**1. Introduction**

198 12 Chapters on Nuclear Medicine

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Dementia describes the loss of brain function that occurs with certain diseases, and which has the potential to affect memory, thinking, language, judgment, and behavior. Most types of dementia involve irreversible neurodegeneration, and Alzheimer's disease (AD) is the most common form. Beyond AD however, there are many other diseases that can lead to dementia including dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), Parkinson's disease with dementia, corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Dementia can also be the result of many small strokes and, in such cases, is called vascular dementia.

Whilst such clinically and neuropathologically overlapping dementia diseases can be predicted by clinical diagnosis, definitively differentiating them from one another has typically been attempted using high-risk diagnostic procedures (e.g. brain biopsy, Lumbar puncture) or, more commonly, during a *post-mortem* examination. This makes it difficult to a) differentiate dementias and treat each appropriately before patient death; b) manage the diseases early, before the onset of cognitive decline; c) select appropriate patients for assisting in dementia-related drug development; and d) track the impact of new dementia therapeutics in clinical trials. Therefore, new non-invasive diagnostic methods for managing dementia are in high demand and, reflecting this, many radiopharmaceuticals (drugs tagged with a radioactive isotope) have been developed over the last 2 decades that allow noninvasive examination of dementia pathophysiology in living human subjects using nuclear medicine imaging techniques. Such techniques include positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging, and have greatly enhanced diagnostic confidence across the entire dementia disease spectrum in recent years. This chapter reviews radiopharmaceuticals commonly employed clinically in the management of dementia patients, suffering from the diseases outlined above, with nuclear medicine modalities. The chapter is divided by disease entity, and progress in imaging the pathophysiology of each disease is highlighted. In addition to those radiopharmaceuticals with approval for human use discussed herein, there are many experimental radiopharmaceuticals for dementia in pre-clinical development, which have not yet been translated into clinical use. Comprehensive review of such pre-clinical radiopharmaceuticals is outside the scope of this book, and pertinent examples are highlighted only when necessary to indicate key concepts involved in imaging dementia patients. The interested reader can obtain additional information on radiopharmaceuticals currently in development

Diagnosis of Dementia Using Nuclear Medicine Imaging Modalities 201

It is thus apparent that there is a great need to revise the way in which AD is conceptualized. Accurate and definitive diagnoses need to occur *ante-mortem*, in lieu of *postmortem*, and preferably in the early pre-dementia (prodromal) stage. Dubois *et al.*, having moved beyond the NINCDS-ADRDA criteria for probable AD, introduced new standards for diagnosis (Dubois, et al., 2007). They include early and significant episodic memory impairment and at least one abnormal *in vivo* biomarker- particularly, medial temporal lobe atrophy, abnormal CSF biomarkers (increased total tau concentrations, increased phosphotau concentrations, low Aß1-42 concentrations, or a combination of all three), brain Aβ load, temporoparietal hypometabolism on [18F]FDG-PET, and/or specific binding pattern with particular PET ligands. Learning more about AD biomarkers, and how they fit into the accepted paradigm for this disease, will allow for decreased dependence on unreliable clinical diagnostic criteria. Non-invasive PET imaging can be particularly useful in this context. Probes are being developed that target specific AD biomarkers, allowing us to monitor AD pathophysiology *in vivo*. The main strategies for exploration of AD pathophysiology using PET imaging have been reviewed (Jagust, 2004; Nordberg, 2004,

[18F]Fluoro-2-deoxy-D-glucose ([18F]FDG) is the most commonly used radiopharmaceutical for clinical PET imaging to date. Patients receive an injection of [18F]FDG, and then images are typically obtained 30 – 60 min later. As a radiolabeled analog of glucose, [18F]FDG is typically employed as a marker of cell proliferation as it preferentially accumulates in cells with increased glucose consumption (e.g. tumors). Therefore, [18F]FDG finds widespread application in oncology including diagnosis and staging of cancers, and monitoring tumor response to chemotherapy. However, glucose is also the main energy supply for the brain and, reflecting this, levels are closely coupled to neuronal function so that measurement of cerebral glucose metabolism can provide diagnostically relevant information about the neurodegenerative disorders described above. According to Herholz and colleagues (Herholz, et al., 2007), typical resting state cerebral metabolic rate for glucose is 40-60 µmol glucose/100 g/min for grey matter, and 15 µmol glucose/100 g/min for white matter, although this does drop off somewhat with age (Kuhl, et al., 1982). Observed regional differences include higher values in the striatum and parietal cortex. Other phylogenetically older brain structures (e.g. medial temporal cortex and cerebellum) have glucose

For at least two decades, significant efforts have been made to image patients at various stages of Alzheimer's disease (including high risk, asymptomatic patients; patients with mild cognitive impairment (MCI); and patients with fully developed Alzheimer's disease) with [18F]FDG (e.g. Figure 1). In patients considered high risk for developing AD (for example because of family history and possession of the ApoE ε4 allele (Reiman, et al., 1996; Small, et al., 1995)), impairment of regional cerebral glucose metabolism has been observed decades before likely onset of dementia and certainly while the patients are still

In 1997, Kuhl and colleagues reported the first example of using posterior cingulate glucose metabolism, determined from [18F]FDG PET scans, to predict progression of disease in patients with MCI (Minoshima, et al., 1997). The results have been echoed by a number of subsequent longitudinal studies, which have confirmed the high predictive power of

2008), and are outlined in the following sections.

**2.2 Imaging Alzheimer's disease with [18F]FDG** 

metabolism rates between grey matter and white matter.

asymptomatic (Reiman, et al., 2004).

for dementia from many excellent and comprehensive review articles available in the literature (Brücke, et al., 2000; Herholz, 2003, 2011; Herholz, et al., 2007; Ishii, 2002; Jagust, 2004; Kadir and Nordberg, 2010; Nordberg, 2004, 2008; Pavese and Brooks, 2009; Sioka, et al., 2010; Vitali, et al., 2008).
