**3.4 Measurement of dopamine transporter binding**

The presynaptic dopamine transporter (DAT) is found in dendrites and axons of dopaminergic neurons and is responsible for uptake of dopamine. Therefore, measurement

Diagnosis of Dementia Using Nuclear Medicine Imaging Modalities 219

colleagues have also demonstrated that [123I]ioflupane SPECT can distinguish between PD and other Parkinsonian disorders that do not have associated degeneration of the nigrostriatal pathway, such as ET (Castrejón, et al., 2005). Despite these positive findings, it is important to note that an abnormal [123I]ioflupane SPECT scan does not necessarily indicate a diagnosis of PD. Similarly, a normal scan is not entirely indicative of ET (Hauser and Grosset, 2011). In each case, multiple other conditions must be considered and eliminated. For example, abnormal striatal uptake of [123I]ioflupane would be expected in all degenerative Parkinsonian syndromes associated with a loss of nigrostriatal dopamine neurons including PD, progressive supranuclear palsy (PSP), multisystem atrophy (MSA), and corticobasal degeneration (CBD). [123I]Ioflupane SPECT cannot differentiate these related disorders and so, in such cases, it might be necessary to run other tests (FDG PET,

As discussed above in the context of AD, microglial activation is the body's natural response to brain injury and associated neuroinflammation. Reflecting this, [11C]PK11195 and [11C]PBR28 have been developed to image microglial activation, and recent studies have explored the use of [11C]PK11195 PET in PD patients. Such studies report significant increases in [11C]PK11195 uptake in striatal and extrastriatal regions of PD patients when compared to healthy control subjects (Gerhard, et al., 2006; Ouchi, et al., 2005; Pavese and Brooks, 2009). These findings, which have been correlated with reduced striatal DAT binding (Ouchi, et al., 2005), suggest that significant microglial activation (and associated neuroinflammation) could contribute to dopaminergic neuron loss in PD. This represents an

Dementia with Lewy bodies (DLB) is a common Parkinsonian neurodegenerative dementia that is characterized by the development of α-synuclein positive Lewy body neuronal inclusions in the cortex, substantia nigra and brainstem. Patients with DLB, suffer from progressive cognitive decline including memory loss, visual hallucinations, cognitive circadian fluctuations and sleep disorders. In FDG PET of DLB patients, unique hypometabolism in the medial and lateral occipital lobes is observed, and is the feature that distinguishes DLB from AD (Ishii, 2002). DLB can also be distinguished from AD using [18F]DOPA PET. Dopamine deficiencies, similar to PD, have been observed in DLB patients,

Frontotemporal lobe degeneration (FTLD) is a cause of degenerative dementias that recent research suggests, in individuals younger than 65, is as common as AD. Frontotemporal dementia (FTD) is the most common example of such diseases, for which clinical and pathological criteria were proposed in 1994 by Brun and colleagues (Brun, et al., 1994). The disease is characterized by behavioral and personality changes that result from the frontotemporal involvement and include apathy, disinhibition, and often sever impairment of language production. In related conditions, such as semantic dementia and progressive non-fluent aphasia, language impairment can be the major symptom, and dementia the

PiB PET etc.) to further distinguish such diseases.

**3.5 Measurement of neuroinflammation in PD** 

avenue of research that has yet to be extensively explored.

**3.6 Imaging of dementia with Lewy bodies** 

but not in AD patients (Hu, et al., 2000).

**4.1 Introduction** 

**4. Frontotemporal lobe degeneration** 

Fig. 4. (A) Representative images of 18F-AV-133 PET BP in HC and PD patient. (B) Areas of reduction in BP of PD patients, compared with HCs, in SPM analysis. Color bars represent t values. P < 0.05, corrected for multiple comparisons. *(Reprinted with permission from Okamura N, Villemagne VL, Drago J, et al. In vivo measurement of vesicular monoamine transporter type 2 density in Parkinson disease with 18F-AV-133. J Nucl Med. 2010;51:223-228)* 

of the DAT can be used as an indicator of the integrity of nigrostriatal projections. Reflecting this, a number of radiopharmaceuticals have been developed that allow for the analysis of DAT activity by PET and SPECT imaging (see the review by Pavese and Brooks for additional information (Pavese and Brooks, 2009)). These include phenyltropane derivatives such as 123I-ß-CIT (Brucke, et al., 1997; Seibyl, et al., 1995), 123I-FP-CIT ([123I]ioflupane; DaTSCAN) (Castrejón, et al., 2005; Hauser and Grosset, 2011), and [99mTc]trodat (M. P. Kung, et al., 1997), that lead to distinctive images such as those shown in Figure 3. For example, [123I]ioflupane, a radiolabeled analog of cocaine, is approved for clinical use in Europe and the United States, and marketed as DaTSCAN. Nuclear medicine physicians use [123I]ioflupane to diagnose Parkinson's disease (PD), and to differentiate PD from other related neurological disorders that present with similar clinical symptoms (e.g. dementia with Lewy bodies (Antonini, 2007; Castrejón, et al., 2005)). [123I]Ioflupane has a high binding affinity for presynaptic dopamine transporters (DAT). Thus, a SPECT scan conducted using [123I]ioflupane provides physicians with a quantitative measure and the spatial distribution of DAT in the brain. A marked reduction in DAT in the striatal region of the brain is indicative of PD (Figure 3), allowing physicians to diagnose or differentiate a patient's neurological condition with improved diagnostic confidence when compared to diagnosing from clinical symptoms alone.

A review of the two major clinical trials of [123I]ioflupane was recently published by Hauser and Grosset (Hauser and Grosset, 2011). The first study compared baseline scans in patients with early suspected Parkinsonism to the consensus clinical diagnosis established 3 years later (Marshall, et al., 2009). The study found 78-79% positive agreement (abnormal baseline scan and positive diagnosis of PD at 3 yrs, n = 71) and 97% negative agreement (normal baseline scan and negative for PD at 3 yrs, n = 28). The second study was a trial of [123I]ioflupane in patients with established diagnoses of PD or essential tremor (ET), and obtained similar results (Benamer, et al., 2000). This study found 92-97% positive agreement (abnormal baseline scan and positive diagnosis of PD at 3 yrs, n = 158) and 74-96% negative agreement (normal baseline scan and clinical diagnosis of ET, n = 27). Castrejón and

Fig. 4. (A) Representative images of 18F-AV-133 PET BP in HC and PD patient. (B) Areas of reduction in BP of PD patients, compared with HCs, in SPM analysis. Color bars represent t values. P < 0.05, corrected for multiple comparisons. *(Reprinted with permission from Okamura N, Villemagne VL, Drago J, et al. In vivo measurement of vesicular monoamine transporter type 2* 

of the DAT can be used as an indicator of the integrity of nigrostriatal projections. Reflecting this, a number of radiopharmaceuticals have been developed that allow for the analysis of DAT activity by PET and SPECT imaging (see the review by Pavese and Brooks for additional information (Pavese and Brooks, 2009)). These include phenyltropane derivatives such as 123I-ß-CIT (Brucke, et al., 1997; Seibyl, et al., 1995), 123I-FP-CIT ([123I]ioflupane; DaTSCAN) (Castrejón, et al., 2005; Hauser and Grosset, 2011), and [99mTc]trodat (M. P. Kung, et al., 1997), that lead to distinctive images such as those shown in Figure 3. For example, [123I]ioflupane, a radiolabeled analog of cocaine, is approved for clinical use in Europe and the United States, and marketed as DaTSCAN. Nuclear medicine physicians use [123I]ioflupane to diagnose Parkinson's disease (PD), and to differentiate PD from other related neurological disorders that present with similar clinical symptoms (e.g. dementia with Lewy bodies (Antonini, 2007; Castrejón, et al., 2005)). [123I]Ioflupane has a high binding affinity for presynaptic dopamine transporters (DAT). Thus, a SPECT scan conducted using [123I]ioflupane provides physicians with a quantitative measure and the spatial distribution of DAT in the brain. A marked reduction in DAT in the striatal region of the brain is indicative of PD (Figure 3), allowing physicians to diagnose or differentiate a patient's neurological condition with improved diagnostic confidence when compared to diagnosing

A review of the two major clinical trials of [123I]ioflupane was recently published by Hauser and Grosset (Hauser and Grosset, 2011). The first study compared baseline scans in patients with early suspected Parkinsonism to the consensus clinical diagnosis established 3 years later (Marshall, et al., 2009). The study found 78-79% positive agreement (abnormal baseline scan and positive diagnosis of PD at 3 yrs, n = 71) and 97% negative agreement (normal baseline scan and negative for PD at 3 yrs, n = 28). The second study was a trial of [123I]ioflupane in patients with established diagnoses of PD or essential tremor (ET), and obtained similar results (Benamer, et al., 2000). This study found 92-97% positive agreement (abnormal baseline scan and positive diagnosis of PD at 3 yrs, n = 158) and 74-96% negative agreement (normal baseline scan and clinical diagnosis of ET, n = 27). Castrejón and

*density in Parkinson disease with 18F-AV-133. J Nucl Med. 2010;51:223-228)* 

from clinical symptoms alone.

colleagues have also demonstrated that [123I]ioflupane SPECT can distinguish between PD and other Parkinsonian disorders that do not have associated degeneration of the nigrostriatal pathway, such as ET (Castrejón, et al., 2005). Despite these positive findings, it is important to note that an abnormal [123I]ioflupane SPECT scan does not necessarily indicate a diagnosis of PD. Similarly, a normal scan is not entirely indicative of ET (Hauser and Grosset, 2011). In each case, multiple other conditions must be considered and eliminated. For example, abnormal striatal uptake of [123I]ioflupane would be expected in all degenerative Parkinsonian syndromes associated with a loss of nigrostriatal dopamine neurons including PD, progressive supranuclear palsy (PSP), multisystem atrophy (MSA), and corticobasal degeneration (CBD). [123I]Ioflupane SPECT cannot differentiate these related disorders and so, in such cases, it might be necessary to run other tests (FDG PET, PiB PET etc.) to further distinguish such diseases.
