areas, as loss-chasing is one of the cardinal symptoms of the disorder [1]. Compared to controls, patients with PG had greater activation of the prefrontal cortex Brodmann Areas (BA) 9 and 44 while watching gambling-related images [5], lending evidence to the hypothesis that prefrontal cortex areas were also involved in craving

178 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Hollander et al. in a previous study [6], in an entirely different cohort of PG patients assessed with FDG-PET, found that monetary-rewarded blackjack was associated with a significantly higher relative metabolic rate in the primary visual cortex (BA 17), the cingulate gyrus (BA 24), the putamen, and prefrontal BA areas 47 and 10 compared to playing blackjack for points only. An fMRI study of the Iowa Gambling Task (IGT) confirmed medial frontal/cingulated activation during decision-making and greater activation in gamblers than controls in ventral medial frontal areas [7]. This pattern suggests heightened limbic and sensory activation in gambling for monetary reward with increased emotional valence, and confirms the salience

Other MRI studies on healthy volunteers responding to monetary consequences reported an activation in prefrontal and premotor cortices. This has been interpreted as related to the integration of reward choice salience and preparatory behaviors for obtaining rewards. The basal ganglia and the caudate nucleus in particular are fundamental structures for liking behavior to rewarding and aversive outcome, and they are also involved in modulation decision-making and risk-taking behaviours. These structures have a key role in learning and

Some studies have proposed that the salience of monetary reward would be correlated to

Over the past 2 decades, National Institute of Mental Health (NIMH) has supported research to understand mental disorders as brain disorders. NIMH has therefore launched the Research

RDoC is an experimental approach to the classification of mental disorders that incorporates multiple dimensions: behavior, thought patterns, neurobiological measures, and genetics. RDoC uses genetics, imaging, and cognitive science for understanding deficits in social behavior. The RDoC project has a primary focus on neural circuits. While genes cut across the current diagnostic labels, neuroimaging often helps us to sub-divide current groups. This is particularly interesting when we consider the PG and signs of behavioral alterations related. The RDoC framework is a heuristic to facilitate the incorporation of behavioral neuroscience in the study of psychopathology. RDoC first aims to identify reliable and valid psychological and biological mechanisms and their disruptions, with an eventual goal of understanding how

reasoning processes, and this is reflected in basal ganglia dysfunction.

caudate and nucleus accumbens activation [3]

Domain Criteria (RDoC) project.

**3. Investigations on neural circuits involved**

anomalies in these mechanisms drive psychiatric symptoms [8].

aspects of pathological gambling.

of monetary reward in PG.

Examples where clinically relevant models of circuitry-behavior relationships augur future clinical use include fear/extinction, reward, executive function, and impulse control. The practitioner of the future could supplement a clinical evaluation of mental disorders with data from functional or structural imaging, genomic sequencing, and laboratory-based evaluations of fear conditioning and extinction to determine prognosis and appropriate treatment, analogous to what is done routinely today in many other areas of medicine.

The RDoC focuses on neural circuitry, with levels of analysis progressing in one of two directions: upwards from measures of circuitry function to clinically relevant variation, or downwards to the genetic and molecular/cellular factors that ultimately influence such function. [9] Fear circuitry and executive functioning are examples of two functional domains where the relevant circuitry and behaviors seem relatively clear, and these have been selected as the initial areas to be developed; other examples might include reward circuitry and frontostriatal circuits. So, we could begin to create neurobiological circuit maps of behavioral and cognitive functioning and explicate the ways in which activity in these circuits becomes dysregulated in mental disorders.

Patient subjects with relevant presenting psychopathology might be grouped on the basis of a genetic polymorphism or a particular response to a neuroimaging task rather than a DSM/ICD diagnosis; in this manner, investigators can query relevant mechanisms as they cut across traditional categories. [10]

The rationale for the RDoC approach is to facilitate translation of modern molecular biology, neuroscience, and behavioral approaches toward explicating the pathophysiology of disor‐ ders. By targeting circuit functioning and relevant behaviors, one particular goal is that this process will direct the search for treatment targets in various domains. [11]

RDoC's integrative approach includes cognition along with social processes, arousal/ regulatory systems, and negative and positive valence systems as the major domains, because these neurobehavioral systems have all evolved to serve the motivational and adaptive needs of the organism. With its focus on neural circuits informed by the grow‐ ing evidence of the neurodevelopmental nature of many disorders and its capacity to capture the patterns of co-occurrence of behaviors and symptoms, the RDoC approach holds promise to advance our understanding of the nature of mental disorders. [12]

Based on RDoC approach, we could identify some neural circuits supposed involved in PG: Nucleos Accumbes (NA) - Orbital Frontal Cortex (OFC) relatively to craving; OFC - Caudates Nucleus (NC) respect to inhibition failure; Limbic system – OFC concerning to affective instability; Anterior Cingulate Cortex (ACC) – OFC about economic decision making. These networks represent hypotheses to be studied to understand the mechanisms underpinning the PG, a disorder regarding addiction and decision making.

in patients with PG [16]. Personality traits commonly associated with PD, such as impulsivity and antisociality, are also associated with increased, and not decreased, mesolimbic DA

Pathological Gambling: PET Studies http://dx.doi.org/10.5772/57125 181

Striatal DA is released during gambling irrespective of gambling outcome suggesting that the mere expectation/prediction of reward is sufficient to induce dopaminergic changes. Greater gambling symptom severity is associated with greater dopaminergic responses. The dopami‐ nergic response to reward-predicting stimulus and the linkage between addiction severity and DA release in pathological gamblers may play roles in the development and the symptoma‐

Individuals suffering from substance abuse and dependence have cognitive and behavioural decision-making impairments similar to PG, that could be associated with dopaminergic dysregulations. Recent researches suggest that the dopamine system and ventral striatum play a central role in PG as well as substance dependence. In healthy controls DA appears to be associated with, instead in PG dopamine might be also associated with monetary losses. This suggest a dopaminergic base of susceptibility to immediate reward seeking in PG [21].

In PG the DA system may be associated with dysfunctional learning (reward prediction error), that is associated with increased activation of midbrain DA neurons, which stimulate synaptic

Impulse control disorders such as PG are a serious and common adverse effect of DA replace‐ ment medication in PD. Patients with PG have increased impulsivity and abnormalities in striatal DA, in common with behavioural and substance addictions in the non-PD population. Symptomatic relief of motor symptoms in PD is achieved by increasing endogenous dopamine levels using levodopa, or by synthetic activation of DA receptors using DA agonists. DA agonists in particular may contribute to the development of impulse control disorders (ICDs) in about 13% of PD patients [22, 23]. PD patients with PG have dysfunctional activation of DA autoreceptors in the midbrain and low DA tone in the anterior cingulated cortex. Thus, altered striatal and cortical DA homeostasis may incur vulnerability for the development of PG in PD, linked with the impulsive personality trait. Natural variation in DA homeostasis in the midbrain and cortex can impact an individuals' propensity for impulsivity and, as such, modulate risk for ICDs in PD. DA agonists may exaggerate these dopaminergic influences over behaviour, turning a previous tendency to engage in rewarding activities into a pathological

More recently, Linnet et al. [25] investigated the dopaminergic coding of reward and uncer‐ tainty in PG sufferers and healthy controls. They used PET with the tracer [(11)C]raclopride to measure DA release, and they used performance on the Iowa Gambling Task (IGT) to determine overall reward and uncertainty. The data supported an inverse relation between striatal DA release and IGT performance if the PG group, but not in the healthy control group. These findings are consistent with the hypothesis of dopaminergic sensitivity toward uncer‐ tainty, and show as dopaminergic sensitivity to uncertainty is pronounced in PG, but not among non-gambling healthy controls. So it's reasonable to assume that, in PG patients, decisions with maximum uncertainty and variance are associated with the highest dopami‐

responses [17,18, 19].

tology of the maladaptive gambling behavior [20].

DA release in the striatum and through the brain.

inability to abstain from them [24].

In this respect, PET could become a key tool in this evolving diagnostic and therapeutic process.

#### **4. The role of dopamine**

Brain dopamine neurons code rewarding environmental stimuli by releasing endogenous dopamine (DA), a transmission signal that is important for reinforcement learning. Human reward-seeking gambling behavior, and especially PG, has been presumed to be modulated by brain DA [13].

Several neurotransmitters, and especially DA, have been implicated in the neurobiology of PG [4]. Its release is associated with change in subjective experience and reinforcement of behavior.

Linnet et al. [4] in their study proposed that DA release would be associated with increased excitement levels in PG compared with healthy controls. The study showed that PG with decreased binding potentials in the ventral striatum had significantly higher excitement levels than healthy controls. DA is a neurotransmitter associated with addictive behaviours through a heightened sensitivity to certain types of "reward" such as foods high in sugar or fat content and substances such as cocaine or metamphetamine.

Even if systemic pharmacological interventions such as cocaine and amphetamine lead to release of DA in the whole dorsal and ventral striatum, it appears that more specific types of stimulation leads to regionally restricted dopamine release. And this is supported by the segregation of cortical and and sub-cortical imputs to the striatum.

The relation between DA release and bahavioural reward suggests that the DA system is associated with maladaptative behavior in PG [14].

The salience of monetary reward was reported as correlated to caudate and nucleus accumbens activation. It has been supposed that a dopaminergic neuron activity in these regions may be involved in the acquisition of the associations between salient contextual stimuli and reward‐ ing events [3].

The role of DA in PG is further supported by reports of associations between dopaminergic medications and impulse control disorders in patients with Parkinson's disease (PD) [15]. There are only a few reported functional imaging studies in pathological gamblers with contradicting support for the concept of reward deficiency.

In pathological gamblers, DA release correlated positively with gambling symptom severity. The gamblers who have the most severe symptoms release the most DA. Correlation analyses showed that the most severely addicted gamblers released more DA during high reward gambling than less addicted gamblers. A Positron Emission Tomography (PET) study investigating PD patients with and without PG, showed increased DA release during gambling in patients with PG [16]. Personality traits commonly associated with PD, such as impulsivity and antisociality, are also associated with increased, and not decreased, mesolimbic DA responses [17,18, 19].

instability; Anterior Cingulate Cortex (ACC) – OFC about economic decision making. These networks represent hypotheses to be studied to understand the mechanisms underpinning the

180 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

In this respect, PET could become a key tool in this evolving diagnostic and therapeutic process.

Brain dopamine neurons code rewarding environmental stimuli by releasing endogenous dopamine (DA), a transmission signal that is important for reinforcement learning. Human reward-seeking gambling behavior, and especially PG, has been presumed to be modulated

Several neurotransmitters, and especially DA, have been implicated in the neurobiology of PG [4]. Its release is associated with change in subjective experience and reinforcement of behavior.

Linnet et al. [4] in their study proposed that DA release would be associated with increased excitement levels in PG compared with healthy controls. The study showed that PG with decreased binding potentials in the ventral striatum had significantly higher excitement levels than healthy controls. DA is a neurotransmitter associated with addictive behaviours through a heightened sensitivity to certain types of "reward" such as foods high in sugar or fat content

Even if systemic pharmacological interventions such as cocaine and amphetamine lead to release of DA in the whole dorsal and ventral striatum, it appears that more specific types of stimulation leads to regionally restricted dopamine release. And this is supported by the

The relation between DA release and bahavioural reward suggests that the DA system is

The salience of monetary reward was reported as correlated to caudate and nucleus accumbens activation. It has been supposed that a dopaminergic neuron activity in these regions may be involved in the acquisition of the associations between salient contextual stimuli and reward‐

The role of DA in PG is further supported by reports of associations between dopaminergic medications and impulse control disorders in patients with Parkinson's disease (PD) [15]. There are only a few reported functional imaging studies in pathological gamblers with

In pathological gamblers, DA release correlated positively with gambling symptom severity. The gamblers who have the most severe symptoms release the most DA. Correlation analyses showed that the most severely addicted gamblers released more DA during high reward gambling than less addicted gamblers. A Positron Emission Tomography (PET) study investigating PD patients with and without PG, showed increased DA release during gambling

PG, a disorder regarding addiction and decision making.

and substances such as cocaine or metamphetamine.

associated with maladaptative behavior in PG [14].

contradicting support for the concept of reward deficiency.

segregation of cortical and and sub-cortical imputs to the striatum.

**4. The role of dopamine**

by brain DA [13].

ing events [3].

Striatal DA is released during gambling irrespective of gambling outcome suggesting that the mere expectation/prediction of reward is sufficient to induce dopaminergic changes. Greater gambling symptom severity is associated with greater dopaminergic responses. The dopami‐ nergic response to reward-predicting stimulus and the linkage between addiction severity and DA release in pathological gamblers may play roles in the development and the symptoma‐ tology of the maladaptive gambling behavior [20].

Individuals suffering from substance abuse and dependence have cognitive and behavioural decision-making impairments similar to PG, that could be associated with dopaminergic dysregulations. Recent researches suggest that the dopamine system and ventral striatum play a central role in PG as well as substance dependence. In healthy controls DA appears to be associated with, instead in PG dopamine might be also associated with monetary losses. This suggest a dopaminergic base of susceptibility to immediate reward seeking in PG [21].

In PG the DA system may be associated with dysfunctional learning (reward prediction error), that is associated with increased activation of midbrain DA neurons, which stimulate synaptic DA release in the striatum and through the brain.

Impulse control disorders such as PG are a serious and common adverse effect of DA replace‐ ment medication in PD. Patients with PG have increased impulsivity and abnormalities in striatal DA, in common with behavioural and substance addictions in the non-PD population. Symptomatic relief of motor symptoms in PD is achieved by increasing endogenous dopamine levels using levodopa, or by synthetic activation of DA receptors using DA agonists. DA agonists in particular may contribute to the development of impulse control disorders (ICDs) in about 13% of PD patients [22, 23]. PD patients with PG have dysfunctional activation of DA autoreceptors in the midbrain and low DA tone in the anterior cingulated cortex. Thus, altered striatal and cortical DA homeostasis may incur vulnerability for the development of PG in PD, linked with the impulsive personality trait. Natural variation in DA homeostasis in the midbrain and cortex can impact an individuals' propensity for impulsivity and, as such, modulate risk for ICDs in PD. DA agonists may exaggerate these dopaminergic influences over behaviour, turning a previous tendency to engage in rewarding activities into a pathological inability to abstain from them [24].

More recently, Linnet et al. [25] investigated the dopaminergic coding of reward and uncer‐ tainty in PG sufferers and healthy controls. They used PET with the tracer [(11)C]raclopride to measure DA release, and they used performance on the Iowa Gambling Task (IGT) to determine overall reward and uncertainty. The data supported an inverse relation between striatal DA release and IGT performance if the PG group, but not in the healthy control group. These findings are consistent with the hypothesis of dopaminergic sensitivity toward uncer‐ tainty, and show as dopaminergic sensitivity to uncertainty is pronounced in PG, but not among non-gambling healthy controls. So it's reasonable to assume that, in PG patients, decisions with maximum uncertainty and variance are associated with the highest dopami‐ nergic activation. Morevover, dopaminergic coding of variance in IGT performance in PG was strongest in the combined striatum and in the ROI(Return On Investment) analysis, only the putamen reached significance level. This may suggest a strong role of the putamen in relation to uncertainty, which may exceed that of the ventral striatum by a factor of 2 to 3.

scans, one with the D3 receptor preferring agonist [11C]-(+)-propyl-hexahydro-naphthooxazin (PHNO) and the other with [11C]raclopride, to assess D2/3 DA receptor availability, and behavioural measures (self-report questionnaires and slot-machine game) to assess subjective effects and relationships to PET measures. The key findings of this study are two: first, in contrast to SUD, PG subjects'binding profile for both D2 and D3 receptor subtypes did not differ significantly from those of healthy controls, suggesting different neurobiological signatures between PG and SUD. Secondly, the study provides novel information regarding the D3 receptor in PG, showing a relationship between D3 levels across PG subjects and symptom severity and impulsiveness. So, D3 may be a viable marker for vulnerability across addictions and a potential target for intervention. The apparent ability of DA agonists in general, and D3-preferring agonists, in particular, to induce impulse control disorders in some patients, suggested an important role for this receptor in PG: its distribution on brain structures receiving afferent ventral striatal projections suggests that its activity can modify limbic

Pathological Gambling: PET Studies http://dx.doi.org/10.5772/57125 183

Savitz et al. [31] have tested the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (Ser9Gly, rs6280) on reward-associated DA release in the Striatum. They used two PET scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). Since PET- [11C]raclopride technique allows exploration of the effects of genetic variation on the amount of DA released under conditions associated with increased phasic release of DA, such as during receipt of unpredicted reward, during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding in the middle caudate and the ventral striatum. Moreover they showed as the glycine allele yields D3 autoreceptors have a

As discussed in Joutsa et al. [13], the binding of [11C]raclopride is sensitive to changes in striatal DA concentration during receipt of non-pharmacological rewards such as a video game, large monetary wins versus large monetary losses and the monetary incentive delay task. Notably, in this study of pathological gamblers and healthy controls who completed 3 PET scans with

11C]raclopride while gambling with a slot machine, the severity of addiction to gambling was positively associated with the degree of DA release in the basal ganglia during gambling.

Consistent with these results, highly impulsive individuals, who are thought to be vulnerable to developing addiction disorders, were shown to have diminished availability of striatal D2/3

The PET imaging data are potentially important because genetically & not genetically-driven differences in DA receptor function may influence the changes in dopaminergic signaling that

autoreceptors, potentially predisposing them to a greater phasic DA response [18].

modulate emotional, motivational and stress responses.

higher affinity for DA and display more robust intracellular signaling.

output, and thus motivation for reward.

[

**6. Conclusions**

#### **5. PET specific studies**

Hollander et al. [26] therefore hypothesized that lithium effects would decrease relative metabolic rate in at least some portions of the cingulate and orbitofrontal systems. Since they have recently reported elevated relative white matter metabolic rates in frontal regions in patients with schizophrenia [20], and since the statistical parametric mapping analysis in fMRI gambling studies showed group difference clusters partially encompassing white matter underlying cortical areas [7], they assessed white matter metabolic rates underlying each BA on an exploratory basis. In another previous treatment study, lithium was effective in reducing both gambling behavior and affective instability [27].

Although mood stabilizers and serotonin reuptake inhibitors have shown some efficacy in the treatment of this condition, there is little known about how these pharmacological interven‐ tions work. In patients with PG, relative glucose metabolic rates (rGMR) in the orbitofrontal cortex and medial frontal cortex were significantly increased at baseline compared to normal controls. Lithium administration was associated with widespread effects in the prefrontal cortex and cingulate gyrus. Lithium increased rGMR further in the orbitofrontal cortex, heightening normal/patient differences, but it also increased the rGMR of the posterior cingulate and the dorsolateral frontal cortex normalizing the metabolic rate in these regions.

Cortical areas implicated in impulse control disorders show increased rGMR in PG at baseline. Lithium treatment, while alleviating the symptoms, further increases rGMR in these areas [18].

Buckholtz et al. [17, 18], using the PET ligand [18F] Fallypride, found that trait impulsivity was negatively associated with binding to DA D2/3 receptors in the midbrain. DA receptors in this region are dominated by autoreceptors [28], which function to limit striatal DA release following reward. This suggests that midbrain autoreceptors influence individuals' propensity for impulsivity, and opens the possibility that excessive striatal DA release following gambling rewards in PD patients with PG, shown in Steeves et al. [29], stems from reduced control overstriatal DA by midbrain autoreceptors.

Ray et al. [19] reported the results of their PET and [11C] FLB-457 study, a radiotracer with high affinity for DA D2/3 receptors, and therefore sensitivity to extrastriatal, showing midbrain and prefrontal cortex dopaminergic differences in PD patients with and without PG. They suggested that impaired DA homeostasis in the midbrain, resulting in increased striatal DA release during reward, may be responsible for increased impulsivity and therefore vulnera‐ bility for addiction in these patients.

Recently, Boileau et al. [30] used PET to test whether PG is associated with abnormalities in D2 and D3 receptor levels, as observed in substance use disorder (SUD). They used Two PET scans, one with the D3 receptor preferring agonist [11C]-(+)-propyl-hexahydro-naphthooxazin (PHNO) and the other with [11C]raclopride, to assess D2/3 DA receptor availability, and behavioural measures (self-report questionnaires and slot-machine game) to assess subjective effects and relationships to PET measures. The key findings of this study are two: first, in contrast to SUD, PG subjects'binding profile for both D2 and D3 receptor subtypes did not differ significantly from those of healthy controls, suggesting different neurobiological signatures between PG and SUD. Secondly, the study provides novel information regarding the D3 receptor in PG, showing a relationship between D3 levels across PG subjects and symptom severity and impulsiveness. So, D3 may be a viable marker for vulnerability across addictions and a potential target for intervention. The apparent ability of DA agonists in general, and D3-preferring agonists, in particular, to induce impulse control disorders in some patients, suggested an important role for this receptor in PG: its distribution on brain structures receiving afferent ventral striatal projections suggests that its activity can modify limbic output, and thus motivation for reward.

Savitz et al. [31] have tested the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (Ser9Gly, rs6280) on reward-associated DA release in the Striatum. They used two PET scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). Since PET- [11C]raclopride technique allows exploration of the effects of genetic variation on the amount of DA released under conditions associated with increased phasic release of DA, such as during receipt of unpredicted reward, during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding in the middle caudate and the ventral striatum. Moreover they showed as the glycine allele yields D3 autoreceptors have a higher affinity for DA and display more robust intracellular signaling.

As discussed in Joutsa et al. [13], the binding of [11C]raclopride is sensitive to changes in striatal DA concentration during receipt of non-pharmacological rewards such as a video game, large monetary wins versus large monetary losses and the monetary incentive delay task. Notably, in this study of pathological gamblers and healthy controls who completed 3 PET scans with [ 11C]raclopride while gambling with a slot machine, the severity of addiction to gambling was positively associated with the degree of DA release in the basal ganglia during gambling.

Consistent with these results, highly impulsive individuals, who are thought to be vulnerable to developing addiction disorders, were shown to have diminished availability of striatal D2/3 autoreceptors, potentially predisposing them to a greater phasic DA response [18].

#### **6. Conclusions**

nergic activation. Morevover, dopaminergic coding of variance in IGT performance in PG was strongest in the combined striatum and in the ROI(Return On Investment) analysis, only the putamen reached significance level. This may suggest a strong role of the putamen in relation

182 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Hollander et al. [26] therefore hypothesized that lithium effects would decrease relative metabolic rate in at least some portions of the cingulate and orbitofrontal systems. Since they have recently reported elevated relative white matter metabolic rates in frontal regions in patients with schizophrenia [20], and since the statistical parametric mapping analysis in fMRI gambling studies showed group difference clusters partially encompassing white matter underlying cortical areas [7], they assessed white matter metabolic rates underlying each BA on an exploratory basis. In another previous treatment study, lithium was effective in reducing

Although mood stabilizers and serotonin reuptake inhibitors have shown some efficacy in the treatment of this condition, there is little known about how these pharmacological interven‐ tions work. In patients with PG, relative glucose metabolic rates (rGMR) in the orbitofrontal cortex and medial frontal cortex were significantly increased at baseline compared to normal controls. Lithium administration was associated with widespread effects in the prefrontal cortex and cingulate gyrus. Lithium increased rGMR further in the orbitofrontal cortex, heightening normal/patient differences, but it also increased the rGMR of the posterior cingulate and the dorsolateral frontal cortex normalizing the metabolic rate in these regions. Cortical areas implicated in impulse control disorders show increased rGMR in PG at baseline. Lithium treatment, while alleviating the symptoms, further increases rGMR in these areas [18]. Buckholtz et al. [17, 18], using the PET ligand [18F] Fallypride, found that trait impulsivity was negatively associated with binding to DA D2/3 receptors in the midbrain. DA receptors in this region are dominated by autoreceptors [28], which function to limit striatal DA release following reward. This suggests that midbrain autoreceptors influence individuals' propensity for impulsivity, and opens the possibility that excessive striatal DA release following gambling rewards in PD patients with PG, shown in Steeves et al. [29], stems from reduced control

Ray et al. [19] reported the results of their PET and [11C] FLB-457 study, a radiotracer with high affinity for DA D2/3 receptors, and therefore sensitivity to extrastriatal, showing midbrain and prefrontal cortex dopaminergic differences in PD patients with and without PG. They suggested that impaired DA homeostasis in the midbrain, resulting in increased striatal DA release during reward, may be responsible for increased impulsivity and therefore vulnera‐

Recently, Boileau et al. [30] used PET to test whether PG is associated with abnormalities in D2 and D3 receptor levels, as observed in substance use disorder (SUD). They used Two PET

to uncertainty, which may exceed that of the ventral striatum by a factor of 2 to 3.

**5. PET specific studies**

both gambling behavior and affective instability [27].

overstriatal DA by midbrain autoreceptors.

bility for addiction in these patients.

The PET imaging data are potentially important because genetically & not genetically-driven differences in DA receptor function may influence the changes in dopaminergic signaling that modulate emotional, motivational and stress responses.

Although large sample sizes are uncommon in PET studies because of cost and radiation exposure, PET has an advantage over MRI because it allows a particular molecular target to be assayed directly. Thus it is likely that true signals can be detected with relatively small sample sizes. Nevertheless, it would be interesting to examine large samples.

[7] Tanabe J, Thompson L, Claus E, Dalwani M, Hutchison K, Banich MT: Prefrontal cor‐ tex activity is reduced in gambling and nongambling substance users during deci‐

Pathological Gambling: PET Studies http://dx.doi.org/10.5772/57125 185

[8] Sanislow CA, Pine DS, Quinn KJ, Kozak MJ, Garvey MA, Heinssen RK, Wang PS, Cuthbert BN. Developing constructs for psychopathology research: research domain

[9] Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K, Sanislow C, Wang P. Research domain criteria (RDoC): toward a new classification framework for re‐

[10] Cuthbert, BN & Insel, TR. Classification issues in women's mental health: Clinical utility and etiological mechanisms. Archives of Women's Mental Health, 2010. Epub

[11] Cuthbert BN, Insel TR. Toward new approaches to psychotic disorders: the NIMH Research Domain Criteria project. Schizophr Bull. 2010 Nov;36(6):1061-2. Epub 2010

[12] Morris SE, Cuthbert BN. Research Domain Criteria: cognitive systems, neural cir‐ cuits, and dimensions of behavior. Dialogues Clin Neurosci. 2012 Mar; 14(1):29-37.

[13] Joutsa J, Johansson J, Niemela S, Ollikainen A, Hirvonen MM, Piepponen P, Arponen E, Alho H, Voon V, Rinne JO, Hietala J, Kaasinen V. Mesolimbic dopamine release is

[14] Linnet J,MollerA, Peterson E, Gjedde A, Doudet D: Inverse association between dop‐ aminergic neurotransmission and lowa Gambling Task performance in Pathological

[15] Voon, V., Fernagut, P.O., Wickens, J., Baunez, C., Rodriguez, M., Pavon, N., Juncos, J.L., Obeso, J.A., Bezard, E., 2009. Chronic dopaminergic stimulation in Parkinson's disease: from dyskinesias to impulse control disorders. Lancet Neurol. 8, 1140–1149.

[16] Steeves, T.D., Miyasaki, J., Zurowski, M., Lang, A.E., Pellecchia, G., Van Eimeren, T., Rusjan, P., Houle, S., Strafella, A.P., 2009. Increased striatal dopamine release in Par‐ kinsonian patients with pathological gambling: a [11C] raclopride PET study. Brain

[17] Buckholtz, J.W., Treadway, M.T., Cowan, R.L., Woodward, N.D., Benning, S.D., Li, R., Ansari, M.S., Baldwin, R.M., Schwartzman, A.N., Shelby, E.S., Smith, C.E., Cole, D., Kessler, R.M., Zald, D.H., 2010a. Mesolimbic dopamine reward system hypersen‐

[18] Buckholtz, J.W., Treadway, M.T., Cowan, R.L., Woodward, N.D., Li, R., Ansari, M.S., Baldwin, R.M., Schwartzman, A.N., Shelby, E.S., Smith, C.E., Kessler, R.M., Zald, D.H., 2010b. Dopaminergic network differences in human impulsivity. Science 329,

sitivity in individuals with psychopathic traits. Nat. Neurosci. 13, 419–421.

linked to symptom severity in pathological gambling. NeuroImage 60(2012)

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532.

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A number of studies have successfully applied multi-modal imaging in order to examine the relationship between serotonergic function or dopamine storage capacity and the hemody‐ namic response to affective stimuli in regions such as the amygdala. A gambling task could be implemented in a cohort of subjects who complete both [11C]raclopride PET and fMRI. So, it's therefore desirable that future multi-modal imaging studies can combine fMRI and PET data.

These studies would also be compatible with the new way of approaching to mental disorders proposed by NIMH.

#### **Author details**

Daniela Santoro and Stefano Pallanti

Careggi University Hospital, Department of Psychiatry, Florence, Italy

#### **References**


[7] Tanabe J, Thompson L, Claus E, Dalwani M, Hutchison K, Banich MT: Prefrontal cor‐ tex activity is reduced in gambling and nongambling substance users during deci‐ sion-making. Hum Brain Mapp 2007; 28: 1276–1286.

Although large sample sizes are uncommon in PET studies because of cost and radiation exposure, PET has an advantage over MRI because it allows a particular molecular target to be assayed directly. Thus it is likely that true signals can be detected with relatively small

184 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

A number of studies have successfully applied multi-modal imaging in order to examine the relationship between serotonergic function or dopamine storage capacity and the hemody‐ namic response to affective stimuli in regions such as the amygdala. A gambling task could be implemented in a cohort of subjects who complete both [11C]raclopride PET and fMRI. So, it's therefore desirable that future multi-modal imaging studies can combine fMRI and PET

These studies would also be compatible with the new way of approaching to mental disorders

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**Section 3**

**PET Imaging in Clinical Oncology**

**PET Imaging in Clinical Oncology**

**Chapter 8**

**PET – Assessment of**

http://dx.doi.org/10.5772/57127

future work are further presented.

**1. Introduction**

**Oncologic Treatment Response**

Additional information is available at the end of the chapter

Positron Emission Tomography (PET), particularly with 18-Fluorodeoxyglucose (FDG), continues to define and expand its role in oncologic management. Beyond tumor size, as definable by computed tomography (CT), PET provides a measure of metabolic activity in tumors and is integral in initial workup for multiple disease sites including head/neck squamous cell carcinoma, non-small cell lung cancer (NSCLC), lymphoma, and many others. For head and neck cancers, FDG PET imaging facilitates early detection of persis‐ tent and recurrent head/neck squamous cell carcinoma after chemoradiotherapy, increas‐ ing deferral of surgical neck dissection to the salvage setting in many cases. In the setting of non-small-cell lung cancer, PET is further considered standard of care for radiotherapy treatment planning. Post-treatment PET has further shown to facilitate assessment of treatment response, with metabolic response seen on PET pre-dating CT-based radiograph‐ ic response. Though routine post-therapy PET after definitive non-surgical management is standard management for head/neck squamous cell carcinomas, evidence to support this routine use for other subsites is lacking and thus currently not recommended for various organ sites including lung. This chapter herein discusses various PET imaging techniques and assessment variables that have been used to investigate assessment of response to oncologic treatment. In particular, assessment of response with early and late post-radiother‐ apy PET imaging for head and neck, NSCLC, rectal cancer, esophageal cancer, and lymphoma are discussed. Recent research involving on-treatment PET imaging as well as

> © 2013 Grills and Mangona; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Inga S. Grills and Victor S. Mangona

#### **Chapter 8**

## **PET – Assessment of Oncologic Treatment Response**

Inga S. Grills and Victor S. Mangona

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57127

#### **1. Introduction**

Positron Emission Tomography (PET), particularly with 18-Fluorodeoxyglucose (FDG), continues to define and expand its role in oncologic management. Beyond tumor size, as definable by computed tomography (CT), PET provides a measure of metabolic activity in tumors and is integral in initial workup for multiple disease sites including head/neck squamous cell carcinoma, non-small cell lung cancer (NSCLC), lymphoma, and many others. For head and neck cancers, FDG PET imaging facilitates early detection of persis‐ tent and recurrent head/neck squamous cell carcinoma after chemoradiotherapy, increas‐ ing deferral of surgical neck dissection to the salvage setting in many cases. In the setting of non-small-cell lung cancer, PET is further considered standard of care for radiotherapy treatment planning. Post-treatment PET has further shown to facilitate assessment of treatment response, with metabolic response seen on PET pre-dating CT-based radiograph‐ ic response. Though routine post-therapy PET after definitive non-surgical management is standard management for head/neck squamous cell carcinomas, evidence to support this routine use for other subsites is lacking and thus currently not recommended for various organ sites including lung. This chapter herein discusses various PET imaging techniques and assessment variables that have been used to investigate assessment of response to oncologic treatment. In particular, assessment of response with early and late post-radiother‐ apy PET imaging for head and neck, NSCLC, rectal cancer, esophageal cancer, and lymphoma are discussed. Recent research involving on-treatment PET imaging as well as future work are further presented.

© 2013 Grills and Mangona; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **2. PET technique**

#### **2.1. 18F-FDG**

PET is a medical imaging technique employing the unique parameters of decay of positronemitting isotopes. Today, PET is routinely used in conjunction with computed tomography (CT) in a combined medical imaging device, PET-CT, allowing anatomic image correlation with the functional imaging obtained by PET.

synthesis. As thymidine is unique to DNA, this has been exploited with various radiotracers including 11C-thymidine—which is limited by the short half-life of 11C—as well as thymidine

is a substrate of thymidine kinase 2 (TK2), located in mitochondria, resulting in different distributions of these markers in tissue [9,10]. Although tumors tend to be less avid of 18F-FLT in comparison go 18F-FDG, tumor delineation from background tissue can be superior with 18F-FLT in regions such as the brain, mediastinum, and intestines, where normal physiologic uptake of 18F-FLT in these areas are much lower, yielding a high tumor-to-background ratio [1,11–13]. In a head-to-head comparison of 18F-FLT to 18F-FDG to assess chemotherapy response in patients with breast cancer who had imaging with both radiotracers, change in FLT uptake after one cycle of chemotherapy better predicted late changes in tumor marker levels and correlated well with eventual radiographic tumor response [14]. Though less employed in comparison to 18F-FLT, 18F-FMAU has shown ability to visualize breast, brain, lung, and prostate tumors. As 18F-FMAU shows low uptake in normal bone marrow—as opposed to 18F-FLT, which has high bone marrow uptake—18F-FMAU is more suitable for visualization of

Radiolabeled Cu-ATSM (60/62/64Cu-ATSM) and 18F-FMISO are currently the two primary radiotracers employed for imaging tissue hypoxia—correlated with decreased sensitivity to treatment—and has been with worse clinical outcomes [15,16]. 60Cu-ATSM has been found to predict aresponse to therapy for NSCLC and predict both recurrence and survival outcomes for cervical and rectal cancers [17–19]. Clinically, pretreatment 18F-FMISO has been shown to predict survival in patients with head and neck cancer and glioblastoma multiforme [20,21].

Various amino acid radiotracers have been used, with 11C-MET (a methionine analog) the most common. It has found a niche in CNS malignancies. In malignant gliomas, decreased uptake during temozolomide therapy has shown improved time to progression; areas of uptake have shown areas at high risk of recurrence, and has helped distinguish post-radiation necrosis

An additional class of radiotracers have aimed to assess hormone receptors, as receptors play an integral role in malignancies, paticulary prostate and breast cancers. 18F-FES is the most commonly used, showing correlation with estrogen receptor (ER) levels as well as response to aromatase inhibitors [25,26]. Ultimately, pretreatment uptake values have shown to predict patients who would or would not respond to therapy [25]. For prostate cancer, 18F-FDHT is an analog of 5α-dihydrotestosterone. Correlation with treatment response has not as well been shown in prostate cancer with this marker, though 18F-FDHT uptake has been associated with

Historically, PET imaging was obtained with a single static set of images obtained up to 1 hour after injection of 18F-FDG. As noted previously, a diagnostic limitation of PET imaging for oncologic diagnosis are the false positive findings secondary to inflammation quite commonly associated to therapeutic response. As 18F-FDG uptake and retention kinetics are potentially

cytosolic thymidine kinase 1 (TK1), a key enzyme for salvage DNA synthesis, and 8

F-FMAU with the longer half-life of 18F [8]. 18F-FLT acts as a substrate of

PET – Assessment of Oncologic Treatment Response

http://dx.doi.org/10.5772/57127

F-FMAU

193

analogs 18F-FLT and 8

metastatic prostate cancer.

versus recurrent malignancy [22–24].

**Single-phase / Dual-phase / Dynamic PET**

high PSA levels [27].

A number of PET radiotacers have been used in oncology, though 18F-Flourodeoxyglucose (FDG) is FDA-approved and most commonly employed. Other agents including 18F-FMISO (18F-Fluoromisonidazole), 18FLT (18F-Fluorothymidine), 16b-18F-Fluoro-5a-Dihydrotestoster‐ one (18F-FDHT), 60Cu-ATSM (Copper-diacetyl-bis(N4-methylthiosemicarbazone)), 18F-FES (16a-18F-fluoro-17b-estradiol), 11C-MET (11C-methionine), show significant potential to monitor the response to therapy before, during, or after therapeutic intervention[1].

18F-FDG chemically is 2-deoxy-2-18F-fluoro-D-glucose, a glucose analog. On 18FDG, the positron-emitting radioactive isotope fluorine-18 is substituted at the 2' position of the glucose molecule preventing glycolysis, which requires a hydroxyl group at the 2' position. It has significantly increased uptake in tissues with increased metabolic activity, in particular, most malignancies [2]. With increased demand for gluose, tumors tend to have increased expression of glucose transport proteins at the cellular membrane as well as increased hexokinase [3]. With its relatively short half-life of 110 minutes, in tissues with rapid uptake, the 18F decay occurs primarily when trapped intracellularly, helping visualize these areas on PET. Malig‐ nancies with moderate to high 18F-FDG uptake include most lung cancers, colorectal cancers, esophageal cancers, gastric cancers, head and neck cancers, cervical cancers, ovarian cancers, breast cancers, lymphomas, and melanoma [4]. Hepatocellucar carcinoma, testicular cancers, renal cancers, sarcomas, and neuroendocrine tumors have variable 18F-FDG uptake [4]. Prostate adenocarcinoma, the most common cancer in males, has generally low metabolic activity, rendering 18F-FDG particularly less helpful for this malignancy in the primary setting, leading to potential false negative interpretation [5–7]. As 18F-FDG undergoes physiologic excretion through the bladder hinders evaluation of both bladder and prostate malignancies. Overall, 18F-FDG has been the most used oncologic tracer, but its applicability is not universal across all malignancies, nor is its uptake specific to only neoplasm. Though aberrant tumor growth in malignancy routinely results in increased 18F-FDG avidity, it is not tumor specific other benign tissue and benign conditions can also have variable uptake of 18F-FDG (e.g. inflammation or hyperplastic bone marrow) potentially leading to false positive findings [4,7]. As bone marrow hyperplasia and inflammation are not uncommon consequences after oncologic treatment including surgery, radiation therapy, and/or chemotherapy, 18F-FDG PET has limitations particulary in post-therapeutic assessment.

#### **2.2. Other radiotracers**

Beyond 18F-FDG, other markers exploit other cellular mechanisms for biologic imaging with PET. Other markers have been used to assess tumor proliferation with markers of DNA synthesis. As thymidine is unique to DNA, this has been exploited with various radiotracers including 11C-thymidine—which is limited by the short half-life of 11C—as well as thymidine analogs 18F-FLT and 8 F-FMAU with the longer half-life of 18F [8]. 18F-FLT acts as a substrate of cytosolic thymidine kinase 1 (TK1), a key enzyme for salvage DNA synthesis, and 8 F-FMAU is a substrate of thymidine kinase 2 (TK2), located in mitochondria, resulting in different distributions of these markers in tissue [9,10]. Although tumors tend to be less avid of 18F-FLT in comparison go 18F-FDG, tumor delineation from background tissue can be superior with 18F-FLT in regions such as the brain, mediastinum, and intestines, where normal physiologic uptake of 18F-FLT in these areas are much lower, yielding a high tumor-to-background ratio [1,11–13]. In a head-to-head comparison of 18F-FLT to 18F-FDG to assess chemotherapy response in patients with breast cancer who had imaging with both radiotracers, change in FLT uptake after one cycle of chemotherapy better predicted late changes in tumor marker levels and correlated well with eventual radiographic tumor response [14]. Though less employed in comparison to 18F-FLT, 18F-FMAU has shown ability to visualize breast, brain, lung, and prostate tumors. As 18F-FMAU shows low uptake in normal bone marrow—as opposed to 18F-FLT, which has high bone marrow uptake—18F-FMAU is more suitable for visualization of metastatic prostate cancer.

Radiolabeled Cu-ATSM (60/62/64Cu-ATSM) and 18F-FMISO are currently the two primary radiotracers employed for imaging tissue hypoxia—correlated with decreased sensitivity to treatment—and has been with worse clinical outcomes [15,16]. 60Cu-ATSM has been found to predict aresponse to therapy for NSCLC and predict both recurrence and survival outcomes for cervical and rectal cancers [17–19]. Clinically, pretreatment 18F-FMISO has been shown to predict survival in patients with head and neck cancer and glioblastoma multiforme [20,21].

Various amino acid radiotracers have been used, with 11C-MET (a methionine analog) the most common. It has found a niche in CNS malignancies. In malignant gliomas, decreased uptake during temozolomide therapy has shown improved time to progression; areas of uptake have shown areas at high risk of recurrence, and has helped distinguish post-radiation necrosis versus recurrent malignancy [22–24].

An additional class of radiotracers have aimed to assess hormone receptors, as receptors play an integral role in malignancies, paticulary prostate and breast cancers. 18F-FES is the most commonly used, showing correlation with estrogen receptor (ER) levels as well as response to aromatase inhibitors [25,26]. Ultimately, pretreatment uptake values have shown to predict patients who would or would not respond to therapy [25]. For prostate cancer, 18F-FDHT is an analog of 5α-dihydrotestosterone. Correlation with treatment response has not as well been shown in prostate cancer with this marker, though 18F-FDHT uptake has been associated with high PSA levels [27].

#### **Single-phase / Dual-phase / Dynamic PET**

**2. PET technique**

with the functional imaging obtained by PET.

has limitations particulary in post-therapeutic assessment.

**2.2. Other radiotracers**

PET is a medical imaging technique employing the unique parameters of decay of positronemitting isotopes. Today, PET is routinely used in conjunction with computed tomography (CT) in a combined medical imaging device, PET-CT, allowing anatomic image correlation

192 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

A number of PET radiotacers have been used in oncology, though 18F-Flourodeoxyglucose (FDG) is FDA-approved and most commonly employed. Other agents including 18F-FMISO (18F-Fluoromisonidazole), 18FLT (18F-Fluorothymidine), 16b-18F-Fluoro-5a-Dihydrotestoster‐ one (18F-FDHT), 60Cu-ATSM (Copper-diacetyl-bis(N4-methylthiosemicarbazone)), 18F-FES (16a-18F-fluoro-17b-estradiol), 11C-MET (11C-methionine), show significant potential to

18F-FDG chemically is 2-deoxy-2-18F-fluoro-D-glucose, a glucose analog. On 18FDG, the positron-emitting radioactive isotope fluorine-18 is substituted at the 2' position of the glucose molecule preventing glycolysis, which requires a hydroxyl group at the 2' position. It has significantly increased uptake in tissues with increased metabolic activity, in particular, most malignancies [2]. With increased demand for gluose, tumors tend to have increased expression of glucose transport proteins at the cellular membrane as well as increased hexokinase [3]. With its relatively short half-life of 110 minutes, in tissues with rapid uptake, the 18F decay occurs primarily when trapped intracellularly, helping visualize these areas on PET. Malig‐ nancies with moderate to high 18F-FDG uptake include most lung cancers, colorectal cancers, esophageal cancers, gastric cancers, head and neck cancers, cervical cancers, ovarian cancers, breast cancers, lymphomas, and melanoma [4]. Hepatocellucar carcinoma, testicular cancers, renal cancers, sarcomas, and neuroendocrine tumors have variable 18F-FDG uptake [4]. Prostate adenocarcinoma, the most common cancer in males, has generally low metabolic activity, rendering 18F-FDG particularly less helpful for this malignancy in the primary setting, leading to potential false negative interpretation [5–7]. As 18F-FDG undergoes physiologic excretion through the bladder hinders evaluation of both bladder and prostate malignancies. Overall, 18F-FDG has been the most used oncologic tracer, but its applicability is not universal across all malignancies, nor is its uptake specific to only neoplasm. Though aberrant tumor growth in malignancy routinely results in increased 18F-FDG avidity, it is not tumor specific other benign tissue and benign conditions can also have variable uptake of 18F-FDG (e.g. inflammation or hyperplastic bone marrow) potentially leading to false positive findings [4,7]. As bone marrow hyperplasia and inflammation are not uncommon consequences after oncologic treatment including surgery, radiation therapy, and/or chemotherapy, 18F-FDG PET

Beyond 18F-FDG, other markers exploit other cellular mechanisms for biologic imaging with PET. Other markers have been used to assess tumor proliferation with markers of DNA

monitor the response to therapy before, during, or after therapeutic intervention[1].

**2.1. 18F-FDG**

Historically, PET imaging was obtained with a single static set of images obtained up to 1 hour after injection of 18F-FDG. As noted previously, a diagnostic limitation of PET imaging for oncologic diagnosis are the false positive findings secondary to inflammation quite commonly associated to therapeutic response. As 18F-FDG uptake and retention kinetics are potentially different between tumor and normal tissue inflammation, people have investigated more dynamic methods of acquiring metabolic PET data.

Though PET imaging acquires three-dimensional (3D) data, as CT technology has advanced to enable four-dimensional (4D) imaging with full 3D CT image sets corresponding to various portions of a respiratory cycle, so now have 4D-PET-CTs come into clinical use, with potential to reduce image smearing, improve accuracy of PET-CT co-registration, and increase the measured SUV [34,35]. A study evaluating 57 pulmonary lesions showed particular benefit in characterizing smaller tumors, with 4D studies showing higher differences in SUVmax percent difference in comparison to 3D studies (p<0.05) assessment of smaller lesion lung lesions, with better characterization [36]. A recent study illustrated utility of respiratory-correlated 4D-PET-CT for target delineation of squamous cell carcinoma of the esophagus, further indicating SUV threshold of 20% or 2.5 for autocontouring the gross tumor volume (GTV) [37]. Algorithms for semiautomatic contouring have also been proposed for pulmonary lesions with minimal difference (0.1 ± 0.1 mm) on phantom studies and 0.8 ± 0.2 mm on patient tumors [38]. Fourdimensional PET/CT has been reported to facilitate planning stereotactic radiotherapy of liver

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From an oncologic standpoint, PET imaging is notably quite useful in its ability to quantitate parameters associated with PET uptake. An assortment of quantitative values can be obtained from each scan and from multiple-time-point scans, as well as across different scans obtained at different time points with respect to treatment (e.g. pre-treatment versus post-treatment),

A common measurement of PET images for clinicians is the semi-quantitative value referred to as "standardized uptake value (SUV) [41]." Standardized uptake values are calculated throughout the three-dimensional array of CT regions, with variable SUVs throughout an image. SUV provides an index of regional tracer uptake and is a function of local radioactivity concentration, injected activity, and patient's weight. 18F-FDG SUV can help differentiate tumor from tissue, and when used, corrections to calculation are recommended [42]. A common method of correction accounts for a patient's lean body mass "SUVlbm," commonly

> ( /) ( )/ ( ) *i*

= (1)

*lean lbm lbw SUV SUV SUV SUL* === (2)

metastases [39] and pulmonary tumors [40].

providing valuable information for treating physicians.

written as "SUVlbw" (lbw="lean body weight"), "SUVlean," or "SUL."[43]

*i Radioactivity C mL SUV*

*Dose mC leanbody mass kg* m

Within a region of interest (ROI) on a PET-CT, various PET quantitative factors can readily be obtained. The most commonly reported value from PET-CT oncologic imaging the maximum SUV value (SUVmax). SUVmax values are measured and reported at areas concern‐

*lean*

**3. PET parameters**

In a series of 21 patients with head and neck carcinomas, dual-time-point 18F-FDG PET studies helped differentiate malignancy from inflammation [28]. Standard uptake values (SUVs) of tumors were shown to increase on the second (delayed) study by mean of 12% in comparison to matched contralateral normal tissue which showed a mean decrease of 5% on delayed imaging (p<0.05) [28]. Inflammatory sites showed relatively stable uptake over the two scans; time interval between scans correlate with tumor SUV increase; and interval of greater than 30 minutes was recommended for separation [28].

For evaluation of pulmonary nodules, an early study of 36 patients siwht 38 pulmonary nodules, malignant or benign, underwent dual-time-point PET at 70 and 123 minutes postinjection [29]. A similar trend was seen with mean increase of tumor SUV of 20% (from 3.7 to 4.4) in malignant lesions from early to delayed scan (P<0.01); benign lesions showed stable and lower mean SUVs (1.1 on both early and delayed imaging) [29]. They determine a threshold of 10% increase from early to delayed imaging as the best predictor, reaching sensitivity of 100% and specificity of 89% [29]. Other data have shown similar trends of increased 18F-FDG uptake from first to second scan in malignant tissue and stable to decreased uptake in benign lesions [30].

In a study of 47 patients with suspected pancreatic cancer, patients had dual-time-point 18F-FDG PET imaging acquired 1 and 2 hours after injection; further, some patients had a third scan at the 3-hour time point after injection [31]. Twenty-two lesions were malignant, whereas 20 were benign. With a constant SUV threshold, the initial 1-hour PET was found to be 95% sensitive, missing one of 22 malignant lesions, and 83% accurate. With addition information of 2-hour PET imaging, retention characteristics of 18F-FDG increased diagnostic accuracy to 91.5%, with no decrease in false negatives [31]. The additional information provided by a 3 hour PET did not improve diagnostic accuracy beyond the dual-phase imaging obtained at the 1-hour and 2-hour time points [31].

With these potential diagnostic advantages from dual-phase PET-CT (with 2 PET scans separated by a time interval) has grown increasingly common. With the extra information provided with dual-phase imaging, people have further investigated 'dynamic PET' imaging, obtaining continuous PET data over time rather than at discrete or brief time spans, adding further breadth of data to kinetic profiles of uptake. Early work used dynamic continuous imaging to model discrete time-point imaging, showing linear change over time in patients with breast cancer. A recent study utilized dynamic PET imaging with 18F-FCho (18F-labelled fluoromethylcholine) to assess time-activity curves of space occupying brain lesions [32]. Another recent study used a dynamic PET-CT approach to assess cervical adenopathy in patients with oral/head and neck cancer; consecutive imaging at nine time points with PET/CT were obtained from 60-115 minutes after injection [33]. At our institution, we have recently initiated an adaptive radiation therapy protocol for patients with head/neck cancer in which patients receive weekly dynamic PET imaging over approximately 90 minutes during the course of treatment.

Though PET imaging acquires three-dimensional (3D) data, as CT technology has advanced to enable four-dimensional (4D) imaging with full 3D CT image sets corresponding to various portions of a respiratory cycle, so now have 4D-PET-CTs come into clinical use, with potential to reduce image smearing, improve accuracy of PET-CT co-registration, and increase the measured SUV [34,35]. A study evaluating 57 pulmonary lesions showed particular benefit in characterizing smaller tumors, with 4D studies showing higher differences in SUVmax percent difference in comparison to 3D studies (p<0.05) assessment of smaller lesion lung lesions, with better characterization [36]. A recent study illustrated utility of respiratory-correlated 4D-PET-CT for target delineation of squamous cell carcinoma of the esophagus, further indicating SUV threshold of 20% or 2.5 for autocontouring the gross tumor volume (GTV) [37]. Algorithms for semiautomatic contouring have also been proposed for pulmonary lesions with minimal difference (0.1 ± 0.1 mm) on phantom studies and 0.8 ± 0.2 mm on patient tumors [38]. Fourdimensional PET/CT has been reported to facilitate planning stereotactic radiotherapy of liver metastases [39] and pulmonary tumors [40].

#### **3. PET parameters**

different between tumor and normal tissue inflammation, people have investigated more

194 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

In a series of 21 patients with head and neck carcinomas, dual-time-point 18F-FDG PET studies helped differentiate malignancy from inflammation [28]. Standard uptake values (SUVs) of tumors were shown to increase on the second (delayed) study by mean of 12% in comparison to matched contralateral normal tissue which showed a mean decrease of 5% on delayed imaging (p<0.05) [28]. Inflammatory sites showed relatively stable uptake over the two scans; time interval between scans correlate with tumor SUV increase; and interval of greater than

For evaluation of pulmonary nodules, an early study of 36 patients siwht 38 pulmonary nodules, malignant or benign, underwent dual-time-point PET at 70 and 123 minutes postinjection [29]. A similar trend was seen with mean increase of tumor SUV of 20% (from 3.7 to 4.4) in malignant lesions from early to delayed scan (P<0.01); benign lesions showed stable and lower mean SUVs (1.1 on both early and delayed imaging) [29]. They determine a threshold of 10% increase from early to delayed imaging as the best predictor, reaching sensitivity of 100% and specificity of 89% [29]. Other data have shown similar trends of increased 18F-FDG uptake from first to second scan in malignant tissue and stable to decreased uptake in benign

In a study of 47 patients with suspected pancreatic cancer, patients had dual-time-point 18F-FDG PET imaging acquired 1 and 2 hours after injection; further, some patients had a third scan at the 3-hour time point after injection [31]. Twenty-two lesions were malignant, whereas 20 were benign. With a constant SUV threshold, the initial 1-hour PET was found to be 95% sensitive, missing one of 22 malignant lesions, and 83% accurate. With addition information of 2-hour PET imaging, retention characteristics of 18F-FDG increased diagnostic accuracy to 91.5%, with no decrease in false negatives [31]. The additional information provided by a 3 hour PET did not improve diagnostic accuracy beyond the dual-phase imaging obtained at

With these potential diagnostic advantages from dual-phase PET-CT (with 2 PET scans separated by a time interval) has grown increasingly common. With the extra information provided with dual-phase imaging, people have further investigated 'dynamic PET' imaging, obtaining continuous PET data over time rather than at discrete or brief time spans, adding further breadth of data to kinetic profiles of uptake. Early work used dynamic continuous imaging to model discrete time-point imaging, showing linear change over time in patients with breast cancer. A recent study utilized dynamic PET imaging with 18F-FCho (18F-labelled fluoromethylcholine) to assess time-activity curves of space occupying brain lesions [32]. Another recent study used a dynamic PET-CT approach to assess cervical adenopathy in patients with oral/head and neck cancer; consecutive imaging at nine time points with PET/CT were obtained from 60-115 minutes after injection [33]. At our institution, we have recently initiated an adaptive radiation therapy protocol for patients with head/neck cancer in which patients receive weekly dynamic PET imaging over

dynamic methods of acquiring metabolic PET data.

30 minutes was recommended for separation [28].

the 1-hour and 2-hour time points [31].

approximately 90 minutes during the course of treatment.

lesions [30].

From an oncologic standpoint, PET imaging is notably quite useful in its ability to quantitate parameters associated with PET uptake. An assortment of quantitative values can be obtained from each scan and from multiple-time-point scans, as well as across different scans obtained at different time points with respect to treatment (e.g. pre-treatment versus post-treatment), providing valuable information for treating physicians.

A common measurement of PET images for clinicians is the semi-quantitative value referred to as "standardized uptake value (SUV) [41]." Standardized uptake values are calculated throughout the three-dimensional array of CT regions, with variable SUVs throughout an image. SUV provides an index of regional tracer uptake and is a function of local radioactivity concentration, injected activity, and patient's weight. 18F-FDG SUV can help differentiate tumor from tissue, and when used, corrections to calculation are recommended [42]. A common method of correction accounts for a patient's lean body mass "SUVlbm," commonly written as "SUVlbw" (lbw="lean body weight"), "SUVlean," or "SUL."[43]

$$\text{LSLV}\_{\text{lauv}} = \frac{\text{Radioactivity} \left(\mu\text{C}\_i / \text{mL}\right)}{\text{Dose} \left(\text{mC}\_i\right) / \text{lean body} \,\text{mass} \left(\text{kg}\right)} \tag{1}$$

$$\text{SLIV}\_{\text{Iauv}} = \text{SLIV}\_{\text{Ibv}} = \text{SLIV}\_{\text{Ibv}} = \text{SLI} \tag{2}$$

Within a region of interest (ROI) on a PET-CT, various PET quantitative factors can readily be obtained. The most commonly reported value from PET-CT oncologic imaging the maximum SUV value (SUVmax). SUVmax values are measured and reported at areas concern‐

ing for malignancy (e.g. a primary tumor and associated regional lymph nodes and distant metastases as well as other highly avid areas that may represent inflammation or reactive changes). Pre-treatment SUVmax with 18F-FDG has been reported to be prognostic for many organ sites including lung [44–46], head and neck [47], esophagus [48,49], gastroesopha‐ geal junction [49] gastric [50], pancreas [51] cervix [52], rectum [53,54], lymphoma [55], and soft tissue sarcoma [56].

Beyond SUVmax of an ROI, the arithmetic mean SUV (SUVmean) of voxels within the ROI have been used for oncologic assessment [57–59]. New parameters, which show promise in oncologic assessment, include the metabolic tumor volume (MTV) and total glycolytic activity (TGA) [60–63]. The MTV is defined as the tumor volume based on PET uptake and can be particularly helpful in comparison to CT-imaging when background density is similar to tumor density on CT. The boundary of MTV can be defined manually or with various parameters such as a fixed SUV threshold, percentage of SUVmax (e.g. 38%, 50%, and 60%), and gradient. On pre-treatment imaging prior to radiotherapy the volume delineated by PETfusion to planning CT effectively corresponds to the MTV, which is utilized for biologicallytargeted radiotherapy [64–66]. Such methods have been used extensively for lung radiotherapy planning, where PET staging is recommended [67]. MTV has shown to predict overall survival in lung cancer [61], head and neck cancer [60], and esophageal cancer [68].

Total glycolytic activity (TGA), defined as the (MTV) x (SUVmean), is the primary PET parameter that includes both both anatomic (size) as well as metabolic parameters (e.g. with 18F-FDG). In an analysis of TGA and MTV in 45 patients with oral or oropharyngeal SCC, stage, on univariate cox regression, MTV and TGA were the most associated with progression-free survival (PFS) and overall survival (OS) (p=0.002 and p=0.006, respectively), moreso than tumor grade (p=004) and SUVmax (p=0.56) [69].

$$TGA = MTV \ge SLIV \text{mean} \tag{3}$$

are used for assessment of treatment response. From such data, inter-PET analysis can be performed (e.g. comparison of a pre-treatment scan to a post-treatment scan), not to be confused with factors such as the RI which are measured across two different scans performed during two time points of a single PET (e.g. early and delayed scans). Inter-PET parameters include the difference or change in (delta, Δ) values of parameters already previously dis‐ cussed as well as "percent of" (e.g. percent of baseline), percent reduction from baseline, and rate of change (velocity "VEL"). Examples of such variables comparing a new PET to a baseline

max max max *new baseline* D= - *SUV SUV SUV* (5)

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*SUV SUV <sup>x</sup> SUV* <sup>=</sup> (6)

max 100% max % % *reduction baseline SUV* = - *SUV* (7)


PET are as indicated below, where *t* is the time between PETs..

%

max

*SUV*

**4. Response criteria**

3, Table 4, and Table 5.

*Baseline*

*SUV SUV VEl*

max max <sup>100</sup> max

*new*

*baseline*

max max *new baseline*

*t*

Various methods for assessing and categorizing response of tumors based on radiographic imaging have been proposed, including the World Health Organization (WHO) criteria, the Response Evaluation Criteria in Solid Tumors (RECIST), and RECIST 1.1 [72–75]. Such criterica, depend on radiographic imaging, which may not best assess the biologic response, particularly given that metabolic response on PET routinely anatomic radiographic response on CT [76]. Accordingly, methods of categorizing response with PET have been developed, namely the European Organization for Research and Treatment of Cancer (EORTC) criteria and newer PET Response Criteria in Solid Tumors (PERCIST, version 1.0) [43,77]. A separate metric of response definitions using 18F-FDG PET has been developed for lymphoma response and used for clinical trials [78]. Definitions of criteria are delineated in Table 1, Table 2, Table

Retention index (RI) is a dynamic parameter that can be calculated with dual-time-point (early and delayed) PET imaging, where RI is the difference of SUVmax on two scans divided by initial SUVmax. Rate of decline of RI during lung irradiation has shown to predict locoregional recurrence [70]. Further, in an analysis of 68 women with breast cancer, in comparison to other parameters including early and delayed SUVmax, RI showed best relation to biologic parameters including grade, Ki-67, and c-erbB-2 expression [71].

$$RI = \frac{SLVV \max\_{delay} - SLV \max\_{cavity}}{SLV \max\_{cavity}} \tag{4}$$

From an oncologic standpoint, beyond the importance of baseline PET imaging for staging and radiotherapy planning, subsequent PET scans, whether during treatment or subsequent, are used for assessment of treatment response. From such data, inter-PET analysis can be performed (e.g. comparison of a pre-treatment scan to a post-treatment scan), not to be confused with factors such as the RI which are measured across two different scans performed during two time points of a single PET (e.g. early and delayed scans). Inter-PET parameters include the difference or change in (delta, Δ) values of parameters already previously dis‐ cussed as well as "percent of" (e.g. percent of baseline), percent reduction from baseline, and rate of change (velocity "VEL"). Examples of such variables comparing a new PET to a baseline PET are as indicated below, where *t* is the time between PETs..

$$\text{ASLIV} \,\text{max} = \text{SLIV} \,\text{max}\_{\text{new}} - \text{SLIV} \,\text{max}\_{\text{baseline}} \tag{5}$$

$$SLVV \max\_{\% \text{Baseline}} = \frac{SLVV \max\_{\text{name}}}{SLVV \max\_{\text{basetime}}} \ge 100\tag{6}$$

max 100% max % % *reduction baseline SUV* = - *SUV* (7)

$$VEl\_{SIV\max} = \frac{SLV\max\_{\max} - SLV\max\_{\text{baseline}}}{t} \tag{8}$$

#### **4. Response criteria**

ing for malignancy (e.g. a primary tumor and associated regional lymph nodes and distant metastases as well as other highly avid areas that may represent inflammation or reactive changes). Pre-treatment SUVmax with 18F-FDG has been reported to be prognostic for many organ sites including lung [44–46], head and neck [47], esophagus [48,49], gastroesopha‐ geal junction [49] gastric [50], pancreas [51] cervix [52], rectum [53,54], lymphoma [55], and

196 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Beyond SUVmax of an ROI, the arithmetic mean SUV (SUVmean) of voxels within the ROI have been used for oncologic assessment [57–59]. New parameters, which show promise in oncologic assessment, include the metabolic tumor volume (MTV) and total glycolytic activity (TGA) [60–63]. The MTV is defined as the tumor volume based on PET uptake and can be particularly helpful in comparison to CT-imaging when background density is similar to tumor density on CT. The boundary of MTV can be defined manually or with various parameters such as a fixed SUV threshold, percentage of SUVmax (e.g. 38%, 50%, and 60%), and gradient. On pre-treatment imaging prior to radiotherapy the volume delineated by PETfusion to planning CT effectively corresponds to the MTV, which is utilized for biologicallytargeted radiotherapy [64–66]. Such methods have been used extensively for lung radiotherapy planning, where PET staging is recommended [67]. MTV has shown to predict overall survival

Total glycolytic activity (TGA), defined as the (MTV) x (SUVmean), is the primary PET parameter that includes both both anatomic (size) as well as metabolic parameters (e.g. with 18F-FDG). In an analysis of TGA and MTV in 45 patients with oral or oropharyngeal SCC, stage, on univariate cox regression, MTV and TGA were the most associated with progression-free survival (PFS) and overall survival (OS) (p=0.002 and p=0.006, respectively), moreso than

Retention index (RI) is a dynamic parameter that can be calculated with dual-time-point (early and delayed) PET imaging, where RI is the difference of SUVmax on two scans divided by initial SUVmax. Rate of decline of RI during lung irradiation has shown to predict locoregional recurrence [70]. Further, in an analysis of 68 women with breast cancer, in comparison to other parameters including early and delayed SUVmax, RI showed best relation to biologic parameters

> max max max *delayed early early*

From an oncologic standpoint, beyond the importance of baseline PET imaging for staging and radiotherapy planning, subsequent PET scans, whether during treatment or subsequent,

*SUV SUV*

*SUV*

*TGA MTV x SUVmean* = (3)


in lung cancer [61], head and neck cancer [60], and esophageal cancer [68].

tumor grade (p=004) and SUVmax (p=0.56) [69].

including grade, Ki-67, and c-erbB-2 expression [71].

*RI*

soft tissue sarcoma [56].

Various methods for assessing and categorizing response of tumors based on radiographic imaging have been proposed, including the World Health Organization (WHO) criteria, the Response Evaluation Criteria in Solid Tumors (RECIST), and RECIST 1.1 [72–75]. Such criterica, depend on radiographic imaging, which may not best assess the biologic response, particularly given that metabolic response on PET routinely anatomic radiographic response on CT [76]. Accordingly, methods of categorizing response with PET have been developed, namely the European Organization for Research and Treatment of Cancer (EORTC) criteria and newer PET Response Criteria in Solid Tumors (PERCIST, version 1.0) [43,77]. A separate metric of response definitions using 18F-FDG PET has been developed for lymphoma response and used for clinical trials [78]. Definitions of criteria are delineated in Table 1, Table 2, Table 3, Table 4, and Table 5.


**Response IWC[79] IWC+PET[80]**


and negative BMB if positive prior to therapy - PD by IWC with a completely negative PET and CT abnormalities (new lesion or increasing size of previous lesion) ≥ 1.5 cm (≥ 1.0 cm in the lungs) and

negative BMB if positive prior to therapy

an indeterminate BMB

1.1-1.5 cm

previous lesion)

(not defined)

Adapted from Juweid *et al.* (2005) [79]. IWC, International Workshop Criteria; PET, positron emission tomography; CR, complete remission; CRu, unconfirmed complete response, BMB, bone marrow biopsy, CT, computed tomography; PR, Partial Response; SPD, sum of the product of the diameters; SD, stable disease; PD, progressive disease; RD, relapsed

**Table 3.** IWC+PET-based response definitions for lymphoma based on IWC designations and PET findings

cm (< 1.0 cm in the lungs)

SD - less than PR but not PD - SD by IWC with a positive PET at the site of a


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of a previously involved node/nodal mass

previously involved node/nodal mass








CR - no detectable clinical or radiographic evidence of disease

≤ 1.5 cm

to ≤ 1.0 cm

nodes


CRu - same as CR but either residual lymph mass

PR - ≥ 50% reduction in SPD of the six largest dominant nodes or nodal masses


PD - applies only to patients with PR or nonresponders


involved sites or


axis or

disease

RD - applies only to patients with CR or Cru

> 1.5cm transverse diameter that has regressed > 75% or indeterminate BMB

RECIST, Response Evaluation Criteria in Solid Tumors, European Organization for Research and Treatment of Cancer; PERCIST, PET Response Criteria in Solid Tumors; CT, Computed Tomography, ROI: Region of interest, SD, standard deviation.

#### **Table 1.** Evaluation of baseline lesions


Adapted from Eisenhauer *et al*. (2009) [75]. CR, Complete Response; PR, Partial Response; SD, Stable Disease; PD, Progressive Disease; N/A, Not Applicable

**Table 2.** RECIST 1.1 (Non-metabolic) response criteria


**RECIST 1.1 (2009) [75]**

Measurable lesions have minimum size of 10 mm by CT scan,10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with calipers should be recorded as non-measurable), or 20 mm by chest X-ray. All other lesions are considered non-measurable

**Table 1.** Evaluation of baseline lesions

mm.

diameters.

least 5 mm.

Disease; N/A, Not Applicable

**Non-CR/ Non-PD**

considered progression.

**Table 2.** RECIST 1.1 (Non-metabolic) response criteria

**CR** Disappearance of all target lesions. Any pathological

**PR** ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum

**SD** Neither sufficient shrinkage to qualify for PR nor

**PD** ≥ 20% increase in the sum of diameters of target

sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

lesions, taking as reference the smallest sum on study (including the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at

The appearance of one or more new lesions is also

lymph nodes must have reduction in short axis to <10

**EORTC (1990) [77] (Metabolic)**

be recorded.

as MBq/L.

of 18F-FDG uptake.

Tumor regions defined on pretreatment scan should be drawn on region of high 18F-FDG uptake representing viable tumor. Whole tumor uptake should also

198 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Uptake measurements should be made for mean and maximal tumor ROI counts per pixel per second calibrated

Partial volume may affect measurement

Tumor size from anatomic imaging in relation to PET scanner resolution should be documented where possible.

RECIST, Response Evaluation Criteria in Solid Tumors, European Organization for Research and Treatment of Cancer; PERCIST,

PET Response Criteria in Solid Tumors; CT, Computed Tomography, ROI: Region of interest, SD, standard deviation.

**Target Lesions Non-Target Lesions**

**PERCIST (2009) [43] (Metabolic)**

extended over 2-cm z-axis.

Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).

Unequivocal progression of existing non-target lesions. The appearance of one or more new lesions is

maintenance of tumor marker level above the normal

SUL

N/A

N/A

N/A Persistence of one or more non-target lesion(s) and/or

Adapted from Eisenhauer *et al*. (2009) [75]. CR, Complete Response; PR, Partial Response; SD, Stable Disease; PD, Progressive

limits.

considered progression.

Measurable target lesion is hottest single tumor lesion SUVlbw of ''maximal 1.2-cm diameter volume ROI in tumor" (Peak SUVlbw). Peak SUVlbw is at least 1.5-fold greater than liver SUVlbw mean +2 SDs (in 3-cm spherical ROI in normal right lobe of liver). If liver is abnormal, primary tumor should have uptake > 2.0 SUVlbw mean of blood pool in 1 cm-diameter ROI in descending thoracic aorta

Uptake measurements should be made for peak and maximal single-voxel tumor SUVlbw. Other SUV metrics, including SUVlbw mean at 50% or 70% of Peak SUV, can be collected as exploratory data; TLG can be collected ideally on basis of voxels more intense than 2 SDs above liver mean

**(Anatomic)**

Adapted from Juweid *et al.* (2005) [79]. IWC, International Workshop Criteria; PET, positron emission tomography; CR, complete remission; CRu, unconfirmed complete response, BMB, bone marrow biopsy, CT, computed tomography; PR, Partial Response; SPD, sum of the product of the diameters; SD, stable disease; PD, progressive disease; RD, relapsed disease

**Table 3.** IWC+PET-based response definitions for lymphoma based on IWC designations and PET findings

**Response EORTC PERCIST 1.0 PERCIST Comment**

typical of cancer.

No new lesions.

baseline).

Peak\*

Or

Or

PERCIST be larger than the 1.5-cm-diameter volume ROI used to minimize partial-volume effects.

**Table 5.** Metabolic Objective Response Assessment with 18F-FDG PET: EORTC & PERCIST 1.0

treatment effect.

no decline in SUVlbw

Complete resolution of 18F-FDG uptake within measurable target lesion so that it is Percent reduction in SUVlbw should be recorded from measurable region and time (weeks) after treatment initiated (i.e., CMR 290, 4).

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PET – Assessment of Oncologic Treatment Response

If anatomic progression by RECIST, must verify with follow-up.

Measurement is of the single most active lesion after treatment that was also present at baseline (e.g. may be a different lesion). Percent reduction in SUVlbw should be recorded and time in weeks after

If anatomic progression by RECIST, must verify with follow-up. Reduction in extent of tumor 18F-FDG uptake is not requiremed.

lesion should be recorded, as well as time (weeks) from initation of most recent therapy, in weeks

PD other than new visceral lesions should be confirmed on follow-up study within 1 month unless clearly associated with PD by RECIST 1.1. Should report percent change in Peak SUVlbw, time elased since treatment (weeks) and whether new lesions are present/absent

treatment initiated (i.e., PMR -40, 3).

(i.e., SMD -15, 7).

and their number (i.e., PMD, 135, 4, new: 5).

No CMR, PMR, or PMD. Peak SUVlbw in metabolic target

less than mean liver activity and indistinguishable from surrounding background blood-pool levels. No new 18F-FDG-avid lesions in pattern

Disappearance of all other lesions to background blood-pool levels.

≥ 0.8 and ≥ 30% reduction of Peak\* 18F-FDG SUVlbw in target measurable tumor.

SUVlbw measurement is obtained from the most active lesion also present at baseline (even if a different lesion than measured at

No increase > 30% in SUVlbw or size of target or nontarget lesions.

(1) >30% and >0.8 increase in 18F-FDG

(2) Visible increase in extent of 18F-FDG tumor uptake (75% in TGA volume with

(3) New 18F-FDG-avid lesions that are typical of cancer and not related to treatment effect or infection.

Adapted from Wahl *et al*.[43]. TLG, total lesion glycolysis; CMR, complete metabolic response; PMR, partial metabolic response; PD, progressive disease; SMD, stable metabolic disease; PMD, progressive metabolic disease; CR, complete remission; PR, partial

\*Single-voxel SUVlbw (e.g. "SUVmax") is commonly used but has been reported to be less reproducible than Peak SUVlbw, especially with very small single-voxel values. Peak SUVlbw represents the highest mean value of a 1.2-cm-diameter spherical volume with‐ in a lesion and reduces variability secondary to voxel-to-voxel noise. It is suggested, but not required, that lesions assessed on

 SUVlbw from baseline in pattern typical of tumor and not of infection/

Metabolic CR (CMR)

Metabolic PR (PMR)

Metabolic SD (SMD)

Metabolic PD (PMD)

remission.

Complete resolution of 18F-FDG uptake within tumor volume so that it was indistinguishable from surrounding normal tissue.

Reduction of minimum of 15% ± 25% in tumor 18F-FDG SUV after 1 cycle of chemotherapy, and >25% after >1 treatment cycle. Reduction in extent of tumor 18F-FDG uptake is not a requirement for PR.

Increase in tumor 18F-FDG SUV <25% or decrease of < 15% and no visible increase in extent of 18F-FDG tumor uptake (20% in longest

Increase in 18F-FDG tumor SUV of >25% within tumor region defined on baseline scan; visible increase in extent of 18F-FDG tumor uptake (20% in longest dimension) or appearance of new 18F-FDG uptake in metastatic

dimension).

lesions.


From Cheson *et al.* Revised Response Criteria for Malignant Lymphoma (2007) [78]. CR, Complete Remission; FDG, <sup>18</sup>Ffluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography; PR = Partial Remission, SPD = sum of the product of the diameters; SD, stable disease; PD, progressive disease.

**Table 4.** PET response definitions for clinical trials


**Response Definition Nodal Masses Spleen, Liver Bone Marrow**

200 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Not palpable, nodules disappeared

≥ 50% decrease in SPD of nodules (for single nodule in greatest transverse diameter); no increase in size of liver or spleen

> 50% increase from nadir in the SPD of any previous

lesions

Infiltrate cleared on repeat biopsy; if indeterminate by

immunohistochemistry

Irrelevant if positive prior to therapy; cell type should be

morphology,

specified

New or recurrent involvement

(a) FDG-avid or PET positive prior to therapy; mass of any size permitted if PET negative (b) Variably FDG-avid or PET negative; regression to normal

≥ 50% decrease in SPD of up to 6 largest dominant masses; no increase in size of other

(a) FDG-avid or PET positive prior to therapy; one or more PET positive at previously

(b) Variably FDG-avid or PET negative; regression on CT

(a) FDG-avid or PET positive prior to therapy; PET positive at prior sites of disease and no new sites on CT or PET (b) Variably FDG-avid or PET negative; no change in size of previous lesions on CT

Appearance of a new lesion(s) > 1.5 cm in any axis, 50% increase in SPD of more than one node, or > 50% increase in longest diameter of a previously identified node >1

cm in short axis

prior to therapy.

sum of the product of the diameters; SD, stable disease; PD, progressive disease.

Lesions PET positive if FDGavid lymphoma or PET positive

From Cheson *et al.* Revised Response Criteria for Malignant Lymphoma (2007) [78]. CR, Complete Remission; FDG, <sup>18</sup>Ffluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography; PR = Partial Remission, SPD =

size on CT

nodes

involved site

CR Disappearance of

PR Regression of

SD Failure to attain

Relapsed Disease or PD CR/PR, or PD

Any new lesion or increase of previously involved sites by ≥ 50% from nadir.

**Table 4.** PET response definitions for clinical trials

all evidence of disease

measurable disease and no new sites

> Adapted from Wahl *et al*.[43]. TLG, total lesion glycolysis; CMR, complete metabolic response; PMR, partial metabolic response; PD, progressive disease; SMD, stable metabolic disease; PMD, progressive metabolic disease; CR, complete remission; PR, partial remission.

> \*Single-voxel SUVlbw (e.g. "SUVmax") is commonly used but has been reported to be less reproducible than Peak SUVlbw, especially with very small single-voxel values. Peak SUVlbw represents the highest mean value of a 1.2-cm-diameter spherical volume with‐ in a lesion and reduces variability secondary to voxel-to-voxel noise. It is suggested, but not required, that lesions assessed on PERCIST be larger than the 1.5-cm-diameter volume ROI used to minimize partial-volume effects.

**Table 5.** Metabolic Objective Response Assessment with 18F-FDG PET: EORTC & PERCIST 1.0

#### **4. Clinical relevance of treatment response assessment**

#### **4.1. Head & neck cancer – Definitive/preoperative chemoradiation**

18F-FDG PET has found a particularly significant role in treatment of head and neck cancers. It has long shown promise in its ability to prognosticate; in 37 patients from 1991-1994 with head and neck squamous cell carcinomas (HNSCC) receiving baseline 18F-FDG PET, SUVmax showed correlation with aggressive disease and potential prediction for survival [81].

up of 34 months). One of the 27 observed patients had recurrence, yielding 97% negative predictive value. They conclude that in patients with a residual neck mass that is PET-negative 12 weeks after definitive radiotherapy (± chemotherapy), neck dissection is not required, and

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203

Such studies support timing of follow-up 18F-FDG PET to be 12 weeks post-treatment [84,85,88]. High negative predictive value (91%) has been shown at 16 weeks [86] posttreatment, though early time points (e.g. 4 weeks) have shown increased false positives [87]. Metaanalyses support PET ≥ 12 weeks after completion of definitive therapy for moderately higher diagnostic accuracy. An added benefit of 18F-FDG PET at this early follow-up interval is the potential to spare neck dissection in patients who show early distant metastatic disease

Despite lack of any randomized prospective studies, significant retrospective evidence has continued to show similar findings. Recent metaanalyses [90–92], discuss 26, 27, and 51 studies including up to 2335 patients [92], overall supporting the high negative predictive value (approximately 95%) of follow-up PET and its value in omitting planned neck dissection. Further, despite the increased costs of PET imaging, PET-guided management in patients with complete response at the primary site has shown to be the more cost effective than CT-guided

Similar to HNSCC, first line treatment for locally-advanced rectal cancer includes upfront chemoradiation. In this setting, however, subsequent planned surgery remains standard of care. This multimodality neoadjuvant approach has shown to decrease local recurrence and improve overall survival [94,95]. Furthermore, neoadjuvant treatment has shown to increase sphincter-preserving surgery, conferring decreased surgical morbidity and improved quality

Deferring subsequent surgical intervention in this disease site has similarly been investigated. In a cohort of 71 patients with distal rectal carcinoma considered resectable prior to concurrent chemoradiation with subsequent complete clinical response treated subsequently with observation alone (no planned surgery), five-year overall and disease-free survivals were 100%

Improving restaging methods after neoadjuvant chemotherapy provides clinicians with increased information to guide management. Radiographic imaging modalities, however, are less sensitive to assessment of pathologic response, which is better characterized by metabolic

A number of studies have attempted correlation of 18F-FDG PET with tumor downstaging and response to neoadjuvant chemoradiation [100–105]. In a study by Capirci *et al.* [100] including 81 patients with locally-advanced rectal cancer, percent reduction of SUVmax from baseline to follow-up 18F-FDG PET at 5-6 weeks after concurrent chemoradiation was most predictive of responders (71% reduction) versus non-responders (38% reduction) based on Mandard's criteria. They propose a cutoff of 65% reduction, yielding 85% sensitivity, 80% specificity, 81%

positive predictive value, 84% negative predictive value, and 81% accuracy.

patients can be safely observed.

management or planned neck dissection [93].

**4.2. Rectal cancer – Preoperative chemoradiation**

[88,89].

of life [96–98].

and 92%, respectively.

imaging with 18F-FDG PET [54,99,100].

Beyond prognostication, 18F-FDG PET is now routinely used to adapt treatment management, particularly in obviating surgical neck dissection in patients with complete response to initial radiation or chemoradiation therapy. Early studies have supported observation and omission of planned dissection after definitive radiotherapy for node-positive HNSCC with complete response on CT imaging, though at least selective nodal dissection was routinely practiced for residual neck masses [82,83]. With implementation of 18F-FDG PET, its negative predictive value has further supported omission of planned neck dissection, including in patients with residual neck mass/lymphadenopathy [84–88].

In an early study by Yao *et al.* [84], 41 patients from 2000-02 with locally-advanced HNSCC received radiation therapy with or without chemotherapy as upfront treatment had pretreat‐ ment and follow-up CT and 18F-FDG PET, with follow-up imaging 2.5-6 months (usually 3-4 months) post-treatment. Those without residual lymphadenopathy were observed. Twelve of 41 had residual lymphadenopathy; all had pathological testing, four with fine needle aspira‐ tion (FNA) biopsy, and eight had neck dissection. Follow-up 18F-FDG PET correlated better than follow-up CT for residual disease, and SUVmax cutoff of < 3.0 had 100% negative predictive value and 80% positive predictive value, serving as a good "rule-out" test for residual disease and potential to forego planned neck dissection in favor of initial observation, thus decreasing overall toxicity [84].

In a further analysis, Yao *et al.* (2005) [85] reviewed findings in 53 patients (70 heminecks; 17 patients with bilateral disease) with N2A or higher HNSCC with complete response to radiation therapy (± chemotherapy). Forty-two had clinically positive (exam or CT) lympha‐ denopathy but negative PET; this group had option to pursue dissection; 17 were observed, and 4 had negative neck dissection. The remaining 7 heminecks had clinically and PET-positive lymphadenopathy, six had neck dissection, one FNA; three were positive and four were negative for residual disease. No regional recurrences had occurred after median follow-up of 26 months (range 12-57 months). Negative predictive value of PET was 100% and positive predictive value 43%. They conclude that observation is safe if both CT and PET-negative 12 weeks after treatment and potentially also if CT reveals small (e.g. <2-3 cm) but PET-negative lymphadenopathy.

Porceddu *et al*. [88] analyzed a select cohort of 39 patients with HNSCC treated with definitive radiotherapy (± chemotherapy) with (a) complete regression of the primary HNSCC, (b) clinical evidence of residual neck mass by exam or CT imaging 8 weeks after treatment, (c) a follow-up 18F-FDG PET (median 12 weeks), and (d) either pathologic confirmation of neck status or > 12 months follow-up. Seven patients had residual PET uptake in the mass and proceeded to neck dissection (five were positive). Of the 32 with no residual tumor uptake, five had neck dissection (all pathologically negative), and 27 were observed (median followup of 34 months). One of the 27 observed patients had recurrence, yielding 97% negative predictive value. They conclude that in patients with a residual neck mass that is PET-negative 12 weeks after definitive radiotherapy (± chemotherapy), neck dissection is not required, and patients can be safely observed.

Such studies support timing of follow-up 18F-FDG PET to be 12 weeks post-treatment [84,85,88]. High negative predictive value (91%) has been shown at 16 weeks [86] posttreatment, though early time points (e.g. 4 weeks) have shown increased false positives [87]. Metaanalyses support PET ≥ 12 weeks after completion of definitive therapy for moderately higher diagnostic accuracy. An added benefit of 18F-FDG PET at this early follow-up interval is the potential to spare neck dissection in patients who show early distant metastatic disease [88,89].

Despite lack of any randomized prospective studies, significant retrospective evidence has continued to show similar findings. Recent metaanalyses [90–92], discuss 26, 27, and 51 studies including up to 2335 patients [92], overall supporting the high negative predictive value (approximately 95%) of follow-up PET and its value in omitting planned neck dissection. Further, despite the increased costs of PET imaging, PET-guided management in patients with complete response at the primary site has shown to be the more cost effective than CT-guided management or planned neck dissection [93].

#### **4.2. Rectal cancer – Preoperative chemoradiation**

**4. Clinical relevance of treatment response assessment**

**4.1. Head & neck cancer – Definitive/preoperative chemoradiation**

residual neck mass/lymphadenopathy [84–88].

overall toxicity [84].

lymphadenopathy.

18F-FDG PET has found a particularly significant role in treatment of head and neck cancers. It has long shown promise in its ability to prognosticate; in 37 patients from 1991-1994 with head and neck squamous cell carcinomas (HNSCC) receiving baseline 18F-FDG PET, SUVmax showed correlation with aggressive disease and potential prediction for survival [81].

202 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Beyond prognostication, 18F-FDG PET is now routinely used to adapt treatment management, particularly in obviating surgical neck dissection in patients with complete response to initial radiation or chemoradiation therapy. Early studies have supported observation and omission of planned dissection after definitive radiotherapy for node-positive HNSCC with complete response on CT imaging, though at least selective nodal dissection was routinely practiced for residual neck masses [82,83]. With implementation of 18F-FDG PET, its negative predictive value has further supported omission of planned neck dissection, including in patients with

In an early study by Yao *et al.* [84], 41 patients from 2000-02 with locally-advanced HNSCC received radiation therapy with or without chemotherapy as upfront treatment had pretreat‐ ment and follow-up CT and 18F-FDG PET, with follow-up imaging 2.5-6 months (usually 3-4 months) post-treatment. Those without residual lymphadenopathy were observed. Twelve of 41 had residual lymphadenopathy; all had pathological testing, four with fine needle aspira‐ tion (FNA) biopsy, and eight had neck dissection. Follow-up 18F-FDG PET correlated better than follow-up CT for residual disease, and SUVmax cutoff of < 3.0 had 100% negative predictive value and 80% positive predictive value, serving as a good "rule-out" test for residual disease and potential to forego planned neck dissection in favor of initial observation, thus decreasing

In a further analysis, Yao *et al.* (2005) [85] reviewed findings in 53 patients (70 heminecks; 17 patients with bilateral disease) with N2A or higher HNSCC with complete response to radiation therapy (± chemotherapy). Forty-two had clinically positive (exam or CT) lympha‐ denopathy but negative PET; this group had option to pursue dissection; 17 were observed, and 4 had negative neck dissection. The remaining 7 heminecks had clinically and PET-positive lymphadenopathy, six had neck dissection, one FNA; three were positive and four were negative for residual disease. No regional recurrences had occurred after median follow-up of 26 months (range 12-57 months). Negative predictive value of PET was 100% and positive predictive value 43%. They conclude that observation is safe if both CT and PET-negative 12 weeks after treatment and potentially also if CT reveals small (e.g. <2-3 cm) but PET-negative

Porceddu *et al*. [88] analyzed a select cohort of 39 patients with HNSCC treated with definitive radiotherapy (± chemotherapy) with (a) complete regression of the primary HNSCC, (b) clinical evidence of residual neck mass by exam or CT imaging 8 weeks after treatment, (c) a follow-up 18F-FDG PET (median 12 weeks), and (d) either pathologic confirmation of neck status or > 12 months follow-up. Seven patients had residual PET uptake in the mass and proceeded to neck dissection (five were positive). Of the 32 with no residual tumor uptake, five had neck dissection (all pathologically negative), and 27 were observed (median followSimilar to HNSCC, first line treatment for locally-advanced rectal cancer includes upfront chemoradiation. In this setting, however, subsequent planned surgery remains standard of care. This multimodality neoadjuvant approach has shown to decrease local recurrence and improve overall survival [94,95]. Furthermore, neoadjuvant treatment has shown to increase sphincter-preserving surgery, conferring decreased surgical morbidity and improved quality of life [96–98].

Deferring subsequent surgical intervention in this disease site has similarly been investigated. In a cohort of 71 patients with distal rectal carcinoma considered resectable prior to concurrent chemoradiation with subsequent complete clinical response treated subsequently with observation alone (no planned surgery), five-year overall and disease-free survivals were 100% and 92%, respectively.

Improving restaging methods after neoadjuvant chemotherapy provides clinicians with increased information to guide management. Radiographic imaging modalities, however, are less sensitive to assessment of pathologic response, which is better characterized by metabolic imaging with 18F-FDG PET [54,99,100].

A number of studies have attempted correlation of 18F-FDG PET with tumor downstaging and response to neoadjuvant chemoradiation [100–105]. In a study by Capirci *et al.* [100] including 81 patients with locally-advanced rectal cancer, percent reduction of SUVmax from baseline to follow-up 18F-FDG PET at 5-6 weeks after concurrent chemoradiation was most predictive of responders (71% reduction) versus non-responders (38% reduction) based on Mandard's criteria. They propose a cutoff of 65% reduction, yielding 85% sensitivity, 80% specificity, 81% positive predictive value, 84% negative predictive value, and 81% accuracy.

Notably, surgery is routinely planned approximately 6 weeks after neoadjuvant treatment, as surgery at 6-weeks was shown to have more tumor downstaging than at 2 weeks [106]. However, further tumor response and increased survival has been noted with intervals > 7 weeks [107]. A recent similar study by Perez *et al.* (2012) [105] of 91 patients with follow-up 18F-FDG PET at 6 weeks but also again at 12 weeks showed best separation of good responders (49%) versus bad responders (51%) at 12 weeks (SUVmax of 9.1 in bad responders vs. 4.3 in good responders, p<0.001) rather than at 6 weeks (SUVmax of 6.4 in bad responders versus 5.8 in good responders, p=0.5). Good responders were more likely to have complete clinical response (38% vs. 7%, p=0.001) complete or near-complete pathologic response (45% vs. 16%, p=0.008) and smaller pathologic size (3.3 vs. 4.4, p=0.03). Increase from early-phase (1 hour after injection) to delayed-phase PET (3 hours after injection) at the 6 –week time point was 67% accurate of predicting good vs. bad responders. A good responder was considered anyone with SUV12week < SUV6week. They conclude that approximately half of patients will have continued improved response beyond 6 weeks, whereas approximately half will have increased meta‐ bolic activity. Dual-phase imaging at the 6-week point may help stratify the two groups, which may help guide clinicians in best timing for planned surgery.

21 months). Two-year PFS rates were 85% vs. 4% for PET- vs. PET+ patients (p<0.0001). Halasz *et al.* (2011) [117] report a summary of post-chemotherapy and interim PET results. They further report a cohort of 59 patients with NHL, receiving 36 Gy (median) consolidative in-field radiation therapy (RT) (all patients) and R-CHOP chemotherapy (58 of 59 patients). Median follow-up was 47 months. In the 66% with negative PET after chemotherapy, 3-year PFS was 97%. However, with this treatment including RT, 3-year PFS was 90% in those with positive

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**Author Year n PPV (%) NPV (%)**

Spaepen [115] 2001 60 100 91% Cerci [118] 2010 130 92% 100% Engert [119] 2012 728 N/A 95%

Bangerter [120] 1998 89 90% 98% Jerusalem [114] 1999 35 43% 100% Zinzani [121] 1999 31 93% 100% Mikhaeel [122] 2000 45 60% 100% Naumann [123] 2001 15 86% 88% Spaepen [116] 2001 93 70% 100% Gigli [124] 2008 42 75% 94% Cashen [125] 2011 50 80% 92%

Adapted from Cheson [113]. HL, Hodgkin Lymphoma; NHL, Non-Hodgkin Lymphoma; PPV, positive predictive value; NPV,

More research has investigated interim (during chemotherapy) 18FDG-PET for assessment of treatment response and prognostication (see Table 7). Cerci *et al.* [126] assessed interim PET after 2 cycles of ABVD (coxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy in 104 patients with early and advanced Hodgkin lymphoma. Negativity vs. positivity at interim PET significantly predicted event-free survival (EFS), 91% vs. 53% at 3 years for PETvs. PET+ patients (p<0.001). On univariate analysis, interim PET was the best prognosticator of event-free survival (p<0.001), more so than stage, bulky disease, and international prognostic score (IPS) (p=0.24, p=0.15, p=0.99, respectively). It however failed to prognosticate survival (p=0.2), which was better predicted by age (cutoff 45 years, p=0.01) and IPS (0-2 vs. 3-7, p=0.04).

**Table 6.** Positive and negative predictive value of PET-CT in lymphoma staging

PET after chemotherapy (p-value not reported).

**HL**

**NHL**

negative predictive value

**Interim (during-chemotherapy) PET**

In rectal cancer, 18F-FDG PET restaging does show promise in potentially affecting treatment management; prospective studies investigating its role in this setting are awaited.

#### **4.3. Lymphoma**

<sup>18</sup>FDG-PET finds various roles in management of lymphoma. For staging in Hodgkin lym‐ phoma (HL) and non-Hodgkin lymphoma (NHL), PET with CT (PET-CT) has been shown to improve sensitivity and specificity in evaluation of nodal and extranodal sites in comparison to contrast-enhanced CT without PET [108,109]. It has further shown to be 92% sensitive for bone marrow involvement in HL [110]. Beyond staging, PET has been used for post-chemo‐ therapy restaging, assessing response during chemotherapy at initial diagnosis, and also during salvage treatment. In current NCCN guidelines for both HL & NHL, PET-CT has variably been incorporated into staging, restaging during chemotherapy, and restaging after chemotherapy; routine PET-CT in the surveillance setting, however, is recommended against secondary to false-positive risk [111,112].

#### **Restaging**

The role for PET in lymphoma is clearest in the setting of restaging, either during or subsequent to treatment. PET has a very high negative predictive value (88-100%, see Table 6) [113]. Further, after treatment, PET is superior to CT for distinguishing residual mass with versus without residual viable disease (e.g. post-treatment fibrosis) [114]. Spaepen *et al.* report on two cohorts, one with HL [115] and one with NHL [116] who were assessed with PET at baseline and after completion of chemotherapy. In the HL cohort [115] of 60 patients, 55 were PET- (PET negative) after chemotherapy and 5 were PET+ (PET positive). All 5 PET+ patients had relapse of disease. Of the PET- patients, 91% remained without recurrence after median follow-up of 32 months. Two-year PFS rates were 91% vs. 0% for PET- vs. PET+ patients (p<0.0001). Similarly, in the NHL cohort [116] of 93 patients, all 27 PET+ patients after chemotherapy had relapse (median 2.4 months), whereas 84% of the PET- patients remained in remission (median 21 months). Two-year PFS rates were 85% vs. 4% for PET- vs. PET+ patients (p<0.0001). Halasz *et al.* (2011) [117] report a summary of post-chemotherapy and interim PET results. They further report a cohort of 59 patients with NHL, receiving 36 Gy (median) consolidative in-field radiation therapy (RT) (all patients) and R-CHOP chemotherapy (58 of 59 patients). Median follow-up was 47 months. In the 66% with negative PET after chemotherapy, 3-year PFS was 97%. However, with this treatment including RT, 3-year PFS was 90% in those with positive PET after chemotherapy (p-value not reported).


Adapted from Cheson [113]. HL, Hodgkin Lymphoma; NHL, Non-Hodgkin Lymphoma; PPV, positive predictive value; NPV, negative predictive value

**Table 6.** Positive and negative predictive value of PET-CT in lymphoma staging

#### **Interim (during-chemotherapy) PET**

Notably, surgery is routinely planned approximately 6 weeks after neoadjuvant treatment, as surgery at 6-weeks was shown to have more tumor downstaging than at 2 weeks [106]. However, further tumor response and increased survival has been noted with intervals > 7 weeks [107]. A recent similar study by Perez *et al.* (2012) [105] of 91 patients with follow-up 18F-FDG PET at 6 weeks but also again at 12 weeks showed best separation of good responders (49%) versus bad responders (51%) at 12 weeks (SUVmax of 9.1 in bad responders vs. 4.3 in good responders, p<0.001) rather than at 6 weeks (SUVmax of 6.4 in bad responders versus 5.8 in good responders, p=0.5). Good responders were more likely to have complete clinical response (38% vs. 7%, p=0.001) complete or near-complete pathologic response (45% vs. 16%, p=0.008) and smaller pathologic size (3.3 vs. 4.4, p=0.03). Increase from early-phase (1 hour after injection) to delayed-phase PET (3 hours after injection) at the 6 –week time point was 67% accurate of predicting good vs. bad responders. A good responder was considered anyone with SUV12week < SUV6week. They conclude that approximately half of patients will have continued improved response beyond 6 weeks, whereas approximately half will have increased meta‐ bolic activity. Dual-phase imaging at the 6-week point may help stratify the two groups, which

204 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

In rectal cancer, 18F-FDG PET restaging does show promise in potentially affecting treatment

<sup>18</sup>FDG-PET finds various roles in management of lymphoma. For staging in Hodgkin lym‐ phoma (HL) and non-Hodgkin lymphoma (NHL), PET with CT (PET-CT) has been shown to improve sensitivity and specificity in evaluation of nodal and extranodal sites in comparison to contrast-enhanced CT without PET [108,109]. It has further shown to be 92% sensitive for bone marrow involvement in HL [110]. Beyond staging, PET has been used for post-chemo‐ therapy restaging, assessing response during chemotherapy at initial diagnosis, and also during salvage treatment. In current NCCN guidelines for both HL & NHL, PET-CT has variably been incorporated into staging, restaging during chemotherapy, and restaging after chemotherapy; routine PET-CT in the surveillance setting, however, is recommended against

The role for PET in lymphoma is clearest in the setting of restaging, either during or subsequent to treatment. PET has a very high negative predictive value (88-100%, see Table 6) [113]. Further, after treatment, PET is superior to CT for distinguishing residual mass with versus without residual viable disease (e.g. post-treatment fibrosis) [114]. Spaepen *et al.* report on two cohorts, one with HL [115] and one with NHL [116] who were assessed with PET at baseline and after completion of chemotherapy. In the HL cohort [115] of 60 patients, 55 were PET- (PET negative) after chemotherapy and 5 were PET+ (PET positive). All 5 PET+ patients had relapse of disease. Of the PET- patients, 91% remained without recurrence after median follow-up of 32 months. Two-year PFS rates were 91% vs. 0% for PET- vs. PET+ patients (p<0.0001). Similarly, in the NHL cohort [116] of 93 patients, all 27 PET+ patients after chemotherapy had relapse (median 2.4 months), whereas 84% of the PET- patients remained in remission (median

management; prospective studies investigating its role in this setting are awaited.

may help guide clinicians in best timing for planned surgery.

**4.3. Lymphoma**

**Restaging**

secondary to false-positive risk [111,112].

More research has investigated interim (during chemotherapy) 18FDG-PET for assessment of treatment response and prognostication (see Table 7). Cerci *et al.* [126] assessed interim PET after 2 cycles of ABVD (coxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy in 104 patients with early and advanced Hodgkin lymphoma. Negativity vs. positivity at interim PET significantly predicted event-free survival (EFS), 91% vs. 53% at 3 years for PETvs. PET+ patients (p<0.001). On univariate analysis, interim PET was the best prognosticator of event-free survival (p<0.001), more so than stage, bulky disease, and international prognostic score (IPS) (p=0.24, p=0.15, p=0.99, respectively). It however failed to prognosticate survival (p=0.2), which was better predicted by age (cutoff 45 years, p=0.01) and IPS (0-2 vs. 3-7, p=0.04).

**Drug salvage**

are still awaited.

(PET-negative) versus 10% (PET-positive, p<0.001).

**4.4. Esophageal cancer – Definitive/preoperative**

survival from 24 to 49 months (hazard ratio = 0.66, p=0.003).

esophageal cancer has been an area of increasing research [150–163].

**PET Response-Adapted radiotherapy**

In the setting of relapsing/refractory Hodgkin lymphoma, interim PET after 2 cycles of salvage high-dose chemotherapy has been assessed. Limited retrospective data from Castagna *et al*. [125] has shown similar prognostic potential, reporting 2-year progression-free survival of 93%

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In the German Hodgkin Study Group HD15 trial (2012) [119,140] with over 2,000 patients with advanced-stage Hodgkin lymphoma, 3 BEACOPP chemotherapy regimens were compared in a non-inferiority randomized trial. Radiotherapy was implemented with a "PET-guided" adaptive approach based on post-chemotherapy response regardless of treatment arm. If a PET-positive persistent mass 2.5cm or larger was present after completion of chemotherapy (median 21 days), 30Gy local radiation therapy was administered for consolidation. Negative predictive value for post-chemotherapy PET was 94% at 12 months follow-up. In the 3 arms, five-year freedom from failure ranged from 84%-89%, and five-year survival ranged from 92-95%. Consolidative radiotherapy was not randomized and was administered to 11% of patients (compared to 71% in HD9 [141]). With such excellent outcomes with this PET-guided radiotherapy approach, the authors indicate this approach as their current standard of care. Longer follow-up and prospective clinical trials assessing need for consolidative radiotherapy

The role of multimodality therapy for esophageal and gastroesophageal cancer has historically not been well defined. Resection has been considered standard treatment for patients with resectable/localized disease without strong evidence supporting neoadjuvant therapy, despite significant risk for local and distant recurrences yielding poor 5-year survival rates ranging from 15-39%[142]. Neoadjuvant treatment is increasingly becoming adopted as standard of care for locally-advanced disease, with use continuing to increase [143,144]. Multiple prospec‐ tive trials did not report survival benefit with neoadjuvant chemoradiotherapy [145–147], and randomized studies supporting neoadjuvant treatment are scarce. Walsh *et al.* (1996) [148] showed increased 3-year overall survival from 6% to 32% with neoadjuvant treatment (p<0.01) in a study of 113 patients. In the recently published CROSS trial [149] with 366 patients, addition of neoadjuvant chemoradiation increased R0 resection (resection with negative pathologic margins) from 69% to 92% (p<0.001) and more than doubled median overall

In patients receiving neoadjuvant chemoradiation, a portion—29% in the Dutch CROSS study —are found to have pathologic complete response on subsequent surgery. In a singleinstitution review, pathologic complete response from neoadjuvant treatment was associated with higher 5-year and overall survival (48% vs. 18% and 50 months vs. 28 months, respec‐ tively) in comparison to patients without complete response [150]. With treatment response bearing significant prognostic potential, assessment of response to neoadjuvant treatment for


HL, Hodgkin Lymphoma; NHL, Non-Hodgkin Lymphoma; PET, positron emission tomography; FU, Follow-up; n, number of pa‐ tients in study with interim PET scan; EFS, event-free survival; PFS, progression-free survival; MRU, minimal residual uptake; # cycles, number of cycles of chemotherapy completed prior to interim PET; NR, not reported

**Table 7.** Prognostication of interim PET in lymphoma

#### **Drug salvage**

**Author Year <sup>n</sup> FU**

Hutchings [127] 2005 85 40 2-3

Hutchings [109] 2006 77 23 2

Kostakoglu [128] 2006 23 21 1

Zinzani [129] 2006 40 18 2

Gallamini [130] 2007 260 26 2

Markova [131] 2009 50 25 4

Cerci [126] 2010 104 36 2

Jerusalem [114] 2000 28 18 3

Spaepen [132] 2002 70 36 2-3

Haioun [133] 2005 90 24 2

Mikhaell [134] 2005 121 29 2-3

Ng [135] 2007 45 31 1-5

Han [136] 2009 40 24 2-4

Pregno [137] 2009 88 26 2-4

Safar [138] 2009 112 38 2

Cashen [125] 2011 50 15 2-3

**Table 7.** Prognostication of interim PET in lymphoma

Zinzani [139] <sup>2011</sup> <sup>91</sup> <sup>50</sup> variable 62% PET-

cycles, number of cycles of chemotherapy completed prior to interim PET; NR, not reported

**HL**

**NHL**

**(months) # cycles Interim PET**

206 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**Response**

74% PET-11% PET+ 15% MRU

79% PET-21% PET+

74% PET-26% PET+

80% PET-20% PET+

81% PET-19% PET+

72% PET-28% PET+

71% PET-29% PET+

82% PET-18% PET+

53% PET - 47% PET +

60% PET - 40% PET +

41% PET - 43% PET + 16% MRU

69% PET - 31% PET +

68% PET - 32% PET +

72% PET - 28% PET +

63% PET - 37% PET +

52% PET - 48% PET +

39% PET+

HL, Hodgkin Lymphoma; NHL, Non-Hodgkin Lymphoma; PET, positron emission tomography; FU, Follow-up; n, number of pa‐ tients in study with interim PET scan; EFS, event-free survival; PFS, progression-free survival; MRU, minimal residual uptake; #

**Outcomes p-value**

<0.001

<0.001

<0.001

<0.001

<0.001

NR

<0.001

<0.001

<0.001

<0.001

0.048

<0.001

0.031

<0.001

97% 2y PFS 46% 2y PFS

96% 2y PFS 0% 2y PFS

100% 2y PFS 13% 2y PFS

97% PFS 12% PFS

95% 2y PFS 13% 2y PFS

100% PFS 28% PFS

91% 3y EFS 53% 3y EFS

62% 2y PFS 0% 2y PFS

82% 2y EFS 43% 2y EFS

88% 5y PFS 16% 5y PFS 59% 5y PFS

15% relapsed

10% progressed

85% 2y PFS 72% 2y PFS

84% 3y PFS 47% 3y PFS

85% 2y PFS 63% 2y EFS

75% 4y EFS 18% 4y EFS

16% progressed

100% progressed <0.001

61% relapsed <0.001

71% progressed NR

In the setting of relapsing/refractory Hodgkin lymphoma, interim PET after 2 cycles of salvage high-dose chemotherapy has been assessed. Limited retrospective data from Castagna *et al*. [125] has shown similar prognostic potential, reporting 2-year progression-free survival of 93% (PET-negative) versus 10% (PET-positive, p<0.001).

#### **PET Response-Adapted radiotherapy**

In the German Hodgkin Study Group HD15 trial (2012) [119,140] with over 2,000 patients with advanced-stage Hodgkin lymphoma, 3 BEACOPP chemotherapy regimens were compared in a non-inferiority randomized trial. Radiotherapy was implemented with a "PET-guided" adaptive approach based on post-chemotherapy response regardless of treatment arm. If a PET-positive persistent mass 2.5cm or larger was present after completion of chemotherapy (median 21 days), 30Gy local radiation therapy was administered for consolidation. Negative predictive value for post-chemotherapy PET was 94% at 12 months follow-up. In the 3 arms, five-year freedom from failure ranged from 84%-89%, and five-year survival ranged from 92-95%. Consolidative radiotherapy was not randomized and was administered to 11% of patients (compared to 71% in HD9 [141]). With such excellent outcomes with this PET-guided radiotherapy approach, the authors indicate this approach as their current standard of care. Longer follow-up and prospective clinical trials assessing need for consolidative radiotherapy are still awaited.

#### **4.4. Esophageal cancer – Definitive/preoperative**

The role of multimodality therapy for esophageal and gastroesophageal cancer has historically not been well defined. Resection has been considered standard treatment for patients with resectable/localized disease without strong evidence supporting neoadjuvant therapy, despite significant risk for local and distant recurrences yielding poor 5-year survival rates ranging from 15-39%[142]. Neoadjuvant treatment is increasingly becoming adopted as standard of care for locally-advanced disease, with use continuing to increase [143,144]. Multiple prospec‐ tive trials did not report survival benefit with neoadjuvant chemoradiotherapy [145–147], and randomized studies supporting neoadjuvant treatment are scarce. Walsh *et al.* (1996) [148] showed increased 3-year overall survival from 6% to 32% with neoadjuvant treatment (p<0.01) in a study of 113 patients. In the recently published CROSS trial [149] with 366 patients, addition of neoadjuvant chemoradiation increased R0 resection (resection with negative pathologic margins) from 69% to 92% (p<0.001) and more than doubled median overall survival from 24 to 49 months (hazard ratio = 0.66, p=0.003).

In patients receiving neoadjuvant chemoradiation, a portion—29% in the Dutch CROSS study —are found to have pathologic complete response on subsequent surgery. In a singleinstitution review, pathologic complete response from neoadjuvant treatment was associated with higher 5-year and overall survival (48% vs. 18% and 50 months vs. 28 months, respec‐ tively) in comparison to patients without complete response [150]. With treatment response bearing significant prognostic potential, assessment of response to neoadjuvant treatment for esophageal cancer has been an area of increasing research [150–163].

specificity for prediction of clinical response. Responders had longer time to progression/

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In a follow-up study [152], patients had three 18FDG-PET scans: one pretreatment, one during treatment (2 weeks after starting), then 3-4 weeks preoperatively (but after neoadjuvant treatment. Responders had more decrease at 2 weeks (44% vs. 21%, p<0.01) and preoperatively (70% vs. 51%, p=0.01). During-treatment PET had higher power than the preoperative PET treatment to predict response (area under curve (AUC) of receiver operator characteristic (ROC) 0.78 vs. 0.88), though difference was not statistically significant (p=0.40). Best cutoff for response in this cohort was 30% reduction from baseline (93% sensitive, 88% accurate), who all proceed to have R0 resection. Responders by this PET criteria had higher survival (median

Analysis of gastroesophageal junction tumors again showed improved prognostic potential with PET using percent reduction of SUVmax 2 weeks after treatment start (p=0.03) versus after completion of neoadjuvant treatment (p=0.09) [153]. Though percent reduction is routinely used to assess response, thresholds of decrease of SUVmax (e.g. decrease of ≥10) from before to after neoadjuvant treatment have shown to predict significant histopathologic response [158]. More recent studies have showed other metrics as better predictors of response. In a compar‐ ison of SUVmax, MTV based on fixed threshold of 2.5 SUV, and SUVmean (of MTV), and TGA, MTV and TGA were both 91% sensitive in predicting histopathologic response when also using CT, but MTV increase specificity from 90% to 93%. Most predictive was TGA (AUC=0.95) followed by MTV (AUC=0.92), SUVmax (AUC=0.84), and SUVmean (AUC=0.82) [159]. Further, metabolic response criteria (e.g. PERCIST) have shown better assessed response in comparison

With various studies showing prognostic potential of 18FDG-PET early during treatment, there is question as to the utility of PET to potentially facilitate treatment modification [152]. Kwee (2010) [160] performed a metaanalysis of 20 PET-response studies including 849 patients; it however showed wide ranges of sensitivity and specificity with overall AUC of 0.78. Based on the pooled data, PET was not recommended for routine clinical use to guide neoadjuvant treatment. Furthermore, in a retrospective single-institution review [164], patients treated with neoadjuvant chemotherapy followed by surgery had similar freedom from local failure (p=0.92) and overall survival (p=0.15) in comparison to patients receiving definitive chemora‐ diation who attained metabolic CR (SUV<3). Furthermore, in this retrospective study, though not statistically significant, rate of death in the definitive chemoradiation group was higher

Similar to head and neck cancer, prospective studies are awaited to formally assess necessity of surgical management after complete metabolic response to neoadjuvant chemoradiation

18FDG-PET is currently recommended by NCCN guidelines for routine staging of stage I-III NSCLC [67]. Radiotherapy planning with PET fusion has further been recommended for

recurrence and overall survival.

38 vs. 18 months; 2-year rates 79% vs. 38%, p<0.01).

to non-metabolic methods (e.g. RECIST and WHO) [159,163].

than in the surgical group despite worse baseline characteristics.

therapy in operable/resectable patients.

**4.5. Non-Small Cell Lung Cancer (NSCLC)**

**Figure 1.** This is a 12-year-old female with a history of Stage IIB bulky nodular sclerosing Hodgkin lymphoma involving the bilateral cervical chain and mediastinum. She had achieved a complete response with 6 cycles of COPP-ABV che‐ motherapy. She then received a total radiation dose of 3060 cGy in 17 fractions of 180 cGy to the cervical and media‐ stinal lymph nodes. As seen in the serial PET/CT images (b-f above), the mediastinal and cervical lymph nodes responded well. However, by 28 months post-treatment, a left iliacus muscle lymph node became suspicious for lym‐ phoma involvement (g – max SUV 5.0). By 31 months post-treatment, this node had increased further (h – max SUV 7.7).

In an early study by Weber *et al.* (2001) [151] in forty patients receiving neoadjuvant chemo‐ therapy (without radiotherapy) for esophageal cancer, patients had 18FDG-PET both pretreat‐ ment and after 14 days of treatment (during chemotherapy). Metabolic response was considered decrease of 35% from baseline, which was associated with 93% sensitivity and 95% specificity for prediction of clinical response. Responders had longer time to progression/ recurrence and overall survival.

In a follow-up study [152], patients had three 18FDG-PET scans: one pretreatment, one during treatment (2 weeks after starting), then 3-4 weeks preoperatively (but after neoadjuvant treatment. Responders had more decrease at 2 weeks (44% vs. 21%, p<0.01) and preoperatively (70% vs. 51%, p=0.01). During-treatment PET had higher power than the preoperative PET treatment to predict response (area under curve (AUC) of receiver operator characteristic (ROC) 0.78 vs. 0.88), though difference was not statistically significant (p=0.40). Best cutoff for response in this cohort was 30% reduction from baseline (93% sensitive, 88% accurate), who all proceed to have R0 resection. Responders by this PET criteria had higher survival (median 38 vs. 18 months; 2-year rates 79% vs. 38%, p<0.01).

Analysis of gastroesophageal junction tumors again showed improved prognostic potential with PET using percent reduction of SUVmax 2 weeks after treatment start (p=0.03) versus after completion of neoadjuvant treatment (p=0.09) [153]. Though percent reduction is routinely used to assess response, thresholds of decrease of SUVmax (e.g. decrease of ≥10) from before to after neoadjuvant treatment have shown to predict significant histopathologic response [158].

More recent studies have showed other metrics as better predictors of response. In a compar‐ ison of SUVmax, MTV based on fixed threshold of 2.5 SUV, and SUVmean (of MTV), and TGA, MTV and TGA were both 91% sensitive in predicting histopathologic response when also using CT, but MTV increase specificity from 90% to 93%. Most predictive was TGA (AUC=0.95) followed by MTV (AUC=0.92), SUVmax (AUC=0.84), and SUVmean (AUC=0.82) [159]. Further, metabolic response criteria (e.g. PERCIST) have shown better assessed response in comparison to non-metabolic methods (e.g. RECIST and WHO) [159,163].

With various studies showing prognostic potential of 18FDG-PET early during treatment, there is question as to the utility of PET to potentially facilitate treatment modification [152]. Kwee (2010) [160] performed a metaanalysis of 20 PET-response studies including 849 patients; it however showed wide ranges of sensitivity and specificity with overall AUC of 0.78. Based on the pooled data, PET was not recommended for routine clinical use to guide neoadjuvant treatment. Furthermore, in a retrospective single-institution review [164], patients treated with neoadjuvant chemotherapy followed by surgery had similar freedom from local failure (p=0.92) and overall survival (p=0.15) in comparison to patients receiving definitive chemora‐ diation who attained metabolic CR (SUV<3). Furthermore, in this retrospective study, though not statistically significant, rate of death in the definitive chemoradiation group was higher than in the surgical group despite worse baseline characteristics.

Similar to head and neck cancer, prospective studies are awaited to formally assess necessity of surgical management after complete metabolic response to neoadjuvant chemoradiation therapy in operable/resectable patients.

#### **4.5. Non-Small Cell Lung Cancer (NSCLC)**

In an early study by Weber *et al.* (2001) [151] in forty patients receiving neoadjuvant chemo‐ therapy (without radiotherapy) for esophageal cancer, patients had 18FDG-PET both pretreat‐ ment and after 14 days of treatment (during chemotherapy). Metabolic response was considered decrease of 35% from baseline, which was associated with 93% sensitivity and 95%

7.7).

**Figure 1.** This is a 12-year-old female with a history of Stage IIB bulky nodular sclerosing Hodgkin lymphoma involving the bilateral cervical chain and mediastinum. She had achieved a complete response with 6 cycles of COPP-ABV che‐ motherapy. She then received a total radiation dose of 3060 cGy in 17 fractions of 180 cGy to the cervical and media‐ stinal lymph nodes. As seen in the serial PET/CT images (b-f above), the mediastinal and cervical lymph nodes responded well. However, by 28 months post-treatment, a left iliacus muscle lymph node became suspicious for lym‐ phoma involvement (g – max SUV 5.0). By 31 months post-treatment, this node had increased further (h – max SUV

208 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

18FDG-PET is currently recommended by NCCN guidelines for routine staging of stage I-III NSCLC [67]. Radiotherapy planning with PET fusion has further been recommended for biologically-targeted radiotherapy in which 3D-PET fusion is implemented for tumor delin‐ eation, with PET performed with minimal delay between PET and start of treatment, given propensity for rapid disease progression [64–66,165]. Metabolic (PET) response to treatment has been shown to pre-date radiographic (CT) response. Despite increasing data showing utility of PET for assessing treatment response in NSCLC and predicting outcomes including survival, guidelines currently do not recommend PET in this setting [44,45,67,76,166–177].

**SBRT**

most predictive of LF (p=0.057).

**Hyperfractionated radiotherapy**

Stereotactic body radiotherapy (SBRT), employing modern techniques including 4-D treat‐ ment planning and image-guided radiotherapy (IGRT) has been shown to be an effective, costefficient, treatment option for definitive management of early-stage NSCLC as well as lung metastases from other organs with excellent tumor control rates; in comparison to medicallyoperable patients who are treated with resection, retrospective data of primarily medicallyinoperable patients with poor pulmonary function suggests excellent tumor control with SBRT

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In a large single-institution analysis [45] of 129 consecutive NSCLC tumors treated with SBRT, 58% enrolled on a prospective phase II protocol, patients had baseline and serial follow-up PET imaging. Sixteen patients additionally had weekly on-treatment 4D-PET-CT. Median follow-up was 19 months and median time until local failure (LF) of 15 months. A total of 475 PETs were obtained. Change in SUV from pre-treatment to follow-up are seen in Figure 1 and stratified by status of LF vs. no-LF based on last follow-up. Though baseline SUVmax was higher in the LF group (12.4 vs. 6.5, p=0.0001), difference was not significant at 1.5 and 6 months, as both groups responded. SUV at 12 months, however, was significantly higher for the LF vs. no-LF group (6.8 vs. 2.5, p=0.02). Cutoffs predictive of LF were 12-month SUV ≥ 3.9 (100 sensitive), 12-month SUV ≥ 6 (100 specific), and 12-month SUV ≥ 40% of baseline (see Table 8). Analysis of SUVmax velocity showed trend for higher velocity at 12 months (+0.18 SUV/ month vs. -0.03 SUV/month, p=0.058). On multivariate logistic regression, 12-month SUV was

In a cohort of 16 patients with locally-advanced NSCLC enrolled on a phase II protocol, patients had PET at baseline, weekly during treatment, and at follow-up [70,192] (see Figure 2). Patients received hyperfractionated radiation therapy 1.5 Gy BID with concurrent chemotherapy either as definitive treatment (n=12) or as neoadjuvant treatment (n=4) delivering RT with daily online cone-beam CT for image guidance and intensity modulated radiotherapy (IMRT) to minimize potential normal tissue toxicity [190,193,194]. After potential follow-up of 20 months (range 12-28), 7 had locoregional recurrence (LRR), and 8 died (5 of disease). Interestingly, there was trend for higher SUVmax at baseline in those without LRR (the no-LRR group) than in those with LRR (19.0 vs. 11.9, p=0.08), an inverse relationship than expected. The rate of SUV decrease in the LRR group during RT was 1.6 per week, significantly faster than the no-LRR group (0.23 per week, p=0.02) such that SUV values were similar for both groups by the 4th ontreatment PET (p=0.95) (see Table 9). A during-RT decrease of less than 4 from baseline was predictive of LRR (p<0.01), and a during-RT decrease less 30% from baseline was predictive of death from disease (p<0.01). Velocity of retention index from PET1 to PET-FU predicted overall survival (+1.6%/week in those who died vs. -1.7%/week in those alive, p=0.03).

with rates similar to that of sublobar resection and minimal toxicity [179–191].

In an early study of 15 patients receiving chemotherapy for IIIB-IV NSCLC, patients received weekly PET starting at initiation of chemotherapy until completion of 2 cycles (6 weeks later) [171]. Reduction of SUVmax by 50% week 1 to week 3 was predictive of survival of > 6 months, thus facilitating prediction of response to treatment. Those with less reduction died within 6 months. In patients without early response, management may thus be altered to forego futile chemotherapy. In an early study [167] of 15 stage I-III patients receiving radiotherapy, patients received 3 PETs: one pre-treatment, one during treatment after approximately 45 Gy, and one 3 months post-treatment. Response during treatment was shown to correlate with overall response after treatment (p=0.03), and SUV during treatment correlated with SUV 3 months after(p<0.001). Anumber of studies with prospective PET data with cutoffs are listed in Table 8.


Adapted from Hicks *et al.* [170]. CMR, complete metabolic response; OS, overall survival; LF, local failure; CSS, causespecific survival; LRR, locoregional recurrence; NS, not statistically significant.\*100% sensitive. †100% specific.

**Table 8.** PET Cutoffs/Criteria and Outcomes in NSCLC

#### **SBRT**

biologically-targeted radiotherapy in which 3D-PET fusion is implemented for tumor delin‐ eation, with PET performed with minimal delay between PET and start of treatment, given propensity for rapid disease progression [64–66,165]. Metabolic (PET) response to treatment has been shown to pre-date radiographic (CT) response. Despite increasing data showing utility of PET for assessing treatment response in NSCLC and predicting outcomes including survival, guidelines currently do not recommend PET in this setting [44,45,67,76,166–177].

210 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

In an early study of 15 patients receiving chemotherapy for IIIB-IV NSCLC, patients received weekly PET starting at initiation of chemotherapy until completion of 2 cycles (6 weeks later) [171]. Reduction of SUVmax by 50% week 1 to week 3 was predictive of survival of > 6 months, thus facilitating prediction of response to treatment. Those with less reduction died within 6 months. In patients without early response, management may thus be altered to forego futile chemotherapy. In an early study [167] of 15 stage I-III patients receiving radiotherapy, patients received 3 PETs: one pre-treatment, one during treatment after approximately 45 Gy, and one 3 months post-treatment. Response during treatment was shown to correlate with overall response after treatment (p=0.03), and SUV during treatment correlated with SUV 3 months after(p<0.001). Anumber of studies with prospective PET data with cutoffs are listed in Table 8.

**Author Year n Stage Criteria Outcome p**

week 3

At 12 months

During treatment

30% decrease decrease ≥ 4

Adapted from Hicks *et al.* [170]. CMR, complete metabolic response; OS, overall survival; LF, local failure; CSS, causespecific survival; LRR, locoregional recurrence; NS, not statistically significant.\*100% sensitive. †100% specific.

SUV ≥ 3.9 60% decrease SUV ≥ 6.0

Tanvetyanon [178] 2008 89 IB-IIIB CMR OS NS

50% decrease from week 1 to

OS <0.01

LF\* <0.01 LF\* <0.01 LF† <0.01

CSS <0.01 LRR <0.01

Vansteenkiste [172] 1985 15 IIIA 50% decrease OS 0.03 MacManus [173] 2003 73 I-III CMR OS <0.01 Weber [174] 2003 57 IIIB-IV 20% decrease OS <0.01 Hellwig [175] 2004 47 IIB-III SUV < 4 OS <0.01 Eschmann [176] 2007 70 III CMR or 80% decrease OS <0.01 de Geus-Oei [177] 2007 51 IB-IV 35% decrease OS 0.02

Nahmias [171] 2007 16 IIIB-IV

Mangona [45] 2012 129 IA-IB

Mangona [70] 2012 16 IIB-IIIB

**Table 8.** PET Cutoffs/Criteria and Outcomes in NSCLC

Stereotactic body radiotherapy (SBRT), employing modern techniques including 4-D treat‐ ment planning and image-guided radiotherapy (IGRT) has been shown to be an effective, costefficient, treatment option for definitive management of early-stage NSCLC as well as lung metastases from other organs with excellent tumor control rates; in comparison to medicallyoperable patients who are treated with resection, retrospective data of primarily medicallyinoperable patients with poor pulmonary function suggests excellent tumor control with SBRT with rates similar to that of sublobar resection and minimal toxicity [179–191].

In a large single-institution analysis [45] of 129 consecutive NSCLC tumors treated with SBRT, 58% enrolled on a prospective phase II protocol, patients had baseline and serial follow-up PET imaging. Sixteen patients additionally had weekly on-treatment 4D-PET-CT. Median follow-up was 19 months and median time until local failure (LF) of 15 months. A total of 475 PETs were obtained. Change in SUV from pre-treatment to follow-up are seen in Figure 1 and stratified by status of LF vs. no-LF based on last follow-up. Though baseline SUVmax was higher in the LF group (12.4 vs. 6.5, p=0.0001), difference was not significant at 1.5 and 6 months, as both groups responded. SUV at 12 months, however, was significantly higher for the LF vs. no-LF group (6.8 vs. 2.5, p=0.02). Cutoffs predictive of LF were 12-month SUV ≥ 3.9 (100 sensitive), 12-month SUV ≥ 6 (100 specific), and 12-month SUV ≥ 40% of baseline (see Table 8). Analysis of SUVmax velocity showed trend for higher velocity at 12 months (+0.18 SUV/ month vs. -0.03 SUV/month, p=0.058). On multivariate logistic regression, 12-month SUV was most predictive of LF (p=0.057).

#### **Hyperfractionated radiotherapy**

In a cohort of 16 patients with locally-advanced NSCLC enrolled on a phase II protocol, patients had PET at baseline, weekly during treatment, and at follow-up [70,192] (see Figure 2). Patients received hyperfractionated radiation therapy 1.5 Gy BID with concurrent chemotherapy either as definitive treatment (n=12) or as neoadjuvant treatment (n=4) delivering RT with daily online cone-beam CT for image guidance and intensity modulated radiotherapy (IMRT) to minimize potential normal tissue toxicity [190,193,194]. After potential follow-up of 20 months (range 12-28), 7 had locoregional recurrence (LRR), and 8 died (5 of disease). Interestingly, there was trend for higher SUVmax at baseline in those without LRR (the no-LRR group) than in those with LRR (19.0 vs. 11.9, p=0.08), an inverse relationship than expected. The rate of SUV decrease in the LRR group during RT was 1.6 per week, significantly faster than the no-LRR group (0.23 per week, p=0.02) such that SUV values were similar for both groups by the 4th ontreatment PET (p=0.95) (see Table 9). A during-RT decrease of less than 4 from baseline was predictive of LRR (p<0.01), and a during-RT decrease less 30% from baseline was predictive of death from disease (p<0.01). Velocity of retention index from PET1 to PET-FU predicted overall survival (+1.6%/week in those who died vs. -1.7%/week in those alive, p=0.03).

**PET0 PET1 PET2 PET3 PET4 PET-FU Velocity during**

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LRR 11.9 9.5 11.4 10.6 9.8 6.7 -0.23/week no-LRR 19.0 17.3 16.3 12.8 9.4 4.6 -1.60/week *p 0.08 0.02 0.13 0.32 0.95 0.66 0.02*

LRR 1.90 2.00 2.15 1.30 0.95 -0.05/week no-LRR - 4.20 2.80 1.60 1.55 0.61 -0.68/week *p 0.02 0.15 0.82 0.55 0.82 0.15*

LRR 23.3% 22.5% 22.8% 14.3% 18.4% -0.8%/week no-LRR - 27.1% 19.8% 18.5% 15.3% 17.6% -3.4%/week *p 0.92 0.88 0.16 0.57 0.76 0.04*

Patients had PET-CT before treatment for staging/planning (PET0), weekly during treatment (PET1, PET2, PET3, and PET4), and at 6-12 weeks follow-up (PET-FU); RT, Radiation Therapy; LRR, locoregional recurrence; no-LRR, no locoregional

PET shows prognostic potential in this disease site from prior to treatment to early in treatment, to later in follow-up. It further holds potential for adjusting management (e.g. discontinuing ineffective chemotherapy, potentially modifying radiation therapy during treatment, and predicting delayed local failure for potential earlier biopsy/intervention). We await further prospective PET data and clinical trials to best define the role of PET in assessment of treatment

As PET is used for staging and radiotherapy prior to treatment for a number of organ sites, PET further has potential for restaging and replanning radiotherapy during the course of therapy. Beyond mid-treatment prognostication, this facilitates potential treatment modifica‐ tion. For radiotherapy re-planning, potential changes are include modification of target volumes based on anatomic changes from treatment, modification of boost volumes, and potentially adjustment of prescription dose based on response (e.g. higher dose for poor responders vs. less dose for good responders). Such investigations are currently ongoing in

In treatment of locally-advanced head and neck squamous cell carcinomas, our institution has initiated a prospective, non-randomized trial evaluating the utility of such an adaptive approach focusing on target volume adaptation. Patients receiving 70 Gy IMRT in 35 daily fractions (7 week duration) with concurrent cisplatin or cetuximab are eligible. 18FDG-PET-CT is utilized for treatment planning. Repeat PET-CTs and diagnostic CTs are obtained after

**Table 9.** On-treatment SUV kinetics of locally-advanced NSCLC treated with concurrent chemoradiation

SUVmax

SUVdelayed-SUVearly

Retention Index

in NSCLC.

recurrence at last follow-up.

**5. Future directions**

clinical protocols.

**RT**

213

Assessment of response for NSCLC with serial 18FDG-PET. 129 node-negative non-small-cell lung tumors were treated with stereotactic body radiation therapy (SBRT) and followed with routine follow-up imaging. SUV for tumors with eventual local failure (LF) and no local failure (no-LF) at last follow-up are compared. (a) Plot of SUVmax vs. time, with baseline PET SUVmax at t=0. Tumors with resulting LF show higher SUVmax both at pre-treatment and at 12-months fol‐ low-up, though SUVmax at 1.5 and 6 months were similar. (b) Plot of normalized SUVmax (baseline normalized SUV = 1). Normalized SUVmax is higher at 12 months in the LF group but similar at other time points. Values are plotted as box plots with thick black line representing the median value, lower box border the 25th percentile, upper box border the 75th percentile, and outliers with points. PET SUVs subsequent to any treatment for recurrence (e.g. chemotherapy) were excluded; thus, the no-LF group had data at longer follow-up (e.g. 24, 36, and 48 months).

**Figure 2.** SUV kinetics after stereotactic body radiotherapy for NSCLC


Patients had PET-CT before treatment for staging/planning (PET0), weekly during treatment (PET1, PET2, PET3, and PET4), and at 6-12 weeks follow-up (PET-FU); RT, Radiation Therapy; LRR, locoregional recurrence; no-LRR, no locoregional recurrence at last follow-up.

**Table 9.** On-treatment SUV kinetics of locally-advanced NSCLC treated with concurrent chemoradiation

PET shows prognostic potential in this disease site from prior to treatment to early in treatment, to later in follow-up. It further holds potential for adjusting management (e.g. discontinuing ineffective chemotherapy, potentially modifying radiation therapy during treatment, and predicting delayed local failure for potential earlier biopsy/intervention). We await further prospective PET data and clinical trials to best define the role of PET in assessment of treatment in NSCLC.

#### **5. Future directions**

Assessment of response for NSCLC with serial 18FDG-PET. 129 node-negative non-small-cell lung tumors were treated with stereotactic body radiation therapy (SBRT) and followed with routine follow-up imaging. SUV for tumors with eventual local failure (LF) and no local failure (no-LF) at last follow-up are compared. (a) Plot of SUVmax vs. time, with baseline PET SUVmax at t=0. Tumors with resulting LF show higher SUVmax both at pre-treatment and at 12-months fol‐ low-up, though SUVmax at 1.5 and 6 months were similar. (b) Plot of normalized SUVmax (baseline normalized SUV = 1). Normalized SUVmax is higher at 12 months in the LF group but similar at other time points. Values are plotted as box plots with thick black line representing the median value, lower box border the 25th percentile, upper box border the 75th percentile, and outliers with points. PET SUVs subsequent to any treatment for recurrence (e.g. chemotherapy)

212 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

were excluded; thus, the no-LF group had data at longer follow-up (e.g. 24, 36, and 48 months).

**Figure 2.** SUV kinetics after stereotactic body radiotherapy for NSCLC

As PET is used for staging and radiotherapy prior to treatment for a number of organ sites, PET further has potential for restaging and replanning radiotherapy during the course of therapy. Beyond mid-treatment prognostication, this facilitates potential treatment modifica‐ tion. For radiotherapy re-planning, potential changes are include modification of target volumes based on anatomic changes from treatment, modification of boost volumes, and potentially adjustment of prescription dose based on response (e.g. higher dose for poor responders vs. less dose for good responders). Such investigations are currently ongoing in clinical protocols.

In treatment of locally-advanced head and neck squamous cell carcinomas, our institution has initiated a prospective, non-randomized trial evaluating the utility of such an adaptive approach focusing on target volume adaptation. Patients receiving 70 Gy IMRT in 35 daily fractions (7 week duration) with concurrent cisplatin or cetuximab are eligible. 18FDG-PET-CT is utilized for treatment planning. Repeat PET-CTs and diagnostic CTs are obtained after

1.5 Gy twice daily with concurrent Taxotere. He had a complete metabolic response to treatment evident at first fol‐ low-up PET 1-month after treatment. SUV values (early → delayed): (a) Pre: 29.4 → 36.9; (b) Week 1: 17.8 → 23.6; (c) Week 2: 13.3 → 16.0; (d) Week 3: 15.7 → 17.0; (e) Week 4: 4.6 → 5.8; (f) Week 5: 4.2 → 5.3; (g) 1 month follow-up: 2.0 → 2.2

patients on this protocol will have 18FDG-PET; however, a subset are planned to also have 18F-

SUV values (early → delayed): (a) Pre: 23.4 → 28.7; (b) Week 1: 14.8 → 16.0; (c) Week 2: 11.0 → 12.7; (d) Week 3: 11.0 →

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215

**Figure 4.** This is a 66-year-old male who presented with right shoulder pain. Workup revealed a clinical stage IIIA (T3 N1 M0) squamous cell carcinoma of the right upper lobe of the lobe with chest wall invasion causing destruction of ribs 2-4. He received hyperfractionated intensity-modulated radiotherapy 72Gy, 1.5 Gy twice daily, with concurrent and maintenance taxotere for 4 months. SUV nadir occurred at 6 weeks with evident local progression at 6 months.

12.8; (e) Week 4: 12.1 → 15.; (f) 6-week FU: 6.5 → 8.; (g) 6-month FU: 12.5 → 15.7; (h) 8-month FU: 4.9 → 6.3

As such radiotracers beyond 18F-FDG show particular promise, further results of clinical trials

Over the past 20 years, the body of data assessing treatment response with PET has grown significant. Assessing treatment response with PET can yield highly prognostic information. Such information, however, may have no end-effect on management. As clinicians, many of our PET-based decisions are based on retrospective and prospective data without comparison of management options based on PET results. Such results are significantly hypothesisgenerating. The high negative predictive value of PET in various organ sites may increase comfort of clinicians when considering omitting potentially unnecessary interventions (e.g. neck dissection after complete metabolic response of locally-advanced head and neck cancer

MISO-PET at staging.

**6. Conclusion**

implementing these are awaited.

**Figure 3.** This is a 68-year-old male who presented with dyspnea and hemoptysis. Workup revealed a stage IIIB (T4, N2, M0) squamous cell carcinoma of the right lower lobe, 7cm in size invading the mediastinum. He received hyper‐ fractionated intensity-modulated radiotherapy, 66 Gy in 1.5 Gy fractions twice daily.

fractions 10 and 22 for the purpose of treatment adaptation. Three different treatment plans will be created, one for fractions 1-12 (based on pre-treatment PET-CT), one for fractions 13-24 (based on PET-CT after fraction 10), and one for fractions 25-35 (based on PET-CT after fraction 22). Such an adaptive approach may help decrease dose delivered to normal tissue as tumors decrease in size during treatment, potentially decreasing toxicity. On this protocol, patients also obtain weekly PET-CTs for assessment of treatment response, though prescription dose is not modified in this study.

For non-small cell lung cancer, investigators have further used on-treatment PET to facilitate PET-adaptive replanning, with PET-adaptive dose escalation incorporated into a currentlyenrolling Radition Therapy Oncology Group (RTOG) Protocol, RTOG 1106 [195,196]. All

SUV values (early → delayed): (a) Pre: 23.4 → 28.7; (b) Week 1: 14.8 → 16.0; (c) Week 2: 11.0 → 12.7; (d) Week 3: 11.0 → 12.8; (e) Week 4: 12.1 → 15.; (f) 6-week FU: 6.5 → 8.; (g) 6-month FU: 12.5 → 15.7; (h) 8-month FU: 4.9 → 6.3

**Figure 4.** This is a 66-year-old male who presented with right shoulder pain. Workup revealed a clinical stage IIIA (T3 N1 M0) squamous cell carcinoma of the right upper lobe of the lobe with chest wall invasion causing destruction of ribs 2-4. He received hyperfractionated intensity-modulated radiotherapy 72Gy, 1.5 Gy twice daily, with concurrent and maintenance taxotere for 4 months. SUV nadir occurred at 6 weeks with evident local progression at 6 months.

patients on this protocol will have 18FDG-PET; however, a subset are planned to also have 18F-MISO-PET at staging.

As such radiotracers beyond 18F-FDG show particular promise, further results of clinical trials implementing these are awaited.

#### **6. Conclusion**

fractions 10 and 22 for the purpose of treatment adaptation. Three different treatment plans will be created, one for fractions 1-12 (based on pre-treatment PET-CT), one for fractions 13-24 (based on PET-CT after fraction 10), and one for fractions 25-35 (based on PET-CT after fraction 22). Such an adaptive approach may help decrease dose delivered to normal tissue as tumors decrease in size during treatment, potentially decreasing toxicity. On this protocol, patients also obtain weekly PET-CTs for assessment of treatment response, though prescription dose

1.5 Gy twice daily with concurrent Taxotere. He had a complete metabolic response to treatment evident at first fol‐ low-up PET 1-month after treatment. SUV values (early → delayed): (a) Pre: 29.4 → 36.9; (b) Week 1: 17.8 → 23.6; (c) Week 2: 13.3 → 16.0; (d) Week 3: 15.7 → 17.0; (e) Week 4: 4.6 → 5.8; (f) Week 5: 4.2 → 5.3; (g) 1 month follow-up: 2.0 →

214 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**Figure 3.** This is a 68-year-old male who presented with dyspnea and hemoptysis. Workup revealed a stage IIIB (T4, N2, M0) squamous cell carcinoma of the right lower lobe, 7cm in size invading the mediastinum. He received hyper‐

fractionated intensity-modulated radiotherapy, 66 Gy in 1.5 Gy fractions twice daily.

For non-small cell lung cancer, investigators have further used on-treatment PET to facilitate PET-adaptive replanning, with PET-adaptive dose escalation incorporated into a currentlyenrolling Radition Therapy Oncology Group (RTOG) Protocol, RTOG 1106 [195,196]. All

is not modified in this study.

2.2

Over the past 20 years, the body of data assessing treatment response with PET has grown significant. Assessing treatment response with PET can yield highly prognostic information. Such information, however, may have no end-effect on management. As clinicians, many of our PET-based decisions are based on retrospective and prospective data without comparison of management options based on PET results. Such results are significantly hypothesisgenerating. The high negative predictive value of PET in various organ sites may increase comfort of clinicians when considering omitting potentially unnecessary interventions (e.g. neck dissection after complete metabolic response of locally-advanced head and neck cancer to chemoradiation, esophagectomy after complete metabolic response to chemoradiotion, or consolidative radiotherapy after complete metabolic response in Hodgkin lymphoma). Highlevel evidence to justify such treatment-adapting decisions based on PET are currently lacking, thus we caution application of such data as justification for modifying standard of care. We strongly encourage PET-adaptive management under the guise of clinical trials at this time, as the role of PET in oncology continues to best be defined.

[6] Lee ST, Lawrentschuk N, Scott AM. PET in prostate and bladder tumors. Semin Nucl

PET – Assessment of Oncologic Treatment Response

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217

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#### **Acknowledgements**

Special thanks to Dr. Katie Traylor, Rob Ceruti, and Matthew Johnson of Nuclear Medicine for their assistance with PET figures presented in this chapter.

#### **Author details**

Inga S. Grills1,2 and Victor S. Mangona1

1 Department of Radiation Oncology, Beaumont Cancer Institute, Beaumont Health System, Royal Oak, Michigan, USA

2 Oakland University William Beaumont School of Medicine, Rochester, Michigan, USA

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216 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

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**Chapter 9**

**PET-CT in Anal Cancer: Indications and Limits**

Perianal and anal canal malignancies are uncommon. The anal canal is a small area, rather complex for the presence of different histological features and for the lymphatic spread [1].

In the IUCC, American Joint Committee on Cancer (AJCC) and World Health Organization (WHO) staging systems the anal canal is described as the last part of the gastrointestinal tract extending from the anal ring at the level of the puborectalis muscle (where the rectum enters the pelvic floor), to the perianal tissue that is the junction of the hair- bearing skin and the non-

As cited tumors of the anal canal can present different histological features. These guidelines refer to squamous cell carcinoma (including the so called cloacogenic variant) which consti‐ tutes 80% of all lesions of this area and derives from transitional and squamous cell epithelium. In some pathology literature squamous cell carcinoma of the anal canal is also described according to additional histopathologic feature such as keratinization, presence of mucin and

Lesscommonareadenocarcinomaandmucinousadenocarcinomaoftheanalglandsoroffistula tracts that must be distinguished from very low rectal cancers. Other uncommon neoplasms of the anal canal include small cell carcinoma, carcinoid and other neuroendocrine tumors, malignant melanoma, squamous cell papilloma, papillary hidradenoma, keratoacanthoma, mesenchymal and neurogenic tumors, lymphoma, leiomyosarcoma, and secondary tumors.

Tumors originating from the anal margin should be staged as skin cancer: they can be

This is an important distinction as skin cancers rarely involve lymph nodes or lead to distant

© 2013 Mistrangelo and Lesca; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

squamous cell cancer, basal cell cancer, Bowen's or Paget's disease.

Massimiliano Mistrangelo and Adriana Lesca

Additional information is available at the end of the chapter

keratinizing squamous epithelium of the distal anal canal.

abundance of basement mebrane-like material.

http://dx.doi.org/10.5772/57121

**1. Introduction**

metastases [2-4].


### **PET-CT in Anal Cancer: Indications and Limits**

Massimiliano Mistrangelo and Adriana Lesca

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57121

#### **1. Introduction**

[188] Stone B, Grills I, Mangona V, Ye H, Martin S, Wloch J, et al. Changes in Pulmonary Function Following Imaged Guided Stereotactic Radiotherapy of the Lung. Interna‐

[189] Mangona V, Grills I, Yan D, McInerney E, Martin S, Kestin L, et al. Predictors of Pul‐ monary and Other Thoracic Complications after Lung Stereotactic Body Radiothera‐ py (SBRT) for Primary or Metastatic Lung Tumors: Dose–volume Analysis. International Journal of Radiation Oncology\* Biology\* Physics. 2009;75(3):S161–S161.

[190] Grills IS, Hugo G, Kestin LL, Galerani AP, Chao KK, Wloch J, et al. Image-Guided Radiotherapy via Daily Online Cone-Beam CT Substantially Reduces Margin Re‐ quirements for Stereotactic Lung Radiotherapy. International Journal of Radiation

[191] Galerani AP, Grills I, Hugo G, Kestin L, Mohammed N, Chao KK, et al. Dosimetric impact of online correction via cone-beam CT-based image guidance for stereotactic

[192] McGee M, Grills I, Mangona V, Ionascu D, Margolis J, Welsh R, et al. Feasibility, Tox‐ icity, and Early Outcomes for Dose-escalated 4D Adaptive Image-guided Radiothera‐ py (IGRT) for Non-small Cell Lung Cancer (NSCLC). International Journal of

[193] Shaitelman S, Grills I, Liang J, Zhuang L, Mangona V, Yan D, et al. A Comprehensive Dose-Volume Analysis of Predictors of Pneumonitis and Esophagitis Following Ra‐

diotherapy for Non-Small Cell Lung Cancer (NSCLC). Esophagus. 2009;10:5.

[194] Grills IS, Mangona VS. Intensity-Modulated Radiation Therapy and Volumetric-Modulated Arc Therapy for Lung Cancer. Advances in Radiation Oncology in Lung

[195] Kong F-M. Using FDG-PET During Radiation Therapy in Non-Small Cell Lung Can‐ cer (HUM15709) [Internet]. Available from: http://clinicaltrials.gov/ct2/show/

[196] Kong F-M (Spring). RTOG 1106/ACRIN 6697 Randomized Phase Ii Trial of Individu‐ alized Adaptive Radiotherapy Using During-Treatment FDG-PET/CT And Modern Technology in Locally Advanced Non-Small Cell Lung Cancer (Nsclc) [Internet]. 2012 [cited 2012 Oct 16]. Available from: http://www.rtog.org/ClinicalTrials/Proto‐

lung radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 2010 Dec 1;78(5):1571–8.

Oncology\*Biology\*Physics. 2008 Mar;70(4):1045–56.

Radiation Oncology\* Biology\* Physics. 2011;81(2):S165–S166.

Cancer. 2011;691–713.

colTable/StudyDetails.aspx?study=1106

NCT01190527

tional Journal of Radiation Oncology\* Biology\* Physics. 2011;81(2):S611.

234 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Perianal and anal canal malignancies are uncommon. The anal canal is a small area, rather complex for the presence of different histological features and for the lymphatic spread [1].

In the IUCC, American Joint Committee on Cancer (AJCC) and World Health Organization (WHO) staging systems the anal canal is described as the last part of the gastrointestinal tract extending from the anal ring at the level of the puborectalis muscle (where the rectum enters the pelvic floor), to the perianal tissue that is the junction of the hair- bearing skin and the nonkeratinizing squamous epithelium of the distal anal canal.

As cited tumors of the anal canal can present different histological features. These guidelines refer to squamous cell carcinoma (including the so called cloacogenic variant) which consti‐ tutes 80% of all lesions of this area and derives from transitional and squamous cell epithelium. In some pathology literature squamous cell carcinoma of the anal canal is also described according to additional histopathologic feature such as keratinization, presence of mucin and abundance of basement mebrane-like material.

Lesscommonareadenocarcinomaandmucinousadenocarcinomaoftheanalglandsoroffistula tracts that must be distinguished from very low rectal cancers. Other uncommon neoplasms of the anal canal include small cell carcinoma, carcinoid and other neuroendocrine tumors, malignant melanoma, squamous cell papilloma, papillary hidradenoma, keratoacanthoma, mesenchymal and neurogenic tumors, lymphoma, leiomyosarcoma, and secondary tumors.

Tumors originating from the anal margin should be staged as skin cancer: they can be squamous cell cancer, basal cell cancer, Bowen's or Paget's disease.

This is an important distinction as skin cancers rarely involve lymph nodes or lead to distant metastases [2-4].

© 2013 Mistrangelo and Lesca; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **2. Incidence**

Anal cancer remains a rare disease but its incidence is increasing [5], mainly in association with human papillomaviruses (HPV) infection. An estimated 5820 new cases (2140 men and 3680 women) were estimated to occur in the United States in 2011, accounting for approximately 2.1% of digestive system cancers. It has been estimated that 770 deaths due to anal cancer will occurr in U.S. alone in 2011 [6].

After solid organ transplant, patients receive chronic immunosuppressive therapy, so they are exposed to higher risk of various squamous cell carcinoma, such as of the anal canal [11]. Moreover, the use of corticosteroids can increase the risk of developing anal cancer [18].

PET-CT in Anal Cancer: Indications and Limits

http://dx.doi.org/10.5772/57121

237

Several studies made a connection between cigarette smoking and risk of developing anal

Macroscopically the squamous anal cancer appears as a small ulceration or fissure, exophytic, with indurated margins and irregular thickening [20]. Sometimes large lesions are observed.

Symptoms are rectal bleeding, rectal pain, tenesmus or mass sensation, but about 20% of

Prior to the mid-1980s, the treatment of choice for anal cancer was abdominoperineal resection (APR). The 5-year survival rate after APR for anal cancer was 40-70%, with worse outcomes for those with larger tumors and nodal metastases. In the 1920s and 1930s inguinal node dissection was included in the surgical management of these patients, and it was generally reserved for those patients with clinically enlarged (though not necessarily involved) inguinal nodes [21]. By the 1950s it had became clear that the morbidity associated with lymph node dissection was much greater than any survival benefit, so the procedure was gradually abandoned [22]. In 1974 Nigro proposed a multimodality treatment combining radiation and chemotherapy which has since then become the standard treatment with surgery reserved for salvage treatment following local failure [23]. Local control rates of 60-90% over all stages are achievable, with sphincter preservation in about 65% of cases. The prognosis after combined radiochemotherapy for anal cancer may be influenced by several factors: high tumor stage and regional nodal involvement; tumor site in the anal canal; inguinal lymph node involvement in anal canal carcinoma. Synchronous inguinal metastases occur in 10-25% of patients [24] and constitute an independent prognostic factor for local failure and overall mortality according to a multivariate analysis in a phase 3 EORTC trial [25]. Metachronous metastases have been

Adverse effects of chemoradiation therapy can be mucositis, diarrhea, skin desquamation and erytema, mielosuppression, ulcers, fistulae, necrosis, and stenosis [19]. Surgery treatment is reserved for salvage theraphy, in subjects with persistent or recurrent disease [19, 26-28]. The elective treatment of metastatic disease (often hepatic nodules), is chemotherapy; therapeutic

plans include cisplatin and 5-FU, carboplatin, doxorubicin and semustine [29-32].

cancer, and this risk diminished after smoking cessation [19].

patients are asymptomatic at the time of diagnosis [6].

**4. Clinical manifestations**

reported in 5-25% of patients [10].

**5. Treatment**

In western Europe the average annual incidence of anal carcinoma is 1 to 3 cases per 100,000 with a female prevalence (two to four times that of men [7]) and a highest incidence during the sixth and seventh decades of life [8]. The annual incidence incidence can be up to 35 per 100,000 in men who practice anal-receptive sexual intercourse, and those who are human immunodeficiency virus (HIV)-positive have twice the risk of those who are not [7].

In particular, squamous cell carcinoma (the other names, epidermoid or spinocellular, are no longer used) is the most common histological type of anal carcinoma and constitutes up to the 80% of all malignant anal tumours [9].

#### **3. Etiology**

Chromosome 11 deletions (11q22) or the short arm of chromosome 3 (3p22), environmental factors such as cigarette smoking, sexual orientation and a high number of sexual partners, anoreceptive intercourse, male homosexuality, viral infections of the anogenital area (human papillomavirus (HPV) virus type 16 and 18) and immunodeficiency, are all considered as causative factors of anal cancer [8, 10-11].

The introduction of antiretroviral drugs have improved the life expectancy of HIV- positive patients. This has contributed to increasing the incidence of anal cancer in this population.

HPV infection (type 16 in about 87% of cases [12]) and anogenital warts are closely associated with anal cancer. Anal canal lesions are more often HPV positive than perianal lesions. Ninetyfive percent of anal canal cancer in women and 83% in men is HPV- positive while cancer located at the anal margin are HPV- positive in only 80% of women and 28% of men [12]. Because of this high association with anal cancer HPV is considered to be the most important causative factor much like in cases of cervical cancer [13-16].

In particular, HPV is involved in the pathogenesis of anal intraepithelial neoplasia (AIN) which progresses from dysplasia to invasive cancer. HPV type 16 seems to be associated with a higher risk of malignant transformation [17].

Other viral infections such as herpes simplex virus (HSV) have been studied but are considered to play only a marginal role in disease progression.

After solid organ transplant, patients receive chronic immunosuppressive therapy, so they are exposed to higher risk of various squamous cell carcinoma, such as of the anal canal [11]. Moreover, the use of corticosteroids can increase the risk of developing anal cancer [18].

Several studies made a connection between cigarette smoking and risk of developing anal cancer, and this risk diminished after smoking cessation [19].

#### **4. Clinical manifestations**

Macroscopically the squamous anal cancer appears as a small ulceration or fissure, exophytic, with indurated margins and irregular thickening [20]. Sometimes large lesions are observed.

Symptoms are rectal bleeding, rectal pain, tenesmus or mass sensation, but about 20% of patients are asymptomatic at the time of diagnosis [6].

#### **5. Treatment**

**2. Incidence**

**3. Etiology**

occurr in U.S. alone in 2011 [6].

80% of all malignant anal tumours [9].

causative factors of anal cancer [8, 10-11].

risk of malignant transformation [17].

to play only a marginal role in disease progression.

causative factor much like in cases of cervical cancer [13-16].

Anal cancer remains a rare disease but its incidence is increasing [5], mainly in association with human papillomaviruses (HPV) infection. An estimated 5820 new cases (2140 men and 3680 women) were estimated to occur in the United States in 2011, accounting for approximately 2.1% of digestive system cancers. It has been estimated that 770 deaths due to anal cancer will

236 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

In western Europe the average annual incidence of anal carcinoma is 1 to 3 cases per 100,000 with a female prevalence (two to four times that of men [7]) and a highest incidence during the sixth and seventh decades of life [8]. The annual incidence incidence can be up to 35 per 100,000 in men who practice anal-receptive sexual intercourse, and those who are human

In particular, squamous cell carcinoma (the other names, epidermoid or spinocellular, are no longer used) is the most common histological type of anal carcinoma and constitutes up to the

Chromosome 11 deletions (11q22) or the short arm of chromosome 3 (3p22), environmental factors such as cigarette smoking, sexual orientation and a high number of sexual partners, anoreceptive intercourse, male homosexuality, viral infections of the anogenital area (human papillomavirus (HPV) virus type 16 and 18) and immunodeficiency, are all considered as

The introduction of antiretroviral drugs have improved the life expectancy of HIV- positive patients. This has contributed to increasing the incidence of anal cancer in this population.

HPV infection (type 16 in about 87% of cases [12]) and anogenital warts are closely associated with anal cancer. Anal canal lesions are more often HPV positive than perianal lesions. Ninetyfive percent of anal canal cancer in women and 83% in men is HPV- positive while cancer located at the anal margin are HPV- positive in only 80% of women and 28% of men [12]. Because of this high association with anal cancer HPV is considered to be the most important

In particular, HPV is involved in the pathogenesis of anal intraepithelial neoplasia (AIN) which progresses from dysplasia to invasive cancer. HPV type 16 seems to be associated with a higher

Other viral infections such as herpes simplex virus (HSV) have been studied but are considered

immunodeficiency virus (HIV)-positive have twice the risk of those who are not [7].

Prior to the mid-1980s, the treatment of choice for anal cancer was abdominoperineal resection (APR). The 5-year survival rate after APR for anal cancer was 40-70%, with worse outcomes for those with larger tumors and nodal metastases. In the 1920s and 1930s inguinal node dissection was included in the surgical management of these patients, and it was generally reserved for those patients with clinically enlarged (though not necessarily involved) inguinal nodes [21]. By the 1950s it had became clear that the morbidity associated with lymph node dissection was much greater than any survival benefit, so the procedure was gradually abandoned [22]. In 1974 Nigro proposed a multimodality treatment combining radiation and chemotherapy which has since then become the standard treatment with surgery reserved for salvage treatment following local failure [23]. Local control rates of 60-90% over all stages are achievable, with sphincter preservation in about 65% of cases. The prognosis after combined radiochemotherapy for anal cancer may be influenced by several factors: high tumor stage and regional nodal involvement; tumor site in the anal canal; inguinal lymph node involvement in anal canal carcinoma. Synchronous inguinal metastases occur in 10-25% of patients [24] and constitute an independent prognostic factor for local failure and overall mortality according to a multivariate analysis in a phase 3 EORTC trial [25]. Metachronous metastases have been reported in 5-25% of patients [10].

Adverse effects of chemoradiation therapy can be mucositis, diarrhea, skin desquamation and erytema, mielosuppression, ulcers, fistulae, necrosis, and stenosis [19]. Surgery treatment is reserved for salvage theraphy, in subjects with persistent or recurrent disease [19, 26-28]. The elective treatment of metastatic disease (often hepatic nodules), is chemotherapy; therapeutic plans include cisplatin and 5-FU, carboplatin, doxorubicin and semustine [29-32].

#### **6. Diagnosis**

Clinical workup in the staging of anal cancer comprises digital rectal examination, anoscopy with biopsy of suspicious lesions, palpation of inguinal lymph nodes, tumor marker assay, chest X-ray, rigid proctoscopy, total colonoscopy, rectal endosonography, contrast-enhanced diagnostic computed tomography (CT) and/or magnetic resonance imaging (MRI).

the TNM system in a single whole-body imaging procedure: demonstrate the extent of the primary tumor; detect lymph node metastases; and reveal any sites of distant metastases [55]. The 2007 National Comprehensive Cancer Network treatment guidelines included PET/CT as a part of the standard pre-treatment workup of patients diagnosed with anal carcinoma [56]. The new version 2.2012 consider PET-CT scan for work up, even if its use for staging or treatment planning has not been validated [57]. The Authors suggest that PET-CT actually

Evidence from published data indicates that PET/CT is clearly superior to CT in visualizing the biopsy-proven primary tumor, although the lack of sensitivity did not affect treatment. Analyzing the Literature PET-CT detected the primary anal tumor in 59-100% of cases, while CT scan only in 47-75%. In almost all large series are included some patients, who previously were submitted to surgical removal of the anal cancer but with histologically confirmed positive surgical margins. In these cases PET-CT resulted negative (false negative). When we exclude these patients by the review, the percentage of the detection of the primary neoplasm with PET-CT arises to 87.5-100% of cases. This suggests that both PET/CT and CT were unable

Results are repoted in Table 1 [34-54]. Figures 1 and 2 present two cases of PET-CT positive

**Detection Previous**

**Trautmann, 2005** 21 21/21 (100%) 0 21/21 (100%) n.r. **Cotter, 2006** 41 31/41 (75.6%) 7 31/34 (91%) 20/34 (59%) **Piperkova, 2006** 1 1/1 (100%) 0 1/1 (100%) 1/1 (100%) **Anderson, 2007** 3 3/3 (100%) 0 3/3 (100%) n.r. **Joon, 2007\*** 48 40/48 (83.3%) 7 40/41 (97.5%) 24/41 (58.5%) **Schwarz, 2008** 53 n.r. n.r. n.r. n.r. **Nguyen, 2008\*** 48 40/48 (83.3%) 7 40/41 (97.5%) 22/38 (58%) **Iagaru, 2009** 8 7/8 (87.5%) 0 7/8 (87.5%) n.r. **de Winton, 2009** 61 45/61 (73.7%) 16 45/45 (100%) n.r. **Forrest, 2009** 39 38/39 (97%) 0 38/39 (97%) 22/39 (56%) **Renaud, 2009** 20 20/20 (100%) n.r. 20/20 (100%) n.r. **Kidd, 2010** 77 n.r. n.r. n.r. n.r. **Krengli, 2010** 27 26/27 (96.3%) n.r. 26/27 n.r. **Bannas, 2010** 22 15/17 (88%) n.r. 15/17 (88%) 8/22 (47%) **Engledow, 2010** 40 40/40 (100%) n.r. 40/40 (100%) n.r.

**surgery**

**Excluding previous surgery**

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**Detection CT scan**

does not replace a diagnostic CT scan [57].

**9. Detection of primary neoplam**

to detect residual tumor after surgical excision.

**(Total)**

for anal cancer.

**Author, year Patients**

In effect, physical examination, biopsy of the tumor and endorectal ultrasonography can help in determining the tumor depth and the invasion of perirectal limph nodes; instead, palpation of the groin, CT and MRI can give important information about inguinal and iliac lymph node involvement and the evidence of distant visceral metastasis. In recent years, fluorodeoxyglu‐ cose-positron emission tomography (18F-FDG-PET/CT) has rapidly gained a expanding role in oncology, with mounting evidence for its effectiveness in the staging and management of various types of tumors.

#### **7. PET-CT and tumor**

2-deoxy-2[F-18]fluoro-D-glucose (FDG) Positron Emission Tomography (PET) scan is a medical examination currently approved and used in the staging work-up of primary cancers of several sites, such as lung, head and neck, oesophagus, breast, colorectum, melanoma, the Hodgkin's disease and non-Hodgkin's limphomas.

High rates of glycolysis are found in many malignant tumor cells and high uptake of FDG is usually associated with a high expression of glucose transporters. Many tumors are avid of FDG and PET/CT scan can help in staging the primary cancer, in choosing the best side for biopsy, in evaluating the treatment response, in searching other synchronous tumors, in suspect recurrence of tumor with markers increasing, and in planning radiation treatment. We must remember that increased FDG uptake is not specific for neoplasm but inflammatory processes may also show increased uptake, so that abscesses, tuberculosis, inflammations, fungal infections, inflammation related to radiation treatment can concentrate radioglucose, causing false positive results [33].

Evaluation of PET images can be performed visually or semiquantitatively, using the Stand‐ ardized Uptake Value (SUV). Semiquantitative evaluation offers a more objective way of reporting lesion than visual image interpretation and is useful for comparing lesion activity in consecutive studies. However, visual interpretation is equally effective for one-time diagnosis [33].

#### **8. PET-CT and anal cancer**

Since 2005, the use of PET-CT in anal cancer has been described [34-54]. As suggested by Grigsby et al., the advantage of FDG-PET/CT is that it can address all three staging criteria of the TNM system in a single whole-body imaging procedure: demonstrate the extent of the primary tumor; detect lymph node metastases; and reveal any sites of distant metastases [55]. The 2007 National Comprehensive Cancer Network treatment guidelines included PET/CT as a part of the standard pre-treatment workup of patients diagnosed with anal carcinoma [56]. The new version 2.2012 consider PET-CT scan for work up, even if its use for staging or treatment planning has not been validated [57]. The Authors suggest that PET-CT actually does not replace a diagnostic CT scan [57].

#### **9. Detection of primary neoplam**

**6. Diagnosis**

various types of tumors.

**7. PET-CT and tumor**

causing false positive results [33].

**8. PET-CT and anal cancer**

diagnosis [33].

Hodgkin's disease and non-Hodgkin's limphomas.

Clinical workup in the staging of anal cancer comprises digital rectal examination, anoscopy with biopsy of suspicious lesions, palpation of inguinal lymph nodes, tumor marker assay, chest X-ray, rigid proctoscopy, total colonoscopy, rectal endosonography, contrast-enhanced

238 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

In effect, physical examination, biopsy of the tumor and endorectal ultrasonography can help in determining the tumor depth and the invasion of perirectal limph nodes; instead, palpation of the groin, CT and MRI can give important information about inguinal and iliac lymph node involvement and the evidence of distant visceral metastasis. In recent years, fluorodeoxyglu‐ cose-positron emission tomography (18F-FDG-PET/CT) has rapidly gained a expanding role in oncology, with mounting evidence for its effectiveness in the staging and management of

2-deoxy-2[F-18]fluoro-D-glucose (FDG) Positron Emission Tomography (PET) scan is a medical examination currently approved and used in the staging work-up of primary cancers of several sites, such as lung, head and neck, oesophagus, breast, colorectum, melanoma, the

High rates of glycolysis are found in many malignant tumor cells and high uptake of FDG is usually associated with a high expression of glucose transporters. Many tumors are avid of FDG and PET/CT scan can help in staging the primary cancer, in choosing the best side for biopsy, in evaluating the treatment response, in searching other synchronous tumors, in suspect recurrence of tumor with markers increasing, and in planning radiation treatment. We must remember that increased FDG uptake is not specific for neoplasm but inflammatory processes may also show increased uptake, so that abscesses, tuberculosis, inflammations, fungal infections, inflammation related to radiation treatment can concentrate radioglucose,

Evaluation of PET images can be performed visually or semiquantitatively, using the Stand‐ ardized Uptake Value (SUV). Semiquantitative evaluation offers a more objective way of reporting lesion than visual image interpretation and is useful for comparing lesion activity in consecutive studies. However, visual interpretation is equally effective for one-time

Since 2005, the use of PET-CT in anal cancer has been described [34-54]. As suggested by Grigsby et al., the advantage of FDG-PET/CT is that it can address all three staging criteria of

diagnostic computed tomography (CT) and/or magnetic resonance imaging (MRI).

Evidence from published data indicates that PET/CT is clearly superior to CT in visualizing the biopsy-proven primary tumor, although the lack of sensitivity did not affect treatment. Analyzing the Literature PET-CT detected the primary anal tumor in 59-100% of cases, while CT scan only in 47-75%. In almost all large series are included some patients, who previously were submitted to surgical removal of the anal cancer but with histologically confirmed positive surgical margins. In these cases PET-CT resulted negative (false negative). When we exclude these patients by the review, the percentage of the detection of the primary neoplasm with PET-CT arises to 87.5-100% of cases. This suggests that both PET/CT and CT were unable to detect residual tumor after surgical excision.

Results are repoted in Table 1 [34-54]. Figures 1 and 2 present two cases of PET-CT positive for anal cancer.



PS: \* The 2 papers were published separately considering the same series.


**Table 1.** Detection of primary neoplasm.

**Figure 2.** PET-CT positive for anal cancer.

lymph nodes metastases.

**10. Detection of perirectal and pelvic nodes**

tiated more perirectal and pelvic nodes vs CT-scan

Perirectal and/or pelvic nodes were revealed by PET-CT in 4.5-67% and by CT-scan in 13.6-49% of patients. In all the reported series, except the one of Bannas and Coll [47], PET-CT eviden‐

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Results are repoted in Table 2 [34-54]. Figure 3 present a case of PET-CT positive for perirectal

**Figure 1.** PET-CT positive for anal cancer.

**Figure 2.** PET-CT positive for anal cancer.

**Author, year Patients**

**Table 1.** Detection of primary neoplasm.

**Figure 1.** PET-CT positive for anal cancer.

n.r.: Not Reported

**(Total)**

PS: \* The 2 papers were published separately considering the same series.

**Detection Previous**

240 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**Vercellino, 2011** 22 13/22 (59%) 8 13/14 (92.8%) n.r. **Sveistrup, 2012** 91 89/91 (97%) 4 87/87 (100%) n.r. **Mistrangelo, 2012** 53 47/53 (88.7%) 5 47/48 (97.9%) 30/40 (75%) **Wells, 2012** 30 28/30 (93%) 2 28/28 (100%) n.r. **Bhuva, 2012** 43 40/43 (93%) n.r. n.r. n.r.

**surgery**

**Excluding previous surgery**

**Detection CT scan**

#### **10. Detection of perirectal and pelvic nodes**

Perirectal and/or pelvic nodes were revealed by PET-CT in 4.5-67% and by CT-scan in 13.6-49% of patients. In all the reported series, except the one of Bannas and Coll [47], PET-CT eviden‐ tiated more perirectal and pelvic nodes vs CT-scan

Results are repoted in Table 2 [34-54]. Figure 3 present a case of PET-CT positive for perirectal lymph nodes metastases.


**Table 2.** Incidence of perirectal and pelvic metastases in lymph nodes

#### **11. Detection of inguinal lymph nodes**

PET/CT was positive for inguinal metastases in 0-37% of patients, while CT scan in 7.4-41% of them. Mistrangelo et Al [49] compared PET-CT with sentinel lymph node biopsy (SNB) of inguinal nodes in 41 cases. Their findings showed that SNB confirmed the presence of inguinal metastases in only 8 cases, with 4 of 41 patients (9.7%) false positive and 2 of 41 patients (4.9%) false negative. Comparison between SNB and CT findings (34 patients) showed that SNB identified 4 of 34 patients (11.7%) false positive and 4 of 34 patients (11.7%) false negative patients. This is the only paper, to our knowledge, that compares the 2 techniques.

**Figure 3.** PET-CT positive for perirectal lymph nodes metastases.

Cotter and colleagues compared CT and physical examination to 18F-FDG PET/CT in the staging of carcinoma of anal canal, particularly of the inguinal nodal involvement [35]. They enrolled 41 consecutive patients with biopsy proved anal cancer and studied them with physical examination, CT scan and PET-CT scan. PET-CT scans described nodal groin positivities in 15 patients (37%); CT documented abnormal nodes in 9 subjects (22%). Partic‐ ularly, 20% of CT-negative groins were PET positive, leading to upstaging in 8 of the 32 patients (25%). Furthermore, 3 of 13 CT-positive groins were PET-negative (23%) [35]. About 23% of clinically negative groins were PET-positive, leading to upstaging in 9 of the 32 subjects without clinical inguinal nodal involvement. Moreover, about 17% of inguinal stations negative by both CT and physical exam were PET-positive, allowing for upstaging in each of

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**Figure 3.** PET-CT positive for perirectal lymph nodes metastases.

**Author, year Patients**

**Table 2.** Incidence of perirectal and pelvic metastases in lymph nodes

**11. Detection of inguinal lymph nodes**

n.r.: Not Reported

**(Total)**

**Trautmann, 2005** 21 9/21 (42.8%) n.r.

242 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**Piperkova, 2006** 1 1/1 (100%) n.r. **Anderson, 2007** 3 1/3 (33.3%) n.r. **Schwarz, 2008** 53 n.r. n.r. **Nguyen, 2008** 48 9/48 (19%) 7/38 (18%) **Iagaru, 2009** 8 2/8 (20%) n.r. **de Winton, 2009** 61 41/61 (67%) 30/61 (49%). **Forrest, 2009** 39 n.r. n.r. **Renaud, 2009** 20 12/20 (60%) n.r. **Kidd, 2010** 77 8/77 (10.4%) n.r. **Krengli, 2010** 27 n.r. n.r. **Bannas, 2010** 22 2/17 (11.7%) 3/22 (13.6%)

**Engledow, 2010** 40 n.r. n.r. **Vercellino, 2011** 22 1/22 (4.5%) n.r. **Sveistrup, 2012** 91 28/91 (30.7%) n.r. **Mistrangelo, 2012** 53 14/53 (26.4%) 7/40 (17.5%) **Wells, 2012** 30 n.r. n.r. **Bhuva, 2012** 43 n.r. n.r.

PET/CT was positive for inguinal metastases in 0-37% of patients, while CT scan in 7.4-41% of them. Mistrangelo et Al [49] compared PET-CT with sentinel lymph node biopsy (SNB) of inguinal nodes in 41 cases. Their findings showed that SNB confirmed the presence of inguinal metastases in only 8 cases, with 4 of 41 patients (9.7%) false positive and 2 of 41 patients (4.9%) false negative. Comparison between SNB and CT findings (34 patients) showed that SNB identified 4 of 34 patients (11.7%) false positive and 4 of 34 patients (11.7%) false negative

patients. This is the only paper, to our knowledge, that compares the 2 techniques.

**Cotter, 2006** 41 9/41 (22%) 8/41 (20%)

**Incidence PET-CT Incidence CT scan**

Cotter and colleagues compared CT and physical examination to 18F-FDG PET/CT in the staging of carcinoma of anal canal, particularly of the inguinal nodal involvement [35]. They enrolled 41 consecutive patients with biopsy proved anal cancer and studied them with physical examination, CT scan and PET-CT scan. PET-CT scans described nodal groin positivities in 15 patients (37%); CT documented abnormal nodes in 9 subjects (22%). Partic‐ ularly, 20% of CT-negative groins were PET positive, leading to upstaging in 8 of the 32 patients (25%). Furthermore, 3 of 13 CT-positive groins were PET-negative (23%) [35]. About 23% of clinically negative groins were PET-positive, leading to upstaging in 9 of the 32 subjects without clinical inguinal nodal involvement. Moreover, about 17% of inguinal stations negative by both CT and physical exam were PET-positive, allowing for upstaging in each of these cases. Ten of 18 inguinal stations (56%) positive by either physical examination or CT, but not both, were positive by PET. Moreover, all four groins positive by both CT and physical examination were positive by PET [35]. Autors concluded that PET-CT documented more abnormal inguinal nodes than CT or physical examination and they explained that cancer nodal metastases occur in node <5 mm in size, below the limit of detection by CT or physical exam; instead, FDG-PET scan detects pathological sites by differential glucose intake rather than limph node morphology; so that, PET is able in detecting little nodal metastases, but no micrometastases.

Results are repoted in Table 3 [34-54]. Figures 4 and 5 present a case of PET-CT positive for inguinal lymph nodes metastases.


**Figure 4.** PET-CT positive for inguinal lymph nodes metastases.

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PS: \* The 2 papers were published separately considering the same series.

n.r.: Not Reported

**Table 3.** Incidence of metastases in inguinal lymph nodes

**Figure 4.** PET-CT positive for inguinal lymph nodes metastases.

these cases. Ten of 18 inguinal stations (56%) positive by either physical examination or CT, but not both, were positive by PET. Moreover, all four groins positive by both CT and physical examination were positive by PET [35]. Autors concluded that PET-CT documented more abnormal inguinal nodes than CT or physical examination and they explained that cancer nodal metastases occur in node <5 mm in size, below the limit of detection by CT or physical exam; instead, FDG-PET scan detects pathological sites by differential glucose intake rather than limph node morphology; so that, PET is able in detecting little nodal metastases, but no

244 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Results are repoted in Table 3 [34-54]. Figures 4 and 5 present a case of PET-CT positive for

**Trautmann, 2005** 21 0/21 (0%) n.r. **Cotter, 2006** 41 15/41 (37%) 9/41 (22%) **Piperkova, 2006** 1 0/1 (0%) n.r. **Anderson, 2007** 3 0/3 (0%) n.r. **Joon, 2007\*** 48 n.r. n.r. **Schwarz, 2008** 53 n.r. n.r. **Nguyen, 2008\*** 48 8/48 (16.6%) n.r. **Iagaru, 2009** 8 1/8 (12.5%) n.r. **de Winton, 2009** 61 6/61 (10%) 9/61 (15%). **Forrest, 2009** 39 n.r. n.r. **Renaud, 2009** 20 5/20 (25%) 4/20 (20%) **Kidd, 2010** 77 6/77 (7.8%) n.r. **Krengli, 2010** 27 3/27 (11.1%) 2/27 (7.4%) **Bannas, 2010** 22 6/22 (27%) 9/22 (41%) **Engledow, 2010** 40 9/40 (22.5%) 0/40 (0%) **Vercellino, 2011** 22 3/22 (13.6%) n.r. **Sveistrup, 2012** 91 41/91 (45%) n.r. **Mistrangelo, 2012** 53 12/53 (22.6%) 8/40 (20%) **Wells, 2012** 30 n.r. n.r. **Bhuva, 2012** 43 7/43 (16.3%) n.r.

**Incidence PET-CT Incidence CT scan**

**(Total)**

micrometastases.

n.r.: Not Reported

inguinal lymph nodes metastases.

**Author, year Patients**

PS: \* The 2 papers were published separately considering the same series.

**Table 3.** Incidence of metastases in inguinal lymph nodes

**Author, year**

n.r.: Not Reported

**Author, year**

**Table 5.** Follow up at 1 month

**Patients**

PS: \* The 2 papers were published separately considering the same series.

**Patients (Total)**

**Table 4.** Upstaging and downstaging of PET-CT respect CT scan

**(Total) Upstaging Downstaging Invariate Change RT planes**

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**Recurrences at PET-CT FP FN**

**Trautmann, 2005** 21 12/18 (66.6%) 9/12 (75%) 2/6 (33.3%) **Mistrangelo, 2012** 53 10/43 (23.2%) 6/10 (60%) 0/33 (0%)

**Trautmann, 2005** 21 10% n.r. 90% n.r. **Cotter, 2006** 41 17% n.r. 83% n.r. **Piperkova, 2006** 1 100% 0 0 n.r. **Anderson, 2007** 3 33.3% n.r. 66.6% 33.3% **Joon, 2007\*** 48 17% 6% 77% 19% **Schwarz, 2008** 53 n.r. n.r. n.r. n.r. **Nguyen, 2008\*** 48 17% 6% 77% 19% **Iagaru, 2009** 8 n.r. n.r. n.r. n.r. **de Winton, 2009** 61 15% 8% 77% 13% **Forrest, 2009** 39 n.r. n.r. n.r. n.r. **Renaud, 2009** 20 15% n.r. 85% n.r. **Kidd, 2010** 77 n.r. n.r. n.r. n.r. **Krengli, 2010** 27 18.5% 0% 81.5% 3.7% **Bannas, 2010** 22 9% 18% 73% 23% **Engledow, 2010** 40 n.r. n.r. n.r. 12.5% **Vercellino, 2011** 22 n.r. n.r. n.r. 20% **Sveistrup, 2012** 91 14% n.r. 86% 17% **Mistrangelo, 2012** 53 37.5% 25% 37.5% 12.6% **Wells, 2012** 30 17% 19% 65% 29% **Bhuva, 2012** 43 30.2% 11.6% 58.2% n.r.

**Figure 5.** PET-CT positive for inguinal lymph nodes metastases.

#### **12. Pre-treatment final staging**

In the published series tumors were staged according to the American Joint Committee on Cancer staging system [22]. PET/CT upstaged 9-100% and dowstaged 0-25% of patients studied. The radiation fields changed in 3.7-33.3% of cases.

Results are repoted in Table 4 [34-54].


PS: \* The 2 papers were published separately considering the same series.

n.r.: Not Reported

**Figure 5.** PET-CT positive for inguinal lymph nodes metastases.

studied. The radiation fields changed in 3.7-33.3% of cases.

In the published series tumors were staged according to the American Joint Committee on Cancer staging system [22]. PET/CT upstaged 9-100% and dowstaged 0-25% of patients

246 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**12. Pre-treatment final staging**

Results are repoted in Table 4 [34-54].

**Table 4.** Upstaging and downstaging of PET-CT respect CT scan


**Table 5.** Follow up at 1 month


Mistrangelo et Al compared results with anal biopsy: in the detection of recurrence of disease, PET/CT had a sensitivity of 100%, a specificity of 97.4%, a PPV of 66% and a NPV of 100%. Anal biopsy had a sensitivity of 100%, a specificity of 100%, a PPV of 100% and

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Anal cancer is a relatively uncommon tumor, but its incidence increased over the last decades. Accurate clinical staging is important for prognostic information, for planning the radiother‐ apy target volume and for defining therapeutic dose. An accurate evaluation of disease extent can help to individualized radiotherapy planning, ensuring the accurate coverage of disease and sparing of organs at risk. If inguinal node metastasis are known, the radiation plan must include a radiation boost to the groin, but these increased radiation doses are associated with

Since 2005, the use of PET/CT in anal cancer has been described [34-55], but a medline research about the use of PET/CT and anal cancer management shows a relatively little amount of studies. As suggested by Grigsby et al., the advantage of FDG-PET/CT is that it can address all three staging criteria of the TNM system in a single whole-body imaging procedure: demonstrate the extent of the primary tumor, detect lymph node metastases, and reveal any sites of distant metastases [55]. The 2007 National Comprehensive Cancer Network treatment guidelines included PET/CT as a part of the standard pre-treatment workup of patients diagnosed with anal carcinoma [56]. The new version 2.2012 consider PET-CT scan for work up, even if its use for staging or treatment planning has not been validated [57]. The Authors

Otherwise accurate staging of anal cancer followed by optimal planning of combined radio‐ chemotherapy treatment can extend patient survival. Anatomical imaging techniques such as CT and MRI cannot evaluate tumor biology and behavior. PET/CT imaging is increasingly used to stage different malignant diseases [59]. The advantage of PET/CT fusion imaging resides in its ability to correlate findings from anatomic and functional imaging modalities, lending it a more important role than diagnostic CT alone in the selection of proper treatment [36]. Moreover, therapy-induced changes in tumors are related to changes in 18F-FDG uptake, and treatment response can be efficiently monitored by PET/CT also considering the standar‐

Evidence from published data and our study [41] indicates that PET/CT is clearly superior to CT in visualizing the biopsy-proven primary tumor (87.5-100% vs 47-75%), although the lack of sensitivity did not affect treatment. Otherwise both PET/CT and CT were unable to detect

Considering the results of staging anal cancer with PET-CT respect other classical staging tools, pre-treatment PET/CT upstaged 9-37.5% and downstaged 0-25% of patients with anal cancer

acute and late toxicity, like chronic lymph oedema and femoral neck fracture [47].

suggest that PET-CT actually does not replace a diagnostic CT scan [57].

dized uptake value (SUV) of 18F-FDG.

residual tumor after surgical excision.

a NPV of 100% [49].

**13. Discussion**

**Table 6.** Follow up at 3 months

#### **12.1. Follow-up**

Few papers report the results of follow up in patients submitted to combined radiochemo‐ therapy for anal cancer with PET-CT. Moreover PET-CTs of follow up were scheduled differently. This aspect does not permit an adequate comparison between various series.

#### **12.2. Follow-up at 1 month**

Only two papers reported the results of follow up with PET/CT performed 1 month after the end of combined radiochemotherapy [34, 49]. Recurrences are reported respectively in 66.6 and 23.2% of cases. When follow up is analyzed Trautmann [34] reported 75% of false positive (FP) and 33.3% of false negative (FN), while Mistrangelo [49] revealed 60% of FP and none FN. The follow up period was over 18 months in the first study, and 20.3 months in the other one.

Mistrangelo et Al compared also the results of PET-CT with anal biopsy: in the detection of persistence of disease, PET/CT had a sensitivity of 66.6%, a specificity of 92.5%, a positive predictive value (PPV) of 40% and a negative predictive value (NPV) of 97.4%, while anal biopsy had a sensitivity of 100%, a specificity of 97.5%, a PPV of 75% and a NPV of 100% [49].

#### **12.3. Follow-up at 3 months**

The value of PET-CT performed 3 months after combined radiochemotherapy for anal cancer was analyzed in only 8 papers. Recurrences were reported in 4.6-54.5% of cases [39-41, 43-45, 49-50]. False positive were reported in 22.2-62.5%, while FN in 0-5.5% of cases.

Mistrangelo et Al compared results with anal biopsy: in the detection of recurrence of disease, PET/CT had a sensitivity of 100%, a specificity of 97.4%, a PPV of 66% and a NPV of 100%. Anal biopsy had a sensitivity of 100%, a specificity of 100%, a PPV of 100% and a NPV of 100% [49].

#### **13. Discussion**

**Author, year**

n.r.: Not Reported

**12.1. Follow-up**

**Table 6.** Follow up at 3 months

**12.2. Follow-up at 1 month**

**12.3. Follow-up at 3 months**

**Patients (Total)**

**Schwarz, 2008** 53 9/53 (17%) 2/9 (22.2%) n.r. **Nguyen, 2008** 48 5/25 (20%) 3/5 (60%) n.r. **Iagaru, 2009** 8 1/6 (16.6%). n.r. n.r. **Forrest, 2009** 39 13/39 (33.3%) 4/13 (30.7%) n.r.

248 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**Renaud, 2009** 20 6/11 (54.5%) 2/6 (33.3%) 0/5 (0%)

**Kidd, 2010** 77 14/59 (14%) n.r. n.r.

**Vercellino, 2011** 22 18/36 (50%) 4/18 (22.2%) 1/18 (5.5%)

**Mistrangelo, 2012** 53 8/40 (4.6%) 5/8 (62.5%) 0/32 (0%)

Few papers report the results of follow up in patients submitted to combined radiochemo‐ therapy for anal cancer with PET-CT. Moreover PET-CTs of follow up were scheduled differently. This aspect does not permit an adequate comparison between various series.

Only two papers reported the results of follow up with PET/CT performed 1 month after the end of combined radiochemotherapy [34, 49]. Recurrences are reported respectively in 66.6 and 23.2% of cases. When follow up is analyzed Trautmann [34] reported 75% of false positive (FP) and 33.3% of false negative (FN), while Mistrangelo [49] revealed 60% of FP and none FN. The follow up period was over 18 months in the first study, and 20.3 months in the other one.

Mistrangelo et Al compared also the results of PET-CT with anal biopsy: in the detection of persistence of disease, PET/CT had a sensitivity of 66.6%, a specificity of 92.5%, a positive predictive value (PPV) of 40% and a negative predictive value (NPV) of 97.4%, while anal biopsy had a sensitivity of 100%, a specificity of 97.5%, a PPV of 75% and a NPV of 100% [49].

The value of PET-CT performed 3 months after combined radiochemotherapy for anal cancer was analyzed in only 8 papers. Recurrences were reported in 4.6-54.5% of cases [39-41, 43-45,

49-50]. False positive were reported in 22.2-62.5%, while FN in 0-5.5% of cases.

**Recurrences at PET-CT FP FN**

Anal cancer is a relatively uncommon tumor, but its incidence increased over the last decades. Accurate clinical staging is important for prognostic information, for planning the radiother‐ apy target volume and for defining therapeutic dose. An accurate evaluation of disease extent can help to individualized radiotherapy planning, ensuring the accurate coverage of disease and sparing of organs at risk. If inguinal node metastasis are known, the radiation plan must include a radiation boost to the groin, but these increased radiation doses are associated with acute and late toxicity, like chronic lymph oedema and femoral neck fracture [47].

Since 2005, the use of PET/CT in anal cancer has been described [34-55], but a medline research about the use of PET/CT and anal cancer management shows a relatively little amount of studies. As suggested by Grigsby et al., the advantage of FDG-PET/CT is that it can address all three staging criteria of the TNM system in a single whole-body imaging procedure: demonstrate the extent of the primary tumor, detect lymph node metastases, and reveal any sites of distant metastases [55]. The 2007 National Comprehensive Cancer Network treatment guidelines included PET/CT as a part of the standard pre-treatment workup of patients diagnosed with anal carcinoma [56]. The new version 2.2012 consider PET-CT scan for work up, even if its use for staging or treatment planning has not been validated [57]. The Authors suggest that PET-CT actually does not replace a diagnostic CT scan [57].

Otherwise accurate staging of anal cancer followed by optimal planning of combined radio‐ chemotherapy treatment can extend patient survival. Anatomical imaging techniques such as CT and MRI cannot evaluate tumor biology and behavior. PET/CT imaging is increasingly used to stage different malignant diseases [59]. The advantage of PET/CT fusion imaging resides in its ability to correlate findings from anatomic and functional imaging modalities, lending it a more important role than diagnostic CT alone in the selection of proper treatment [36]. Moreover, therapy-induced changes in tumors are related to changes in 18F-FDG uptake, and treatment response can be efficiently monitored by PET/CT also considering the standar‐ dized uptake value (SUV) of 18F-FDG.

Evidence from published data and our study [41] indicates that PET/CT is clearly superior to CT in visualizing the biopsy-proven primary tumor (87.5-100% vs 47-75%), although the lack of sensitivity did not affect treatment. Otherwise both PET/CT and CT were unable to detect residual tumor after surgical excision.

Considering the results of staging anal cancer with PET-CT respect other classical staging tools, pre-treatment PET/CT upstaged 9-37.5% and downstaged 0-25% of patients with anal cancer [34-54]. PET/CT at diagnosis can also be used for radiation therapy treatment planning as it clearly defines sites of metabolically active tumor [47].

Piperkova et al. suggested that PET/CT in anal cancer accurately identifies treatment response [36]. Schwarz et al. [39] reported that posttherapy FDG response was the most significant predictor of progression-free survival (P=0.0003) and that it was more predictive of the treatment outcome than either pre-treatment tumor size (P=0.08) or nodal status (P=0.40).

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Mistrangelo et Al [49] reported that PET/CT assessment at 1 month had a sensitivity of 66.6%, a specificity of 92.5%, a PPV of 40% and a NPV of 97.4% for detecting persistence of anal disease. These data are not comparable to previous observations. Only Trautmann et al. [34] reported on the results of PET/CT assessment at 1 month (persistence of disease of 66.6% of cases), suggesting that PET/CT at 1 month after the end of therapy is of little value in predicting the

In contrast, anal biopsy at 1-month follow-up had higher sensitivity and specificity than PET/ CT, even if assessment with biopsy of non-progressive residual tumor at 1 month after treatment may be misleading as shortly after radiation nonviable cancer cell may look

Considering these aspects biopsy for a non-progressive residual tumor at 1 month after treatment shoud not be taken as this can lead to unnecessary abdominoperineal excision. These

Mistrangelo et Al reported that PET/CT assessment at 3 months had a sensitivity of 100%, a specificity of 97.4%, a PPV of 66% and a NPV of 100%; anal biopsy had the same sensitivity but a better specificity than PET/CT [49]. Vercellino and Coll [50] reported thet sensitivity, specificity and negative predictive value of PET-CT for the detection of recurrent locoregional disease is 93%, 81% and 94% respectively, resulting in an impact on management in 20%.

The role of PET-CT in the evaluation of anal cancer is evolving. PET/CT detect the primary tumor more often than CT, but neither tool is indicated to reveal persistent disease after surgery. PET/CT proved useful in initial staging perirectal/pelvic or inguinal lymph nodes. PET/CT can document also unknown metastases, changing the disease stadiation. However, upstaging related to lymph nodes metastases might have been overestimated, as up to 31% of inguinal metastases identified by PET/CT are reportedly false positive, but metabolic imaging can descover little nodal metastases, too little for CT and clinical evaluation. Currently, inguinal lymph nodes are better staged by sentinel node biopsy. PET/CT assessment at 1-

PET/CT assessment at 3 months more accurately evaluated the persistence or the recurrence of anal disease and thus allowed for better follow up when combined with anal biopsy.

month follow-up had lower sensitivity and specificity than anal biopsy.

Persistent disease is indeed a predictor of poor clinical outcome [39].

durability of response.

morphologically intact [62].

**14. Conclusions**

patients should be closely observed.

Radiation treatment fields changed in 3.7-33.3% of patients [37-38, 40, 42, 46-52]. Only Vercel‐ lino et al. [50] reported no change in treatment fields in their series of 44 patients.

In the majority of studies, upstaging was related to a suggested better staging of metastases in perirectal, pelvic and inguinal lymph nodes. As it defines nodal and metastatic disease, PET imaging can improve the staging of anal cancer [40].

Mai and Coll assumed that PET positive lymph nodes in a setting of anal cancer as defined by SUV uptake raise the likelihood of lymph node involvement, which would warrant more aggressive treatment in patients with PET positive nodes [60].

The sensitivity of CT for detecting nodal metastases in the pelvic and inguinal region is limited to 40-68% [25]. By contrast, PET/CT showed a higher specificity (80-90%) and sensitivity (70-90%) in the detection of nodal and distant metastases for several tumor types like nonsmall-cell lung cancer and head and neck cancer [25]. Also in gynecologic cancer, PET can have a specificity of 90-95%.

Cotter et al. [35] reported that PET/CT upstages inguinal nodes in 17% of patients. They also found a higher rate of PET/CT positive for inguinal metastases in HIV-seropositive versus HIV-seronegative patients (44% vs. 16%), while other Authors observed only a marginal difference in positive inguinal metastases between these two patient subgroups (28.5% vs. 25%) [49].

Otherwise some 5% of inguinal lymph node metastases detected with PET/CT are FP at fineneedle aspiration cytology (FNAC) [48] and up to 57% at histological confirmation of samples from sentinel node biopsy (SNB) [61]. Iagaru [41] and Engledow [48] reported that inguinal lymph nodes positive at PET/CT were negative at FNAC in 50% and at SNB in 5% of cases. Therefore, positive lymph nodes identified by PET/CT should be adequately studied with biopsy before changing radiotherapy plans. In this connection, the high incidence of inguinal metastases found on imaging as compared with conventional staging tools should warn against unnecessary inguinal radiotherapy. Inguinal staging with SNB may explain the lower percentage of change in radiotherapy fields in ours series compared to others.

PET/CT was recently considered also for follow-up of patients undergoing radio- and chemo‐ therapy treatment in anal cancer. Kidd et al. [45] reported that a higher SUVmax was associated with lymph node involvement at diagnosis. These patients were also at higher risk of persistent disease on their post-treatment PET, if the study was performed less than 4 months after completing therapy. The authors go on to suggest that SUVmax for FDG represents a potential new biomarker for anal cancer prognosis, as it is significantly associated with lymph node involvement at diagnosis, treatment response, and disease-free survival [45].

Post-treatment PET/CT is indicated to determine response to therapy and it is highly predictive of long-term clinical outcomes [55]. It can also be used to evaluate sites of recurrent disease. Few studies have examined clinical response to therapy, and clinical workup differs widely. Piperkova et al. suggested that PET/CT in anal cancer accurately identifies treatment response [36]. Schwarz et al. [39] reported that posttherapy FDG response was the most significant predictor of progression-free survival (P=0.0003) and that it was more predictive of the treatment outcome than either pre-treatment tumor size (P=0.08) or nodal status (P=0.40). Persistent disease is indeed a predictor of poor clinical outcome [39].

Mistrangelo et Al [49] reported that PET/CT assessment at 1 month had a sensitivity of 66.6%, a specificity of 92.5%, a PPV of 40% and a NPV of 97.4% for detecting persistence of anal disease. These data are not comparable to previous observations. Only Trautmann et al. [34] reported on the results of PET/CT assessment at 1 month (persistence of disease of 66.6% of cases), suggesting that PET/CT at 1 month after the end of therapy is of little value in predicting the durability of response.

In contrast, anal biopsy at 1-month follow-up had higher sensitivity and specificity than PET/ CT, even if assessment with biopsy of non-progressive residual tumor at 1 month after treatment may be misleading as shortly after radiation nonviable cancer cell may look morphologically intact [62].

Considering these aspects biopsy for a non-progressive residual tumor at 1 month after treatment shoud not be taken as this can lead to unnecessary abdominoperineal excision. These patients should be closely observed.

Mistrangelo et Al reported that PET/CT assessment at 3 months had a sensitivity of 100%, a specificity of 97.4%, a PPV of 66% and a NPV of 100%; anal biopsy had the same sensitivity but a better specificity than PET/CT [49]. Vercellino and Coll [50] reported thet sensitivity, specificity and negative predictive value of PET-CT for the detection of recurrent locoregional disease is 93%, 81% and 94% respectively, resulting in an impact on management in 20%.

#### **14. Conclusions**

[34-54]. PET/CT at diagnosis can also be used for radiation therapy treatment planning as it

250 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Radiation treatment fields changed in 3.7-33.3% of patients [37-38, 40, 42, 46-52]. Only Vercel‐

In the majority of studies, upstaging was related to a suggested better staging of metastases in perirectal, pelvic and inguinal lymph nodes. As it defines nodal and metastatic disease, PET

Mai and Coll assumed that PET positive lymph nodes in a setting of anal cancer as defined by SUV uptake raise the likelihood of lymph node involvement, which would warrant more

The sensitivity of CT for detecting nodal metastases in the pelvic and inguinal region is limited to 40-68% [25]. By contrast, PET/CT showed a higher specificity (80-90%) and sensitivity (70-90%) in the detection of nodal and distant metastases for several tumor types like nonsmall-cell lung cancer and head and neck cancer [25]. Also in gynecologic cancer, PET can have

Cotter et al. [35] reported that PET/CT upstages inguinal nodes in 17% of patients. They also found a higher rate of PET/CT positive for inguinal metastases in HIV-seropositive versus HIV-seronegative patients (44% vs. 16%), while other Authors observed only a marginal difference in positive inguinal metastases between these two patient subgroups

Otherwise some 5% of inguinal lymph node metastases detected with PET/CT are FP at fineneedle aspiration cytology (FNAC) [48] and up to 57% at histological confirmation of samples from sentinel node biopsy (SNB) [61]. Iagaru [41] and Engledow [48] reported that inguinal lymph nodes positive at PET/CT were negative at FNAC in 50% and at SNB in 5% of cases. Therefore, positive lymph nodes identified by PET/CT should be adequately studied with biopsy before changing radiotherapy plans. In this connection, the high incidence of inguinal metastases found on imaging as compared with conventional staging tools should warn against unnecessary inguinal radiotherapy. Inguinal staging with SNB may explain the lower

PET/CT was recently considered also for follow-up of patients undergoing radio- and chemo‐ therapy treatment in anal cancer. Kidd et al. [45] reported that a higher SUVmax was associated with lymph node involvement at diagnosis. These patients were also at higher risk of persistent disease on their post-treatment PET, if the study was performed less than 4 months after completing therapy. The authors go on to suggest that SUVmax for FDG represents a potential new biomarker for anal cancer prognosis, as it is significantly associated with lymph node

Post-treatment PET/CT is indicated to determine response to therapy and it is highly predictive of long-term clinical outcomes [55]. It can also be used to evaluate sites of recurrent disease. Few studies have examined clinical response to therapy, and clinical workup differs widely.

percentage of change in radiotherapy fields in ours series compared to others.

involvement at diagnosis, treatment response, and disease-free survival [45].

lino et al. [50] reported no change in treatment fields in their series of 44 patients.

clearly defines sites of metabolically active tumor [47].

imaging can improve the staging of anal cancer [40].

a specificity of 90-95%.

(28.5% vs. 25%) [49].

aggressive treatment in patients with PET positive nodes [60].

The role of PET-CT in the evaluation of anal cancer is evolving. PET/CT detect the primary tumor more often than CT, but neither tool is indicated to reveal persistent disease after surgery. PET/CT proved useful in initial staging perirectal/pelvic or inguinal lymph nodes. PET/CT can document also unknown metastases, changing the disease stadiation. However, upstaging related to lymph nodes metastases might have been overestimated, as up to 31% of inguinal metastases identified by PET/CT are reportedly false positive, but metabolic imaging can descover little nodal metastases, too little for CT and clinical evaluation. Currently, inguinal lymph nodes are better staged by sentinel node biopsy. PET/CT assessment at 1 month follow-up had lower sensitivity and specificity than anal biopsy.

PET/CT assessment at 3 months more accurately evaluated the persistence or the recurrence of anal disease and thus allowed for better follow up when combined with anal biopsy.

[11] Ryan D, Compton C, Mayer R. Carcinoma of the anal canal. N Engl J Med 2000; 342:792–

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253

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#### **Author details**

Massimiliano Mistrangelo1\* and Adriana Lesca2

\*Address all correspondence to: mistrangelo@katamail.com

1 Digestive and Colorectal Surgical Department, Centre of Minimal Invasive Surgery, University of Turin, Città della Salute e della Scienza Hospital, Italy

2 Department of Nuclear Medicine, Città della Salute e della Scienza Hospital, Italy

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**Chapter 10**

**Early Prediction of Tumor Response: A Future Strategy**

Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) is successfully capable of imaging glucose metabolism of the tumor cells. Tumor glucose metabolism using FDG-PET has a potential to distinguish viable cancer cells from those in suspension or necrotic components because the degree of tumor FDG uptake is closely associated with its prolifera‐ tion activity. There is cumulative evidence showing that reduction in FDG uptake value on the early phase after the initiation of chemotherapy more reliably predicts a favorable outcome of patients with breast cancer. Therefore, FDG-PET could help to individualize treatment and to avoid potentially ineffective chemotherapies. In this article, we discuss and illustrate the role and limitations of FDG-PET in the management of neoadjuvant chemotherapy in breast

FDG-PET has proven useful in the management of various cancers [1]. FDG-PET is known to play an important role in the detection of distant metastasis and recurrence [2, 3]. In addition, it provides quantitative information on tumor glucose metabolic activity, allowing the measurement of metabolic changes and cancer activity shortly after initiation of therapy and before tumor volume reduction [4]. This functional imaging tool may also be useful in

Tumor response to therapy is traditionally assessed by comparison of tumor size before and after treatment, which is determined using anatomical imaging devices such as ultrasonogra‐ phy and computed tomography (CT) on the basis of the Response Evaluation Criteria in Solid

> © 2013 Ueda and Saeki; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

predicting tumor response to therapy and optimizing individual treatment [5].

**for Optimizing Cancer Treatment**

Additional information is available at the end of the chapter

Shigeto Ueda and Toshiaki Saeki

http://dx.doi.org/10.5772/57120

**2. Tumor metabolic response**

**1. Introduction**

cancer.


### **Early Prediction of Tumor Response: A Future Strategy for Optimizing Cancer Treatment**

Shigeto Ueda and Toshiaki Saeki

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57120

#### **1. Introduction**

[52] Wells IT., Fox BM. PET/CT in anal cancer – is it worth doing? Clinical Radiol 2012; 67:

256 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

[53] Bhuva NJ., Glynne-Jones R., Sonoda L., Wong W-L., Harrison MK. To PET or not to

PET? That is the question. Staging in anal cancer. Ann Oncol 2012; 23 (8): 2078-2082.

[54] Saboo SS., Zukotynski K., Shinagare AB., Krajewski KM., Ramaiya N. Anal carcinoma: FDG PET/CT in staging, response evaluation, and follow up. Abdom Imaging 2012;

[55] Grigsby PW. FDG-PET/CT: New horizons in anal cancer. Gastroenterol Clin Biol 2009;

[56] Engstrom PF, Arnoletti JP, Benson AB 3rd, et al. NCCN clinical practice guidelines in

[57] Benson AB 3rd, Arnoletti JP, Bekaii-Saab T. et Al. NCCN Clinical Practice Guidelines in Oncology: Anal Carcinoma. Version 2.2012: featured updates to the National Comprehensive Cancer Network guidelines. J Natl Compr Canc Netw 2012; 10:

[58] American Joint Commission on Cancer. Anal Canal. In AJCC Cancer Staging Manual

[59] Ell PJ. PET/CT in oncology: a major technology for cancer. Chang Gung Med J. 2005;

[60] Mai SK., Welzel G., Hermann B., et al. Can the radiation dose to CT-enlarged but FDG-PET-negative inguinal lymph nodes in anal cancer be reduced? Strahlenther Onkol

[61] Mistrangelo M., Pelosi E., Bellò M., Castellano I., Cassoni P., Ricardi U., Munoz F., Racca P., Contu V., Beltramo G., Morino M., Mussa A. Comparison of positron

[62] Suit HD, Gallager HS. Intact tumor cells in irradiated tissue. Arch Pathol 1964; 78:

emission tomography scanning and sentinel node biopsy in the detection of inguinal node metastases in patients with anal cancer. Int J Radiation Oncol Biol Phys 2010; 77

oncology. Anal carcinoma. J Natl Compr Canc Netw 2010; 8 (1): 106-120.

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535-540.

33 (5): 456-458.

449-454.

28: 274-283.

(1): 73-78.

648-651.

2009; 185: 254-259.

6th Ed. New York: Springer; 2002: 125-130.

Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) is successfully capable of imaging glucose metabolism of the tumor cells. Tumor glucose metabolism using FDG-PET has a potential to distinguish viable cancer cells from those in suspension or necrotic components because the degree of tumor FDG uptake is closely associated with its prolifera‐ tion activity. There is cumulative evidence showing that reduction in FDG uptake value on the early phase after the initiation of chemotherapy more reliably predicts a favorable outcome of patients with breast cancer. Therefore, FDG-PET could help to individualize treatment and to avoid potentially ineffective chemotherapies. In this article, we discuss and illustrate the role and limitations of FDG-PET in the management of neoadjuvant chemotherapy in breast cancer.

#### **2. Tumor metabolic response**

FDG-PET has proven useful in the management of various cancers [1]. FDG-PET is known to play an important role in the detection of distant metastasis and recurrence [2, 3]. In addition, it provides quantitative information on tumor glucose metabolic activity, allowing the measurement of metabolic changes and cancer activity shortly after initiation of therapy and before tumor volume reduction [4]. This functional imaging tool may also be useful in predicting tumor response to therapy and optimizing individual treatment [5].

Tumor response to therapy is traditionally assessed by comparison of tumor size before and after treatment, which is determined using anatomical imaging devices such as ultrasonogra‐ phy and computed tomography (CT) on the basis of the Response Evaluation Criteria in Solid

© 2013 Ueda and Saeki; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Tumors (RECIST) [6]. Although RECIST has been widely adopted, tumor response must be evaluated for several months until surgery and it does not always reflect the pathological response because of difficulties in distinguishing residual cancer cells from necrotic lesions, fibrosis, or benign masses.

Because of limitations in applying the RECIST criteria using anatomic imaging alone, Wahl et al. proposed a draft framework called the PET Response Criteria in Solid Tumors (PERCIST) [7]. The proposed PERCIST criteria are being used in several current clinical studies. As far as early response assessment with FDG-PET is concerned, clinical studies involving patients with Hodgkin lymphoma and aggressive non-Hodgkin lymphoma have demonstrated that the assessment of changes in FDG uptake on PET imaging after 2 or 3 cycles of chemotherapy was superior for predicting patient prognosis compared with the assessment of morphological changes on computed tomography (CT) [8]. This method was shown to be at least as reliable as definitive response assessment at the end of therapy [8]. In a European multicenter trial monitoring chemotherapy response and survival in 260 patients with lymphoma, an early decrease in FDG uptake on PET after 2 cycles of chemotherapy was significantly correlated with progression-free survival [9]. For other types of cancers, including breast cancer [10], nonsmall cell lung cancer [11], esophageal cancer [12] [13], gastric cancer [14], and colorectal cancer [15], several clinical studies revealed evidence of the emerging role of FDG-PET in predicting both post-therapeutic clinicopathological response and patient survival.

In our institute, a discrepancy was observed between tumor morphological changes and tumor metabolic activity in a patient treated with neoadjuvant chemotherapy for primary breast cancer. FDG-PET was performed at the onset of chemotherapy, at the midpoint of chemother‐ apy, and prior to surgery. The primary tumor appeared to grow rapidly after the start of neoadjuvant chemotherapy despite the gradual reduction in glucose accumulation (Figure 1). Postoperative pathological analysis revealed that the lesion was replaced with scar tissue in addition to the presence of massive bleeding and small residual cancer cell nests. In this case, FDG-PET was able to provide more accurate and clinically beneficial information compared with CT.

specificity: 85%) [18]. Smith et al. also successfully utilized FDG-PET for predicting tumor

**Figure 1.** Transversal slices of FDG-PET/CT of a breast lesion before treatment (left), at the completion of the EC regi‐

SUVmax decreased from 5.8 to 3.0 at the midpoint of treatment and returned to baseline levels prior to surgery. In contrast, the tumor diameter increased from 36 mm to 50 mm at the midpoint of treatment and to 61 mm prior to

Early Prediction of Tumor Response: A Future Strategy for Optimizing Cancer Treatment

http://dx.doi.org/10.5772/57120

259

Our team investigated the maximum changes in SUV (SUVmax) in 32 primary breast cancer lesions in 30 patients. The patients were treated with neoadjuvant chemotherapy comprising 4 cycles of epirubicine and cyclophosphamide on a triweekly basis and sequential weekly cycles of taxane for 12 weeks [20]. Figure 2 shows representative tumor images on FDG-PET performed at baseline, after one cycle of chemotherapy, after four cycles of chemotherapy, and prior to surgery. The serial images on the upper row show a tumor in which a pathological complete response (pCR) can be observed. The middle row depicts a tumor exhibiting a pathological partial response (pPR), and the lower row illustrates pathological progressive disease (pPD). SUV decreased dramatically in the pCR tumor after one cycle of chemotherapy, after which metabolic activity ceased. SUV change in the pPR tumor was lower than that in the pCR tumor after one cycle of chemotherapy, but SUV gradually diminished during further chemotherapeutic treatment. The pPD tumor showed no significant changes in SUV after treatment. In terms of the optimal threshold of a 40% decrease in SUV, the rate of pathological response in terms of pCR or near pCR was higher (71.4%) in metabolic responders than in nonresponders (12.5%). The sensitivity, specificity, positive predictive value (PPV), and

response after the first cycle of chemotherapy (sensitivity: 90%, specificity: 74%) [19].

FDG: fluoro-D-glucose; PET: positron emission tomography; CT: computed tomography SUVmax: maximal standardized uptake value; EC: epirubicin and cyclophosphamide.

men (middle), and at the completion of the paclitaxel regimen (right).

surgery.

negative predictive value (NPV) were 63%, 92%, 71%, and 88%, respectively.

In 2008, Schwarz–Dose et al. performed the first prospective multicenter trial to evaluate the effectiveness of FDG-PET in predicting early pathological response during chemotherapeutic

Clinical studies conducted worldwide have repeatedly revealed the predictive value of FDG-PET in patients with advanced breast cancer treated by chemotherapy. As early as 1993, Wahl et al. studied 11 patients with locally advanced breast cancer before and after 1 cycle of chemotherapy. A significant difference was observed in tumor FDG influx rate (K) from baseline levels between responders and nonresponders (sensitivity: 100%, specificity: 100%) [16]. In 1996, Bassa et al. conducted a retrospective study of 13 patients with breast cancer for whom FDG-PET scans were performed prior to chemotherapy, at the end of the first cycle, at the midpoint of chemotherapy, and before surgery. The mean standardized uptake value (SUV) of the tumor after the first cycle of chemotherapy was significantly lower than the baseline value (*p* < 0.01) [17]. In 2000, reports of clinical studies from two separate institutes showed the usefulness of FDG-PET in the early evaluation of tumor metabolic response to chemotherapy. Schelling et al. demonstrated the ability of FDG-PET to differentiate between responders and nonresponders after the first course of chemotherapy (sensitivity: 100%,

SUVmax decreased from 5.8 to 3.0 at the midpoint of treatment and returned to baseline levels prior to surgery. In contrast, the tumor diameter increased from 36 mm to 50 mm at the midpoint of treatment and to 61 mm prior to surgery.

FDG: fluoro-D-glucose; PET: positron emission tomography; CT: computed tomography SUVmax: maximal standardized uptake value; EC: epirubicin and cyclophosphamide.

Tumors (RECIST) [6]. Although RECIST has been widely adopted, tumor response must be evaluated for several months until surgery and it does not always reflect the pathological response because of difficulties in distinguishing residual cancer cells from necrotic lesions,

258 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Because of limitations in applying the RECIST criteria using anatomic imaging alone, Wahl et al. proposed a draft framework called the PET Response Criteria in Solid Tumors (PERCIST) [7]. The proposed PERCIST criteria are being used in several current clinical studies. As far as early response assessment with FDG-PET is concerned, clinical studies involving patients with Hodgkin lymphoma and aggressive non-Hodgkin lymphoma have demonstrated that the assessment of changes in FDG uptake on PET imaging after 2 or 3 cycles of chemotherapy was superior for predicting patient prognosis compared with the assessment of morphological changes on computed tomography (CT) [8]. This method was shown to be at least as reliable as definitive response assessment at the end of therapy [8]. In a European multicenter trial monitoring chemotherapy response and survival in 260 patients with lymphoma, an early decrease in FDG uptake on PET after 2 cycles of chemotherapy was significantly correlated with progression-free survival [9]. For other types of cancers, including breast cancer [10], nonsmall cell lung cancer [11], esophageal cancer [12] [13], gastric cancer [14], and colorectal cancer [15], several clinical studies revealed evidence of the emerging role of FDG-PET in predicting

In our institute, a discrepancy was observed between tumor morphological changes and tumor metabolic activity in a patient treated with neoadjuvant chemotherapy for primary breast cancer. FDG-PET was performed at the onset of chemotherapy, at the midpoint of chemother‐ apy, and prior to surgery. The primary tumor appeared to grow rapidly after the start of neoadjuvant chemotherapy despite the gradual reduction in glucose accumulation (Figure 1). Postoperative pathological analysis revealed that the lesion was replaced with scar tissue in addition to the presence of massive bleeding and small residual cancer cell nests. In this case, FDG-PET was able to provide more accurate and clinically beneficial information

Clinical studies conducted worldwide have repeatedly revealed the predictive value of FDG-PET in patients with advanced breast cancer treated by chemotherapy. As early as 1993, Wahl et al. studied 11 patients with locally advanced breast cancer before and after 1 cycle of chemotherapy. A significant difference was observed in tumor FDG influx rate (K) from baseline levels between responders and nonresponders (sensitivity: 100%, specificity: 100%) [16]. In 1996, Bassa et al. conducted a retrospective study of 13 patients with breast cancer for whom FDG-PET scans were performed prior to chemotherapy, at the end of the first cycle, at the midpoint of chemotherapy, and before surgery. The mean standardized uptake value (SUV) of the tumor after the first cycle of chemotherapy was significantly lower than the baseline value (*p* < 0.01) [17]. In 2000, reports of clinical studies from two separate institutes showed the usefulness of FDG-PET in the early evaluation of tumor metabolic response to chemotherapy. Schelling et al. demonstrated the ability of FDG-PET to differentiate between responders and nonresponders after the first course of chemotherapy (sensitivity: 100%,

both post-therapeutic clinicopathological response and patient survival.

fibrosis, or benign masses.

compared with CT.

**Figure 1.** Transversal slices of FDG-PET/CT of a breast lesion before treatment (left), at the completion of the EC regi‐ men (middle), and at the completion of the paclitaxel regimen (right).

specificity: 85%) [18]. Smith et al. also successfully utilized FDG-PET for predicting tumor response after the first cycle of chemotherapy (sensitivity: 90%, specificity: 74%) [19].

Our team investigated the maximum changes in SUV (SUVmax) in 32 primary breast cancer lesions in 30 patients. The patients were treated with neoadjuvant chemotherapy comprising 4 cycles of epirubicine and cyclophosphamide on a triweekly basis and sequential weekly cycles of taxane for 12 weeks [20]. Figure 2 shows representative tumor images on FDG-PET performed at baseline, after one cycle of chemotherapy, after four cycles of chemotherapy, and prior to surgery. The serial images on the upper row show a tumor in which a pathological complete response (pCR) can be observed. The middle row depicts a tumor exhibiting a pathological partial response (pPR), and the lower row illustrates pathological progressive disease (pPD). SUV decreased dramatically in the pCR tumor after one cycle of chemotherapy, after which metabolic activity ceased. SUV change in the pPR tumor was lower than that in the pCR tumor after one cycle of chemotherapy, but SUV gradually diminished during further chemotherapeutic treatment. The pPD tumor showed no significant changes in SUV after treatment. In terms of the optimal threshold of a 40% decrease in SUV, the rate of pathological response in terms of pCR or near pCR was higher (71.4%) in metabolic responders than in nonresponders (12.5%). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 63%, 92%, 71%, and 88%, respectively.

In 2008, Schwarz–Dose et al. performed the first prospective multicenter trial to evaluate the effectiveness of FDG-PET in predicting early pathological response during chemotherapeutic

high rate, with a sensitivity of 73%, specificity of 63%, PPV of 36%, and NPV of 90% [10]. Other representative studies published in the literature since 2000 are listed in Table 1 [21-25].

In 2011, a meta-analysis in this field summarized 16 articles including a total of 920 patients with breast cancer [26]. To predict histopathological response in primary lesions, the pooled sensitivity, specificity, PPV, NPV, and diagnostic odds ratios were calculated. The results for these parameters were 84% [95% confidence interval (CI), 78%–88%], 66% (95% CI, 62%–70%), 50% (95% CI, 44%–55%), 91% (95% CI, 87%–94%), and 11.90 (95% CI, 6.33%–22.36%), respec‐ tively. Although the checkpoints of FDG-PET administration in these trials differed, a subset analysis showed that early response of glucose metabolism after the first or second cycle of chemotherapy provided a significantly better indicator of accuracy compared with a later response (third cycle or later). The subset analysis results showed in Table1. These data indicate that changes in SUV during the first 1–3 cycles of chemotherapy are better indicators of clinical

Authors Year Study Type stage Population The timing of PETscans Early assessment Endpoint Cutoff Se Sp PPV NPV Accuracy Martoni, et al.<sup>22</sup> 2010 one center LABC 34 Baseline,after 2 cycles, 4 cycles, at the end after 2 cycles pCR+pMRD 50% in △SUV 100 30 27 100 44

Kumar, et al.21 2009 one center LABC 23 Baseline, after 2 cycle after 2 cycles pCR+pMRD 50% in △SUV 93 75 87

al.10 2008 multiple centers LABC 104 baseline, after 1 cycle, after 2 cycle after 1 cycle pCR+pMRD 45% in △SUV 73 63 36 90 65

cycles, after 6 cycles after 2 cycles 50% or more absence

Authors Year Study Type stage Population The timing of PET scans Evaluation of the timing Endpoint Cutoff Se Sp PPV NPV Accuracy Wang, et al.26 2011 meta-analysis LABC 920(Total) Various Various Various Various 84 66 50 91

The high sensitivity and high NPV reported above indicate that FDG-PET may be useful for the identification of nonresponders among patients in the early phases of treatment with neoadjuvant chemotherapy. However, in cases where FDG-PET indicates changes in SUV (responders), decision-making regarding continuation of treatment may still be difficult. This problem has been addressed in research on lymphoma patients. Randomized trials have been conducted to determine whether response-guided treatment using early response to therapy as measured by FDG-PET scans is feasible or useful in decreasing the cumulative dose of potentially cytotoxic agents in nonresponders [27], [28]. These trials aim at treatment modifi‐ cation based on PET response by comparing risk-adapted treatment guided by FDG-PET with

An emerging paradigm for a treatment strategy using FDG-PET has been introduced in addition to traditional assessment of tumor response on the basis of staging and tumor subtyping [30]. A specific treatment was chosen from a number of chemotherapeutic drugs, and the usefulness of FDG-PET was analyzed in comparison to assessment based on staging

pCR+less than 3% disappearance of tumor ells

Early Prediction of Tumor Response: A Future Strategy for Optimizing Cancer Treatment

of tumor 40% in △SUV 77 80

of tumor cells 40% in △SUV 89 95 <sup>85</sup>

Widow/Orphan control **Table 1.** Optimal timing of FDG PET during chemotherapy

midpoint, at the end after 1 cycle pCR+pMRD 34% in △SUV 100 66

cycles, at the end after 1 cycle pCRmicro/macro 20% in △DUR 90 74

347(subset) Various After 1-2 cycles Various Various 88 70 61 92 76 400(subset) Various After 3 cycles or later Various Various 81 61 34 93 65

40% in △SUV 63 92 71 88 84

http://dx.doi.org/10.5772/57120

261

**Formatted:** Justified, Line spacing: 1.5 lines,

**Formatted:** Left, Line spacing: single,

No widow/orphan control **Field Code Changed**

end after 1 cycle

Schelling, et al.18 2000 one center LABC 22 Baseline, after 1 cycle, after 2 cycles after 1 cycle pCR and pMRD 55% in △SUV 100 85

LABC, Laegelly advanced breast cancer; pCR, pathological complete response; MRD, macroscope residual disease; Se, sensitivity; Sp, specificity; PPV, positive predictive value; NPV, negative predictive value

25

outcome compared with changes during the later cycles.

al.23 2007 one center LABC 50 Baseline, after 2 cycle after 2 cycles 75% or more absence

Table 1. Studies evaluating treatment response with FDG PET or FDG PET/CT in breast cancer patients

Ueda, et al.20 2010 one center LABC <sup>32</sup> Baseline, after 1 cycyle, after 4 cycles, at the

McDemott, et al.<sup>25</sup> 2007 one center LABC <sup>96</sup> Baseline, after 1cycle, after 2 cycles, at the

Rousseau, et al.24 2006 one center LABC <sup>64</sup> Baseline, after 1 cycle, after 2 cycles, after 3

Smith, et al.19 2000 one center LABC <sup>30</sup> Baseline, after 1cycle, after 2 cycles, after 5

standard chemotherapy in these patients [29].

Clinical study

Schwarz-Dose, et

Berrido-Riedinger, et

Meta-analysis

**Figure 2.** Axial FDG-PET/CT images of a pCR tumor (upper row), a pPR tumor (middle row), and a pPD tumor (lower row). Sequential FDG-PET scans were performed at baseline (left), after 1 cycle of chemotherapy (second from the left), after completion of the EC regimen (third from the left), and at the completion of chemotherapy (right).

treatment in 104 patients with locally advanced breast cancer [10]. In that report, when a 40% decrease in SUV occurred in the first cycle after initiation of chemotherapy compared with baseline values, FDG-PET predicted pCR and pathological macroscopic residual disease at a

pCR: pathological complete response; pPR: pathological partial response; pPD: pathological progressive disease; FDG: fluoro-D-glucose; PET: positron emission tomography; CT: computed tomography; EC: epirubicin and cyclophospha‐ mide

**Formatted:** Justified, Line spacing: 1.5 lines,

**Formatted:** Left, Line spacing: single,

No widow/orphan control **Field Code Changed**

high rate, with a sensitivity of 73%, specificity of 63%, PPV of 36%, and NPV of 90% [10]. Other representative studies published in the literature since 2000 are listed in Table 1 [21-25].

In 2011, a meta-analysis in this field summarized 16 articles including a total of 920 patients with breast cancer [26]. To predict histopathological response in primary lesions, the pooled sensitivity, specificity, PPV, NPV, and diagnostic odds ratios were calculated. The results for these parameters were 84% [95% confidence interval (CI), 78%–88%], 66% (95% CI, 62%–70%), 50% (95% CI, 44%–55%), 91% (95% CI, 87%–94%), and 11.90 (95% CI, 6.33%–22.36%), respec‐ tively. Although the checkpoints of FDG-PET administration in these trials differed, a subset analysis showed that early response of glucose metabolism after the first or second cycle of chemotherapy provided a significantly better indicator of accuracy compared with a later response (third cycle or later). The subset analysis results showed in Table1. These data indicate that changes in SUV during the first 1–3 cycles of chemotherapy are better indicators of clinical outcome compared with changes during the later cycles.


#### Widow/Orphan control **Table 1.** Optimal timing of FDG PET during chemotherapy

Table 1. Studies evaluating treatment response with FDG PET or FDG PET/CT in breast cancer patients

treatment in 104 patients with locally advanced breast cancer [10]. In that report, when a 40% decrease in SUV occurred in the first cycle after initiation of chemotherapy compared with baseline values, FDG-PET predicted pCR and pathological macroscopic residual disease at a

pCR: pathological complete response; pPR: pathological partial response; pPD: pathological progressive disease; FDG: fluoro-D-glucose; PET: positron emission tomography; CT: computed tomography; EC: epirubicin and cyclophospha‐

260 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**Figure 2.** Axial FDG-PET/CT images of a pCR tumor (upper row), a pPR tumor (middle row), and a pPD tumor (lower row). Sequential FDG-PET scans were performed at baseline (left), after 1 cycle of chemotherapy (second from the left), after completion of the EC regimen (third from the left), and at the completion of chemotherapy (right).

mide

The high sensitivity and high NPV reported above indicate that FDG-PET may be useful for the identification of nonresponders among patients in the early phases of treatment with neoadjuvant chemotherapy. However, in cases where FDG-PET indicates changes in SUV (responders), decision-making regarding continuation of treatment may still be difficult. This problem has been addressed in research on lymphoma patients. Randomized trials have been conducted to determine whether response-guided treatment using early response to therapy as measured by FDG-PET scans is feasible or useful in decreasing the cumulative dose of potentially cytotoxic agents in nonresponders [27], [28]. These trials aim at treatment modifi‐ cation based on PET response by comparing risk-adapted treatment guided by FDG-PET with standard chemotherapy in these patients [29].

25 An emerging paradigm for a treatment strategy using FDG-PET has been introduced in addition to traditional assessment of tumor response on the basis of staging and tumor subtyping [30]. A specific treatment was chosen from a number of chemotherapeutic drugs, and the usefulness of FDG-PET was analyzed in comparison to assessment based on staging and subtyping. This new strategy to optimize treatment timing includes staging, subtyp‐ ing, and response guiding. Staging and subtyping determine favorable treatment options before the initiation of treatment. Functional imaging with FDG-PET offers opportunities to assess tumor response early in the course of treatment. This response-guiding strategy offers the opportunity to revise treatment and improve outcome. FDG-PET not only provides invaluable prognostic information in patients [31] but also supports efforts to switch to more effective treatment options in the early stages of treatment rather than on completion of therapy (Figure 3).

different combinations of drugs add to the confusion. The optimal timing of PET scanning may depend on dose intensity or regimen. If the regimen changes during the course of treatment, the results may be affected because the mechanism of drug sensitivity differs according to

Early Prediction of Tumor Response: A Future Strategy for Optimizing Cancer Treatment

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263

The optimal timing of FDG-PET scanning after initiation of chemotherapy for the prediction and elimination of progressive disease (PD) has also not been determined till date. In clinical practice, most physicians are more concerned about tumor progression during neoadjuvant chemotherapy than about achieving pCR. Because chemotherapeutic treatment may increase genomic instability in some tumors, and because chemotherapy resistance may develop in severe cases with hypoxia, neoadjuvant chemotherapy may be contraindicated. However, the

The optimal threshold of metabolic change on FDG-PET also remains unclear. A recent draft standard of PERCIST has been advocated as response criteria in solid tumors [7]. It recom‐ mends a ≥30% decrease in SUV as a cutoff value for partial metabolic response, which is associated with clinical outcome after chemotherapy. However, specific response criteria for breast cancer must be defined in order to increase the accuracy of prognosis. Further prospec‐ tive research is needed to determine the optimal cut-off value for predicting tumor response. Thorough evaluation of cost-effectiveness and prognostic impact of early switching from ineffective neoadjuvant chemotherapy to a more effective regimen is essential. In a simula‐ tion study, Schegerin et al. found that early prediction of tumor response using functional imagingdevicessuchasFDG-PETfacilitatedtailoringoftreatmentoptions,whichhadeconomic benefits [42]. Further clinicaltrialsmust be conductedinorderto shedfurtherlight onthis topic. Finally, the European Organization for Research and Treatment of Cancer PET study group recommended improvements in the quality of tumor imaging with FDG-PET. Interinstitu‐ tional bias is another factor in the usefulness of FDG-PET as a prognostic tool. The available data are insufficient to define the optimal time after injection of FDG and the optimal dose of

**4. Early changes in metabolism using molecular-targeted drugs and**

Functional imaging devices may be useful in the assessment of the biological activity of molecular-targeteddrugs [43].These agents arepredominantly cytostatic innature,thatis,they modulate biological behavior and arrest cell cycling rather than totally killing cancer cells [44]. In cases treated with these agents, the traditional endpoints used to evaluate the effects of cytotoxic drugs, such as RECIST criteria, are insufficient and sometimes inappropriate for the prediction of therapeutic outcome. For example, antagonists of the epidermal growth factor receptor(EGFR), such as trastuzumab and cetuximab, block membranous EGFRin cancer cells, haltcellcycling,andinduceapoptosis.Thesedrugsandmanyothersrequiredifferentevaluation criteria to determine their efficacy. FDG-PET may be useful in establishing these criteria.

role of FDG-PET in the early prediction of PD remains to be established.

FDG at which SUV should be measured [41].

**endocrine therapy**

tumor characteristics.

FDG: fluoro-D-glucose; PET: positron emission tomography

**Figure 3.** Treatment strategy options using FDG-PET in conjunction with staging, subtyping, and response-guiding.

#### **3. Limitations of FDG-PET**

Although tumor FDG uptake is an indicator of the viability of cancer cells [31], [32], it is influenced by many biological factors such as stromal cell activity [33], tumor perfusion [34], immune reaction [35], hypoxia [36], [37], and apoptosis. The acute effect of cytotoxic drugs on tumor FDG uptake occurs as a result of high glucose uptake by inflammatory cells and/or energy demand in the process of acute apoptotic death [38], leading to a transient increase in tumor FDG uptake (so-called "flare response") [39], [40]. Therefore, some authors have claimed that the timing of PET scanning soon after the onset of chemotherapy treatment may be crucial. To avoid the flare response, scanning must be delayed for at least 1–2 weeks after the initiation of chemotherapy [41]. PET may be administered immediately before initiation of the second cycle of chemotherapy.

One cause of confusion regarding the results of FDG-PET is the heterogenous results concern‐ ing the pathological criteria of outcome, which distinguishes responders from nonresponders. The overall prognosis of patients remains unconfirmed. In addition, variations in dose and different combinations of drugs add to the confusion. The optimal timing of PET scanning may depend on dose intensity or regimen. If the regimen changes during the course of treatment, the results may be affected because the mechanism of drug sensitivity differs according to tumor characteristics.

and subtyping. This new strategy to optimize treatment timing includes staging, subtyp‐ ing, and response guiding. Staging and subtyping determine favorable treatment options before the initiation of treatment. Functional imaging with FDG-PET offers opportunities to assess tumor response early in the course of treatment. This response-guiding strategy offers the opportunity to revise treatment and improve outcome. FDG-PET not only provides invaluable prognostic information in patients [31] but also supports efforts to switch to more effective treatment options in the early stages of treatment rather than on

262 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

**Figure 3.** Treatment strategy options using FDG-PET in conjunction with staging, subtyping, and response-guiding.

Although tumor FDG uptake is an indicator of the viability of cancer cells [31], [32], it is influenced by many biological factors such as stromal cell activity [33], tumor perfusion [34], immune reaction [35], hypoxia [36], [37], and apoptosis. The acute effect of cytotoxic drugs on tumor FDG uptake occurs as a result of high glucose uptake by inflammatory cells and/or energy demand in the process of acute apoptotic death [38], leading to a transient increase in tumor FDG uptake (so-called "flare response") [39], [40]. Therefore, some authors have claimed that the timing of PET scanning soon after the onset of chemotherapy treatment may be crucial. To avoid the flare response, scanning must be delayed for at least 1–2 weeks after the initiation of chemotherapy [41]. PET may be administered immediately before initiation of the second

One cause of confusion regarding the results of FDG-PET is the heterogenous results concern‐ ing the pathological criteria of outcome, which distinguishes responders from nonresponders. The overall prognosis of patients remains unconfirmed. In addition, variations in dose and

completion of therapy (Figure 3).

FDG: fluoro-D-glucose; PET: positron emission tomography

**3. Limitations of FDG-PET**

cycle of chemotherapy.

The optimal timing of FDG-PET scanning after initiation of chemotherapy for the prediction and elimination of progressive disease (PD) has also not been determined till date. In clinical practice, most physicians are more concerned about tumor progression during neoadjuvant chemotherapy than about achieving pCR. Because chemotherapeutic treatment may increase genomic instability in some tumors, and because chemotherapy resistance may develop in severe cases with hypoxia, neoadjuvant chemotherapy may be contraindicated. However, the role of FDG-PET in the early prediction of PD remains to be established.

The optimal threshold of metabolic change on FDG-PET also remains unclear. A recent draft standard of PERCIST has been advocated as response criteria in solid tumors [7]. It recom‐ mends a ≥30% decrease in SUV as a cutoff value for partial metabolic response, which is associated with clinical outcome after chemotherapy. However, specific response criteria for breast cancer must be defined in order to increase the accuracy of prognosis. Further prospec‐ tive research is needed to determine the optimal cut-off value for predicting tumor response.

Thorough evaluation of cost-effectiveness and prognostic impact of early switching from ineffective neoadjuvant chemotherapy to a more effective regimen is essential. In a simula‐ tion study, Schegerin et al. found that early prediction of tumor response using functional imagingdevicessuchasFDG-PETfacilitatedtailoringoftreatmentoptions,whichhadeconomic benefits [42]. Further clinicaltrialsmust be conductedinorderto shedfurtherlight onthis topic.

Finally, the European Organization for Research and Treatment of Cancer PET study group recommended improvements in the quality of tumor imaging with FDG-PET. Interinstitu‐ tional bias is another factor in the usefulness of FDG-PET as a prognostic tool. The available data are insufficient to define the optimal time after injection of FDG and the optimal dose of FDG at which SUV should be measured [41].

#### **4. Early changes in metabolism using molecular-targeted drugs and endocrine therapy**

Functional imaging devices may be useful in the assessment of the biological activity of molecular-targeteddrugs [43].These agents arepredominantly cytostatic innature,thatis,they modulate biological behavior and arrest cell cycling rather than totally killing cancer cells [44]. In cases treated with these agents, the traditional endpoints used to evaluate the effects of cytotoxic drugs, such as RECIST criteria, are insufficient and sometimes inappropriate for the prediction of therapeutic outcome. For example, antagonists of the epidermal growth factor receptor(EGFR), such as trastuzumab and cetuximab, block membranous EGFRin cancer cells, haltcellcycling,andinduceapoptosis.Thesedrugsandmanyothersrequiredifferentevaluation criteria to determine their efficacy. FDG-PET may be useful in establishing these criteria.

Small molecule drugs to block protein kinases, such as gefitinib, have been used for the inhibition of tumor proliferation and neovascularization. A rapid decrease in FDG uptake at 48 hour was seen in lung cancer xenografts treated with gefitinib. Su et al. also reported a very early decrease at 2 hour in gefitinib-sensitive cancer cells and no change in resistant cancer cells [45]. Other reports stated that a reduction in metabolism within 1 week after the com‐ mencement of therapy was associated with sensitivity to certain drugs, for example, an epidermal growth factor receptor/human epidermal growth factor receptor 2 (HER2) dual kinase inhibitor (lapatinib) used for the treatment of breast cancer, a c-kit inhibitor (imatinib mesylate) used for the treatment of gastrointestinal stromal tumors (GIST), a mammalian target of rapamycin inhibitor (rapamycin) used for the treatment of GIST, and various other drugs used for the treatment of uterine and neuroendocrine carcinomas and sarcomas [44]. Moreover, in the clinical setting, FDG-PET was reported to be useful for the evaluation of treatment response to sunitinib, a multitarget tyrosine kinase inhibitor, in patients with GIST resistant to treatment with imatinib [46].

mentioned earlier, the EORTC PET study group recommends that after baseline FDG-PET scanning and before the initiation of chemotherapy, serial scanning using FDG-PET should be performed 1–2 weeks after the first course [41]. Therefore, the consensus till date has been that a waiting period of 1–2 weeks should be observed after initial drug administration or radio‐ therapy in order to avoid the inflammatory response and accurately evaluate tumor activity. However, metabolic flare does not necessarily indicate treatment failure or cancer progression. Table 2 lists the imaging studies reporting the association between tumor metabolic flare and

Early Prediction of Tumor Response: A Future Strategy for Optimizing Cancer Treatment

Year Treatment Cancer type Origin of cell lines Tracer Modality Animal type

Aliga, et al.<sup>56</sup> 2007 doxorubicin MC4L2, MC7L1 breast FDG PET mice 7 days

Aide, et al.55 2009 cisplatin NCCIT testicular FDG PET rats 2 days

Bjurberg, et al.40 2009 cisplatin HNxSCC24 head and neck FDG PET mice 1 day

Bjurberg, et al.57 2010 cisplatin HNxSCC24 head and neck 2‐NBDG Fluorescene

Mortimer JE, et al.<sup>59</sup> 2001 Tamoxifen Advanced/metastatic breast FDG, FES PET

Dehdashti, et al.<sup>60</sup> 2009 Estradiol Advanced breast FDG, FES PET

**Table 2.** Tumor metabolic flare on very early phase of treatment

that exhibit transient cell cycle arrest.

Furuta, et al.54 1997 radiotherapy NNE,GLS,KYG various FDG PET mice 2 hours <sup>A</sup> flare was observed in

Year Treatment Clinical staging Origin Tracer Modality Outcome

In animal experiments, Furuta et al. reported a flare reaction detected by FDG-PET in nude mice with ependymoblastoma, small cell lung cancer, and glioblastoma at 2 h after irradiation with 10 Gy [54]. They claimed that flare intensity was strongest in the ependymoblastoma, the most radiosensitive of these tumors, whereas the two less radiosensitive tumors showed no increase in FDG uptake during the observation period. In human testicular cancer xenografts in nude rats that received cisplatin, Aide et al. reported that FDG-PET scanning detected a peak FDG uptake on day 2, followed by a marked decrease on day 7 despite the lack of change in tumor volume [55]. They observed a transient S and G2/M cell cycle arrest and a marked increase in apoptosis within this phase. A very early increase in FDG uptake may explain the flare reaction that represents increased tumor metabolism in apoptotic cells as well as in cells

metastasis breast Scintigraphy

26

microscope cell culture 2 days

Time of flare reaction occurred

after 2 cycle (4‐6wk)

7‐10 days

1 day

Time of flare reaction occurred

Comments

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265

placebo

radiosensitive tumors

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A flare was related to a transient cell cycle arrest and apoptosis but did not reveal refractory disease

A flare occurred early after cisplatin treatment in responding tumors

A flare response of bone metastasis after 2 cycle resulted in improvement on follow‐up scan

Responders had increase in SUV for FDG (28.4±23.3) while non‐responders had reduce in SUV (‐10.2±16.2) p = 0.0002

Responders had increase in SUV for FDG (20.9±24.2) while non‐responders had reduce in SUV (‐4.3±11.0) p

< 0.0001

A flare reaction was observed 7 days after treatment of doxorubicin, methotrexate, letrozole, or

tumor response to treatment.

Schneider JA, et al.58 1994 Paclitaxel metastatic, bone

Animal experiments

Clinical studies

Table 2. Summary of imaging studies representing tumor metabolic flare after therapy

Endocrine therapy is one of the most common treatment strategies in patients with estrogen receptor (ER)-positive breast cancer. Successful cytostatic drugs include ER antagonists such as tamoxifen, which induce the deprivation of estrogen production, aromatase inhibitors, ER downregulators, or fulvestrant. In 2011, we reported that changes in SUV at approximately 2 weeks after treatment with letrozole, an aromatase inhibitor, was correlated with a drop in proliferative rate of cancer cells measured by immunohistochemical staining of Ki67 [47]. With a tentative threshold value of a 40% decrease in SUV, Ki67 index values were significantly decreased in metabolic responders. The Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) randomized trial revealed that 2 weeks of treatment with the aromatase inhibitor anastrozole suppressed the Ki67 index (as compared with a percentage of baseline expression) to a significantly greater extent than did tamoxifen alone or tamoxifen in combination with anastrozole. The affiliated study showed that after 2 weeks of endocrine therapy, Ki67 index values predicted recurrence-free survival in individual patients [48]. A positive correlation between the Ki67 index and tumor SUV has been reported in some studies [32, 49], [50]. Mortazavi-Jehanno et al. investigated the predictive value of metabolic response in patients with metastatic breast cancer after 8 weeks of endocrine therapy, demonstrating that progression-free survival is related to metabolic response [51]. These observations suggest that changes in tumor SUV after endocrine therapy may be associated with favorable prognosis. Therefore, the biological basis of changes in FDG uptake using cytostatic drugs may be associated more with intracellular pathways of metabolism and cell cycling than with cytotoxic agents.

#### **4.1. Tumor metabolic flare**

Tumor flare reaction denotes a sudden and temporary worsening of tumor-related symptoms after the initiation of treatment [52]. Several studies reported that radiotherapy and some types of chemotherapeutic agents induce diffusely elevated FDG accumulation because of inflam‐ mation. Weber suggested a careful inspection of the degree and pattern of FDG uptake to distinguish between radiation-induced inflammation and residual cancer activity [53]. As

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**Formatted:** Font: (Default) Times New

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mentioned earlier, the EORTC PET study group recommends that after baseline FDG-PET scanning and before the initiation of chemotherapy, serial scanning using FDG-PET should be performed 1–2 weeks after the first course [41]. Therefore, the consensus till date has been that a waiting period of 1–2 weeks should be observed after initial drug administration or radio‐ therapy in order to avoid the inflammatory response and accurately evaluate tumor activity. However, metabolic flare does not necessarily indicate treatment failure or cancer progression. Table 2 lists the imaging studies reporting the association between tumor metabolic flare and tumor response to treatment.


**Table 2.** Tumor metabolic flare on very early phase of treatment

Table 2. Summary of imaging studies representing tumor metabolic flare after therapy

Small molecule drugs to block protein kinases, such as gefitinib, have been used for the inhibition of tumor proliferation and neovascularization. A rapid decrease in FDG uptake at 48 hour was seen in lung cancer xenografts treated with gefitinib. Su et al. also reported a very early decrease at 2 hour in gefitinib-sensitive cancer cells and no change in resistant cancer cells [45]. Other reports stated that a reduction in metabolism within 1 week after the com‐ mencement of therapy was associated with sensitivity to certain drugs, for example, an epidermal growth factor receptor/human epidermal growth factor receptor 2 (HER2) dual kinase inhibitor (lapatinib) used for the treatment of breast cancer, a c-kit inhibitor (imatinib mesylate) used for the treatment of gastrointestinal stromal tumors (GIST), a mammalian target of rapamycin inhibitor (rapamycin) used for the treatment of GIST, and various other drugs used for the treatment of uterine and neuroendocrine carcinomas and sarcomas [44]. Moreover, in the clinical setting, FDG-PET was reported to be useful for the evaluation of treatment response to sunitinib, a multitarget tyrosine kinase inhibitor, in patients with GIST

264 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Endocrine therapy is one of the most common treatment strategies in patients with estrogen receptor (ER)-positive breast cancer. Successful cytostatic drugs include ER antagonists such as tamoxifen, which induce the deprivation of estrogen production, aromatase inhibitors, ER downregulators, or fulvestrant. In 2011, we reported that changes in SUV at approximately 2 weeks after treatment with letrozole, an aromatase inhibitor, was correlated with a drop in proliferative rate of cancer cells measured by immunohistochemical staining of Ki67 [47]. With a tentative threshold value of a 40% decrease in SUV, Ki67 index values were significantly decreased in metabolic responders. The Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) randomized trial revealed that 2 weeks of treatment with the aromatase inhibitor anastrozole suppressed the Ki67 index (as compared with a percentage of baseline expression) to a significantly greater extent than did tamoxifen alone or tamoxifen in combination with anastrozole. The affiliated study showed that after 2 weeks of endocrine therapy, Ki67 index values predicted recurrence-free survival in individual patients [48]. A positive correlation between the Ki67 index and tumor SUV has been reported in some studies [32, 49], [50]. Mortazavi-Jehanno et al. investigated the predictive value of metabolic response in patients with metastatic breast cancer after 8 weeks of endocrine therapy, demonstrating that progression-free survival is related to metabolic response [51]. These observations suggest that changes in tumor SUV after endocrine therapy may be associated with favorable prognosis. Therefore, the biological basis of changes in FDG uptake using cytostatic drugs may be associated more with intracellular pathways of metabolism and cell

Tumor flare reaction denotes a sudden and temporary worsening of tumor-related symptoms after the initiation of treatment [52]. Several studies reported that radiotherapy and some types of chemotherapeutic agents induce diffusely elevated FDG accumulation because of inflam‐ mation. Weber suggested a careful inspection of the degree and pattern of FDG uptake to distinguish between radiation-induced inflammation and residual cancer activity [53]. As

resistant to treatment with imatinib [46].

cycling than with cytotoxic agents.

**4.1. Tumor metabolic flare**

26 In animal experiments, Furuta et al. reported a flare reaction detected by FDG-PET in nude mice with ependymoblastoma, small cell lung cancer, and glioblastoma at 2 h after irradiation with 10 Gy [54]. They claimed that flare intensity was strongest in the ependymoblastoma, the most radiosensitive of these tumors, whereas the two less radiosensitive tumors showed no increase in FDG uptake during the observation period. In human testicular cancer xenografts in nude rats that received cisplatin, Aide et al. reported that FDG-PET scanning detected a peak FDG uptake on day 2, followed by a marked decrease on day 7 despite the lack of change in tumor volume [55]. They observed a transient S and G2/M cell cycle arrest and a marked increase in apoptosis within this phase. A very early increase in FDG uptake may explain the flare reaction that represents increased tumor metabolism in apoptotic cells as well as in cells that exhibit transient cell cycle arrest.

Aliga et al. reported a similar result mice after the administration of doxorubicin to decrease tumor burden in BALB/c mice with breast cancer [56]. They observed a rapid decrease in tumor FDG uptake 24 hour after chemotherapy and a transient accumulation in FDG uptake on day 7. They suggested that a partial agonistic effect of chemotherapy, apoptosis, cell repair mechanisms, or intratumoral inflammation may be responsible for this flare reaction.

tumor microenvironment and promote apoptosis. In addition, tumor cells may be replaced by fibrotic cells, shrinking the tumor several weeks after the initiation of chemotherapy. FDG uptake in the tumor then decreases because of volume reduction (volume reduction phase). In this last phase, morphological changes can be identified by CT or magnetic resonance imaging. Therefore, metabolic flare precedes decreased uptake of FDG. This is not necessarily a confounding factor; rather, it provides an insight into pharmacodynamics [62]. Further understanding of cancer metabolic flare in the early phase after chemotherapy can aid in

Early Prediction of Tumor Response: A Future Strategy for Optimizing Cancer Treatment

http://dx.doi.org/10.5772/57120

267

**Figure 4.** Tumor FDG uptake in response to chemotherapy hypothetically occurs in three biological phases. In the first phase, FDG accumulation occurs because of cellular damage, inflammation, and vascular reaction. In the second

Of late, cancer treatment is frequently optimized on the basis of tumor subtype and stage. Breast cancer is characterized by ER and HER2 status in addition to tumor size and distant metastatic involvement. The advent of commercialized kits containing multiple molecular biomarker assays has shifted the focus in tumor categorization from pathology to molecular analysis. However, rapid development and wide availability of a broad range of new drugs has exceeded the discovery of tumor subtyping methods or the establishment of biomarkers predictive of chemosensitivity. Therefore, a new paradigm that involves response-guided strategies during initial treatment, which can aid in decision-making about the next treatment option, is emerging for cancer treatment. Early response assessment using FDG-PET may eventually be applicable for planning and evaluating future treatment strategies. In future, patients could be allocated to standard or investigational chemotherapy regimens on the basis of metabolic response. Furthermore, in phase 1/2 studies determining the optimal dose of a

phase, apoptosis results in decreasing cellularity. In the third phase, the tumor decreases in size.

strategic planning of successful therapy.

FDG: fluoro-D-glucose

**5. Summary**

Using the fluorescent glucose analog 2-NBDG, Bjurberg et al. reported a very early increase in metabolism in three squamous cell carcinoma cell lines (LU-HNxSCC-7, LU-HNxSCC-24, and LU-CX-2) after exposure to cisplatin [40] [57]. The flare reaction was observed within 3 days after exposure in these cells, whereas FDG uptake in nonmalignant fibroblastic cells was low.

Contrary to recent animal studies revealing a flare phenomenon-associated tumor response, only a few clinical studies have utilized FDG-PET in detecting tumor flare. As early as 1996, Schneiders et al. reported the use of scintigraphy to detect a flare reaction in bone lesions in patients with metastatic disease; the flare reaction occurred despite a favorable overall outcome [58]. This phenomenon may represent enhanced osteoblastic activity, rapid bone repair, and improved blood flow around the responding lesions. Welch et al. conducted an FDG-PET study in which a paradoxical flare phenomenon was detected within 7 to 10 days after the initiation of tamoxifen in patients with breast cancer [59]. An increase in FDG uptake was observed in responding tumors during week 1 after tamoxifen initiation ; however, this was not observed in nonresponding tumors. The transient increase in FDG uptake could reflect hormone receptor-related changes in tumor metabolism, which was predictive of a favorable outcome. Partial agonist–antagonist activity in selective ER modulators such as tamoxifen is known to differ over the treatment course after tissue exposure. The slow onset of action of tamoxifen and the fact that its effects as an estrogen agonist peak 1–2 weeks after the onset of therapy may contribute to the development of the flare reaction. The same group of investi‐ gators conducted a clinical study including an estradiol challenge test to predict hormone sensitivity in women with locally advanced or metastatic ER-positive breast cancer. FDG-PET after 30 mg estradiol induced a metabolic flare, showing greater responsiveness to endocrine therapy and better overall survival in flare patients than in non-flare patients [60].

Results of those animal studies lead to the speculation that tumor metabolic flare is related to the following sequence of events: transient cell cycle arrest, apoptosis, induction of the cancer immune system, and hemodynamic reaction. As for estrogen-positive breast cancer and endocrine therapy, estrogen stimulation may be closely associated with an increase in glucose uptake [61]. At lease, this does not necessarily indicate refractory disease.

Taken together, the underlying presumption in these studies is that changes in FDG uptake in response to chemotherapy occur in three phases (Figure 4). In the first phase, cellular damage followed by inflammation and vascular changes occurs within hours or days, resulting in accumulation of FDG and increased uptake in cancer cells and inflammatory cells such as neutrophils (inflammatory phase). In this phase, pro-inflammatory cytokines may be released because of the tumor's response to chemotherapy, and these cytokines accelerate tumor cell proliferation, activate the immune system, and increase blood flow, resulting in accumulation of tumor FDG. Second, apoptosis, cell cycle arrest, and diminishing inflammation, which occur within days or weeks, lead to a decrease in FDG uptake in cancer cells (apoptotic phase). Decreased blood flow due to vascular damage caused by chemotherapy may deteriorate the tumor microenvironment and promote apoptosis. In addition, tumor cells may be replaced by fibrotic cells, shrinking the tumor several weeks after the initiation of chemotherapy. FDG uptake in the tumor then decreases because of volume reduction (volume reduction phase). In this last phase, morphological changes can be identified by CT or magnetic resonance imaging. Therefore, metabolic flare precedes decreased uptake of FDG. This is not necessarily a confounding factor; rather, it provides an insight into pharmacodynamics [62]. Further understanding of cancer metabolic flare in the early phase after chemotherapy can aid in strategic planning of successful therapy.

#### FDG: fluoro-D-glucose

Aliga et al. reported a similar result mice after the administration of doxorubicin to decrease tumor burden in BALB/c mice with breast cancer [56]. They observed a rapid decrease in tumor FDG uptake 24 hour after chemotherapy and a transient accumulation in FDG uptake on day 7. They suggested that a partial agonistic effect of chemotherapy, apoptosis, cell repair

Using the fluorescent glucose analog 2-NBDG, Bjurberg et al. reported a very early increase in metabolism in three squamous cell carcinoma cell lines (LU-HNxSCC-7, LU-HNxSCC-24, and LU-CX-2) after exposure to cisplatin [40] [57]. The flare reaction was observed within 3 days after exposure in these cells, whereas FDG uptake in nonmalignant fibroblastic cells was low. Contrary to recent animal studies revealing a flare phenomenon-associated tumor response, only a few clinical studies have utilized FDG-PET in detecting tumor flare. As early as 1996, Schneiders et al. reported the use of scintigraphy to detect a flare reaction in bone lesions in patients with metastatic disease; the flare reaction occurred despite a favorable overall outcome [58]. This phenomenon may represent enhanced osteoblastic activity, rapid bone repair, and improved blood flow around the responding lesions. Welch et al. conducted an FDG-PET study in which a paradoxical flare phenomenon was detected within 7 to 10 days after the initiation of tamoxifen in patients with breast cancer [59]. An increase in FDG uptake was observed in responding tumors during week 1 after tamoxifen initiation ; however, this was not observed in nonresponding tumors. The transient increase in FDG uptake could reflect hormone receptor-related changes in tumor metabolism, which was predictive of a favorable outcome. Partial agonist–antagonist activity in selective ER modulators such as tamoxifen is known to differ over the treatment course after tissue exposure. The slow onset of action of tamoxifen and the fact that its effects as an estrogen agonist peak 1–2 weeks after the onset of therapy may contribute to the development of the flare reaction. The same group of investi‐ gators conducted a clinical study including an estradiol challenge test to predict hormone sensitivity in women with locally advanced or metastatic ER-positive breast cancer. FDG-PET after 30 mg estradiol induced a metabolic flare, showing greater responsiveness to endocrine

mechanisms, or intratumoral inflammation may be responsible for this flare reaction.

266 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

therapy and better overall survival in flare patients than in non-flare patients [60].

uptake [61]. At lease, this does not necessarily indicate refractory disease.

Results of those animal studies lead to the speculation that tumor metabolic flare is related to the following sequence of events: transient cell cycle arrest, apoptosis, induction of the cancer immune system, and hemodynamic reaction. As for estrogen-positive breast cancer and endocrine therapy, estrogen stimulation may be closely associated with an increase in glucose

Taken together, the underlying presumption in these studies is that changes in FDG uptake in response to chemotherapy occur in three phases (Figure 4). In the first phase, cellular damage followed by inflammation and vascular changes occurs within hours or days, resulting in accumulation of FDG and increased uptake in cancer cells and inflammatory cells such as neutrophils (inflammatory phase). In this phase, pro-inflammatory cytokines may be released because of the tumor's response to chemotherapy, and these cytokines accelerate tumor cell proliferation, activate the immune system, and increase blood flow, resulting in accumulation of tumor FDG. Second, apoptosis, cell cycle arrest, and diminishing inflammation, which occur within days or weeks, lead to a decrease in FDG uptake in cancer cells (apoptotic phase). Decreased blood flow due to vascular damage caused by chemotherapy may deteriorate the **Figure 4.** Tumor FDG uptake in response to chemotherapy hypothetically occurs in three biological phases. In the first phase, FDG accumulation occurs because of cellular damage, inflammation, and vascular reaction. In the second phase, apoptosis results in decreasing cellularity. In the third phase, the tumor decreases in size.

#### **5. Summary**

Of late, cancer treatment is frequently optimized on the basis of tumor subtype and stage. Breast cancer is characterized by ER and HER2 status in addition to tumor size and distant metastatic involvement. The advent of commercialized kits containing multiple molecular biomarker assays has shifted the focus in tumor categorization from pathology to molecular analysis. However, rapid development and wide availability of a broad range of new drugs has exceeded the discovery of tumor subtyping methods or the establishment of biomarkers predictive of chemosensitivity. Therefore, a new paradigm that involves response-guided strategies during initial treatment, which can aid in decision-making about the next treatment option, is emerging for cancer treatment. Early response assessment using FDG-PET may eventually be applicable for planning and evaluating future treatment strategies. In future, patients could be allocated to standard or investigational chemotherapy regimens on the basis of metabolic response. Furthermore, in phase 1/2 studies determining the optimal dose of a new drug, nonresponsive patients can be eliminated on the basis of metabolic response. Glucose metabolism analysis using FDG-PET will be one of several critical factors for evalu‐ ating tumor response to chemotherapy. Integration of multiple functional imaging systems may also be useful in predicting early tumor response to chemotherapy.

the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer

Early Prediction of Tumor Response: A Future Strategy for Optimizing Cancer Treatment

http://dx.doi.org/10.5772/57120

269

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Finally, considering the phenomenon of tumor metabolic flare, clinical trials must be conduct‐ ed to determine the best timing for the administration of FDG-PET. This information would be useful to predict tumor response in the very early stages of treatment.

#### **Acknowledgements**

We dedicate this review article to the late Dr. Yoshiaki ABE for helpful cooperation with a series of PET studies. We are very grateful to Dr. Hitoshi TSUDA of the National Cancer Institute for his helpful advice and to Dr. Jiro ISHIDA and Dr. Katsumi TAMURA from the Tokorozawa PET Diagnostic Imaging Center for the clinical reading of FDG-PET images.

#### **Author details**

Shigeto Ueda\* and Toshiaki Saeki

Department of Breast Oncology, Saitama Medical University, International Medical Center, Saitam, Japan

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268 Positron Emission Tomography - Recent Developments in Instrumentation, Research and Clinical Oncological Practice

Finally, considering the phenomenon of tumor metabolic flare, clinical trials must be conduct‐ ed to determine the best timing for the administration of FDG-PET. This information would

We dedicate this review article to the late Dr. Yoshiaki ABE for helpful cooperation with a series of PET studies. We are very grateful to Dr. Hitoshi TSUDA of the National Cancer Institute for his helpful advice and to Dr. Jiro ISHIDA and Dr. Katsumi TAMURA from the Tokorozawa PET Diagnostic Imaging Center for the clinical reading of FDG-PET images.

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*Edited by Sandro Misciagna*

Positron Emission Tomography is a nuclear medicine technique first used to study the brain. Several decades ago, PET scanners design and performance have improved considerably: number of detectors has increased from 20 to 20,0000, axial field of view from 2 to 20 cm, spatial resolution has improved from 25 to 5 mm, sensitivity has increased of about 1000 fold. At the same time, clinical applications have grown dramatically. In the first section of this book the authors review some of developments in PET instrumentation, with emphasis on data acquisition, processing and image formation. In the second section authors expose examples of applications in human research. In the last section authors describe applications in assessment and prediction of oncological treatment response.

Positron Emission Tomography - Recent Developments in Instrumentation,

Research and Clinical Oncological Practice

Positron Emission

Tomography

Recent Developments in Instrumentation,

Research and Clinical Oncological Practice

*Edited by Sandro Misciagna*

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