PET Molecular Imaging in Atypical Parkinsonism

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PET Molecular Imaging in Atypical Parkinsonism Zheyu Xu*,†, Javier Arbizu‡, Nicola Pavese*,§,1 *Newcastle University Newcastle Magnetic Resonance Centre & Positron Emission Tomography Centre, Newcastle University Campus for Ageing & Vitality, Newcastle upon Tyne, United Kingdom † Department of Neurology, National Neuroscience Institute, Singapore ‡ Department of Nuclear Medicine, Clinica Universidad de Navarra, University of Navarra, Pamplona, Spain § Department of Clinical Medicine—Positron Emission Tomography Centre, Aarhus University, Aarhus, Denmark 1 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. Multiple System Atrophy 2.1 Dopaminergic Imaging 2.2 Glucose Metabolism 2.3 Cholinergic Imaging 2.4 Sympathetic Imaging 2.5 Serotonergic Imaging 2.6 Other Systems 2.7 Microglial Activation Imaging 2.8 Tau and Alpha-Synuclein Imaging 3. Progressive Supranuclear Palsy 3.1 Dopaminergic Imaging 3.2 Glucose Metabolism 3.3 Cholinergic Imaging 3.4 Other Systems 3.5 Microglial Activation Imaging 3.6 Tau and Amyloid PET Imaging 4. Corticobasal Degeneration 4.1 Dopaminergic Imaging 4.2 Glucose Metabolism 4.3 Other Systems 4.4 Microglial Activation Imaging 4.5 Tau and Amyloid Imaging References

International Review of Neurobiology ISSN 0074-7742 https://doi.org/10.1016/bs.irn.2018.09.001

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Abstract Multiple System Atrophy, Progressive Supranuclear Palsy, and Corticobasal Degeneration are three neurodegenerative disorders characterized by parkinsonism along with involvement of other brain cortical and subcortical regions. The ante mortem diagnosis of these disorders is extremely challenging with up to a quarter of these patients being misdiagnosed, particularly in the early stages of disease. While highly specific and sensitive imaging biomarkers of individual atypical parkinsonisms have not been identified yet, molecular PET and SPECT imaging have improved our knowledge of the physiopathology and neuropathology of these disorders and are often used as supportive criteria for the differential diagnosis of these conditions. This chapter will provide a state-of-the-art overview of the use of PET in atypical parkinsonisms.

1. INTRODUCTION Atypical parkinsonisms include Multiple System Atrophy, Progressive Supranuclear Palsy, and Corticobasal Degeneration. These conditions have heterogeneous clinical phenotypes with considerable clinical overlap not only among one another but also with idiopathic Parkinson’s disease and other neurodegenerative disorders, making the ante mortem diagnosis of these disorders extremely challenging with up to 24% of these patients being misdiagnosed (Meijer et al., 2012). Molecular imaging technologies such as Positron Emission Tomography (PET) and Single-Photon Emission Computed Tomography (SPECT), together with the development of new promising radioligands, have provided a powerful tool to investigate in vivo neurotransmitter systems and explore the neuropathological changes occurring in patients with these neurodegenerative disorders. In PET, positron-emitting radionuclides such as 18F fluorine and 11C carbon are generated in a cyclotron and labeled to physiological substrates before introduction into the body. High energy photons are detected by a PET scanner, and the images subsequently processed to allow temporal changes in the regional distribution, accumulation, and clearance of the positron-emitting activity to be identified. As the half-life of these PET radionuclides is extremely short (2–110 min) in contrast to SPECT radioligands, an adjacent cyclotron or commercial producer laboratory is necessary to generate the positron-emitting radionuclides. Hence, access to PET imaging is more limited compared to SPECT. However, PET imaging has superior sensitivity compared with SPECT imaging and has higher spatial

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resolution and more radiotracers directly related to the pathophysiology of the disease. Both PET and SPECT can be used to detect and quantify dopaminergic nigrostriatal dysfunction in Parkinson’s disease and atypical parkinsonisms. This can be achieved by measuring (1) striatal aromatic amino acid decarboxylase activity with [18F]DOPA-PET; (2) availability of presynaptic dopamine transporter (DAT) with PET tracer such as [11C]CFT, [18F]CFT, [11C]PE2I, [11C]RTI-32, and [18F]PE2I or with SPECT tracers such as [123I]β-CIT, [123I]FP-CIT, [123I]altropane, and [99mTc]TRODAT-1; and (3) availability of vesicular monoamine transporter with [11C]dihydrotetrabenazine (DTBZ) and [18F]FP-DTBZ PET. All these three strategies are very sensitive for detecting presynaptic nigrostriatal degeneration and are useful in clinical practice to distinguish parkinsonian disorders from healthy controls and other conditions where presynaptic dopaminergic function is preserved, such as essential tremor and drug-induced parkinsonism. However, they cannot differentiate between Parkinson’s disease and the different Parkinsonian disorders given that overlapping patterns of dopamine deficiency are seen in patients with these conditions. [18F]fluro-2-deoxy-D-glucose ([18F]FDG) PET is the most widely used ligand. The accumulation of this ligand reflects the metabolic rate and is useful in the imaging of regional glucose consumption in the brain. Decreases in glucose metabolism reflect disease-related changes in neuronal activity. Several studies have been performed to investigate the utility of [18F] FDG-PET in the differential diagnosis of Parkinsonism, including atypical parkinsonism. A recent meta-analysis has reported that [18F]FDG-PET has a sensitivity of 91.4% and specificity of 90.6% for diagnosis of atypical parkinsonian syndromes when using observer-dependent visual reads supported by voxel statistical analyses, and 76.5% sensitivity and 94.7% specificity when automated classification methods are used (Meyer, Frings, Rucker, & Hellwig, 2017). [18F]FDG-PET has also been shown to be useful in predicting survival in patients with atypical parkinsonisms, with the presence of cortical or subcortical hypometabolism at baseline predicting a poorer prognosis (Hellwig et al., 2015). However, inherent limitations to [18F]FDG-PET imaging technology remain the lack of standardization in relation to the large variety across centers in acquisition protocols, choice of reference regions used to standardize regional uptake values, and commercial software used for images analysis. Other neurotransmitter and receptor systems have also been explored using molecular imaging techniques. The cholinergic system has been

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studied using [11C]PMP PET, [11C]MP4A PET, [11C]NMPB-PET, [11C] NMP4A-PET, and [123 I]IBVM SPECT. The sympathetic system has been studied using [123I]MIBG-SPECT and [11C]HED-PET. The serotonergic system has been studied using [18F]DOPA-PET, [123I]beta-CIT, and [123I]FP-CIT binding in the midbrain. Opioid receptor binding has been studied using [11C]diprenorphine-PET and GABA-A receptor binding with [11C]flumazenil-PET. Microglial activation has been studied using [11C] (R)-PK11195 PET. More recently, [18F]AV-1541, [11C]PBB3, and [18F] THK5351 have been developed to measure tau binding and [11C]BF-227 for alpha-synuclein binding. The following sections will provide a state-of-the-art overview of the use of PET in individual atypical parkinsonisms.

2. MULTIPLE SYSTEM ATROPHY Multiple System Atrophy is a progressive neurodegenerative disorder characterized by the presence of variable combinations of autonomic failure, parkinsonism (generally levodopa-unresponsive), cerebellar ataxia, and cortical spinal tract dysfunction (Gilman et al., 2008). Autonomic failure, which typically manifests as urinary incontinence or orthostatic hypotension, is a necessary feature for the clinical diagnosis of Multiple System Atrophy. REM sleep behavior disorder can occur as a prodromal symptom of Multiple System Atrophy. Based on the predominant motor symptom, Multiple System Atrophy is classified into two clinical subtypes: Multiple System Atrophy with predominant cerebellar ataxia (MSA-C) and Multiple System Atrophy with predominant parkinsonism (MSA-P). However, rare forms of Multiple System Atrophy, termed atypical Multiple System Atrophy, are now recognized and expand the clinical phenotype of Multiple System Atrophy. These variants include patients presenting ante mortem with clinical features more suggestive of Frontotemporal Dementia such as Corticobasal Syndrome, Progressive Non-fluent Aphasia, and Behavioral variant Frontotemporal Dementia (Aoki et al., 2015; Rohan et al., 2015). In contrast to the other alpha-synucleinopathies, Multiple System Atrophy has largely been thought not to be associated with significant cognitive impairment. However, this belief has recently been challenged and cognitive decline is currently thought to be an under-recognized feature of the disorder which has not been fully investigated (Stankovic et al., 2014). The pathological hallmark of Multiple System Atrophy is the presence of glial cytoplasmic inclusions in the oligodendrocytes, which contain

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alpha-synuclein (Wenning, Tison, Ben Shlomo, Daniel, & Quinn, 1997). Neuronal loss occurs in the striatal, nigral, and olivo-ponto-cerebellar systems. The ante mortem diagnosis of Multiple System Atrophy is clinically challenging. In a large series of patients with a diagnosis of Multiple System Atrophy made clinically, only 62% had an eventual diagnosis of Multiple System Atrophy on autopsy (Koga et al., 2015). Multiple System Atrophy is often misdiagnosed as Dementia with Lewy Bodies, Parkinson’s disease, and Progressive Supranuclear Palsy, particularly in the early stages of the disease. Currently, three levels of diagnostic certainty—possible, probable, and definite—have been proposed for Multiple System Atrophy, and abnormalities in structural and functional imaging are indicated as features supporting (red flags) a diagnosis of possible Multiple System Atrophy (Gilman et al., 2008).

2.1 Dopaminergic Imaging Early imaging studies using [18F]DOPA PET to investigate presynaptic striatal deficits have shown bilateral reductions in radioligand uptake in the putamen and caudate in Multiple System Atrophy patients (Brooks et al., 1990). Considerable overlap exists in individual putaminal [18F] DOPA PET uptake between Multiple System Atrophy and Parkinson’s disease patients, hence [18F]DOPA PET cannot be used in the clinical setting to differentiate between Multiple System Atrophy and Parkinson’s disease (Burn, Sawle, & Brooks, 1994) (see Fig. 1). These findings have been

Fig. 1 [18F]DOPA PET imaging in healthy controls, early Parkinson’s disease, and Multiple System Atrophy. In Parkinson’s disease (PD), there is a preferential loss of [18F]DOPA PET uptake in the putamen. In Multiple System Atrophy (MSA), the caudate tends to be more severely affected leading to a more homogenous loss of tracer uptake in the striatum. However, considerable overlap exists between putaminal [18F]DOPA PET uptake between MSA and PD patients, and it cannot be used in the clinical setting to differentiate between MSA and PD.

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confirmed by subsequent studies using [123I]beta-CIT SPECT (Varrone, Marek, Jennings, Innis, & Seibyl, 2001). Overall, these early PET and SPECT studies have shown more symmetrical presynaptic striatal deficits in Multiple System Atrophy patients compared to Parkinson’s disease patients. In particular, the caudate nucleus can be more severely affected in Multiple System Atrophy patients compared with Parkinson’s disease patients, resulting in a more homogenous loss of tracer uptake in the striatum (Antonini et al., 1997; Brooks et al., 1990; Pirker et al., 2002). The caudate–putamen index, which is reflective of differences in uptake in the caudate and putamen divided by uptake in the caudate, has been suggested to be helpful in differentiating Multiple System Atrophy from Parkinson’s disease due to the greater caudate involvement observed in Multiple System Atrophy (Otsuka et al., 1997). More recently, presynaptic dopamine transporter loss has also been studied with [18F]FP-CIT PET. Multiple System Atrophy patients were found to have more prominent and earlier DAT loss in the ventral putamen compared to Parkinson’s disease patients and do not exhibit the typical ventrodorsal gradient of putaminal DAT loss that is commonly seen in Parkinson’s disease patients (Oh et al., 2012). Assessment of the ventrodorsal gradient has been suggested by the authors to be a useful measure in differentiating Multiple System Atrophy from Parkinson’s disease even at the early stage of disease. Striatal presynaptic vesicular monoamine transporter (VMAT2) binding in Multiple System Atrophy patients has been studied using 11C-DTMZ PET, which has showed reduced binding in the caudate and putamen compared with healthy controls (Gilman et al., 1996). Reductions in [18F]DOPA uptake in Multiple System Atrophy are also seen in the ventral striatum and globus pallidus. Additionally, reductions in [18F]DOPA uptake have been identified in the red nucleus of Multiple System Atrophy patients compared to healthy controls, which is suggestive of neuronal dysfunction in the midbrain tegmetum, locus coeruleus, and median raphe (Lewis et al., 2012). Similarly, using voxel-wise analysis of [123I]B-CIT SPECT images, MSAP patients were found to have additional reduction of DAT binding in the midbrain compared to Parkinson’s disease patients (Scherfler et al., 2005). Finally, in MSA-C patients, reduced [11C]dihydrotetrabenazine binding was also seen in the cerebellum (Gilman et al., 1999) and reduced cerebellar binding correlated with cerebellar dysfunction (Gilman et al., 1999). In Multiple System Atrophy, presynaptic dopaminergic dysfunction has been associated with clinical symptoms. Reduced [18F]DOPA uptake was found to be correlated with increased motor disability (Brooks et al., 1990) and severity of extrapyramidal symptoms (Taniwaki et al., 2002).

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Reduced [18F]DOPA uptake in the locus coeruleus was correlated with the severity of orthostatic hypotension in Multiple System Atrophy patients (Lewis et al., 2012). Interestingly, reduced striatal [11C]DTBZ-PET binding was found to correlate with severity of REM sleep behavior disorder measured as severity of REM atonia loss (Gilman et al., 2003). Differences in DAT uptake have been reported in the different subtypes of Multiple System Atrophy ( Jin et al., 2013; Oh et al., 2012). In a series of Multiple System Atrophy patients classified according to their [18FDG]PET metabolic patterns (Kim et al., 2016), Multiple System Atrophy patients with parkinsonism or mixed features showed more severe DAT loss in the striatum compared to Multiple System Atrophy patients with cerebellar features. Interestingly, MSA-P patients and patients with both striatal and cerebellar hypometabolism showed an anteroposterior gradient of DAT loss, whereas Multiple System Atrophy patients with cerebellar features had a more diffuse DAT loss within striatal subregions. These findings have recently been confirmed in a large retrospective series of MSA-P and MSA-C patients diagnosed according to clinical criteria (Bu et al., 2018). However, in this series, while all MSA-P patients studied showed a reduction of DAT binding in the striatum, up to a quarter of patients with MSA-C had normal binding. This is in line with a previous study which has shown that 3 out of 13 patients who fulfilled criteria for possible or probable MSA-C had a normal [123I]FP-CIT SPECT (Munoz et al., 2011). Hence, a normal DAT scan does not exclude a diagnosis of MSA-C. Post-synaptic dopamine D2 receptor binding has been studied in Multiple System Atrophy patients with [11C]raclopride-PET, [123I]epidepride-SPECT, and [123I]IBZM-SPECT. In these studies, Multiple System Atrophy patients show reduced striatal dopamine receptor availability compared with Parkinson’s disease and healthy controls (Antonini et al., 1997; Schulz et al., 1994). In Multiple System Atrophy patients, more pronounced D2 receptor loss has been observed in the posterior putamen compared with Parkinson’s disease and Progressive Supranuclear Palsy patients (Kim et al., 2002). However, this reduction in D2 receptor availability observed in Multiple System Atrophy is relatively mild and is not sensitive for distinguishing between Multiple System Atrophy and Parkinson’s disease. In a study using [123I]-epidepride-SPECT, no difference in regional striatal D2 binding and D2 binding asymmetry was observed between subjects with Parkinson’s disease and Multiple System Atrophy although differences in the caudate to putamen D2 binding ratio with a higher binding ratio were seen in multiple atrophy (Knudsen et al., 2004).

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Furthermore, the utility of D2 receptor binding to distinguish between Multiple System Atrophy and Parkinson’s disease remains inferior to [18F] FDG PET studies (Hellwig et al., 2012).

2.2 Glucose Metabolism [18F]FDG PET studies in Multiple System Atrophy patients have shown severe bilateral hypometabolism in the striatum, frontal cortex, cerebellum, and brainstem ( Juh et al., 2005; Otsuka et al., 1996; Taniwaki et al., 2002) (see Fig. 2). These patterns are highly reproducible across studies and, therefore, findings of reduced [18F]FDG-PET uptake in the putamen, brainstem, or cerebellum have been included as part of the criteria to support a diagnosis of Multiple System Atrophy (Gilman et al., 2008). In agreement with [18F] FDG PET studies, reductions in regional cerebral blood flow in the same brain regions have been demonstrated using perfusion SPECT (Cilia, Marotta, Benti, Pezzoli, & Antonini, 2005; Van Laere et al., 2006). Using computer-assisted methodologies, [18F]FDG PET has a reported 96% sensitivity and 99% specificity for the diagnosis of Multiple System

Fig. 2 Voxel-by-voxel analysis of [18F]FDG-PET uptake in Parkinson’s disease, Multiple System Atrophy, Progressive Supranuclear Palsy, and Corticobasal Degeneration showing areas of decreased metabolism. Reprinted and adapted from Teune, L. K., Bartels, A. L., de Jong, B. M., Willemsen, A. T., Eshuis, S. A., de Vries, J. J., van Oostrom, J. C., & Leenders, K. L. 2010. Typical cerebral metabolic patterns in neurodegenerative brain diseases. Movement Disorders, 25(14), p. 2398. Copyright (2010), with permission from John Wiley and Sons.

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Atrophy (Eckert et al., 2005). These figures have been confirmed in subsequent studies (Hellwig et al., 2012; Kwon, Choi, Kim, Lee, & Chung, 2008). [18F]FDG PET has been helpful in the differentiation of Multiple System Atrophy and Parkinson’s disease: visual and statistical parametric mapping analysis of [18F]FDG PET imaging was able to achieve a sensitivity of 90.9% and 95.5%, respectively, at 100% specificity, with [18F]FDG PET achieving a higher sensitivity compared with a 72.7% sensitivity when brain MRI was used (Kwon, Choi, Kim, Lee, & Chung, 2007). In another study where MSA-P and Parkinson’s disease cases were studied using [18F] FDG PET, visual inspection achieved a sensitivity of 95.8% and a specificity of 100%; and statistical parametric mapping achieved a sensitivity of 79.2% and a specificity of 100% in differentiating the two disorders (Kwon et al., 2008). Differences in [18F]FDG PET uptake have been shown in the different subtypes of Multiple System Atrophy. Hypometabolism and hypoperfusion in the cerebellum and pons are particularly marked in MSA-C (Shinotoh et al., 1999), whereas, in MSA-P, hypometabolism is more pronounced in the bilateral putamen (Zhao, Zhang, & Gao, 2012). Patients with early-stage possible Multiple System Atrophy show greater reductions in cerebral glucose metabolism in the putamen or cerebellum in contrast with patients with earlystage probable Multiple System Atrophy with severe autonomic dysfunction (Kwon, Kim, Im, Lee, & Chung, 2009). In comparison with controls, MSA-C patients at the early stage of disease have reduced hypometabolism in a number of different cortical regions, including the frontal cortex, parietal cortex, and further frontal regions as disease progresses (Lee, An, Yong, & Yoon, 2008). In a series of Multiple System Atrophy patients with both cerebellar and parkinsonian features grouped according disease duration, [18F]FDG PET showed that the areas of cortical hypometabolism varied according to disease duration. These findings would suggest that hypometabolism begins in the frontal cortex and then spreads into the parieto-temporal cortex with disease progression (Lyoo et al., 2008). Hypometabolism in the frontal cortex in MSA-P has been shown to be correlated with hypometabolism in the striatum, suggesting occurrence of striato-frontal deafferentiation in patients with MSA-P (Kim et al., 2017). However, in this study, correlations between cognitive function, as assessed by the mini-mental state examination, and frontal hypometabolism could not be demonstrated. Hypometabolism in the brainstem measured with [18F]FDG PET was shown to be correlated with the severity of autonomic dysfunction in early-stage Multiple System Atrophy (Taniwaki et al., 2002).

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Network analysis of metabolic changes across the brain using spatial covariance analysis of [18F]FDG PET scans has identified a Multiple System Atrophy-related pattern (MSARP) which is characterized by covarying metabolic reductions in the putamen and cerebellum (Poston et al., 2012) (see Table 1). MSARP values show a good correlation with both motor disability and disease duration, and could potentially be useful as a clinical biomarker of the disease. These covariance patterns are highly reproducible and have been used in several prospective cohorts to classify patients (Eckert et al., 2008; Ko, Lee, & Eidelberg, 2017).

2.3 Cholinergic Imaging Cholinergic pathways have been studied in MSA-P patients using [11C] PMP PET, a marker of acetylcholinesterase activity. Cortical cholinergic activity appears to be decreased to similar levels in both MSA-P and Parkinson’s disease compared with normal controls. However, compared with Parkinson’s disease, MSA-P patients had greater decreases in subcortical cholinergic activity, particularly in the pontine cholinergic complex (Gilman et al., 2010). Decreases in acetylcholinesterase activity in the brainstem and cerebellum in MSA-P, Parkinson’s disease, and Progressive Supranuclear Palsy correlated with gait dysfunction. The more severe cholinergic dysfunction in these regions in MSA-P could explain why these patients have more severe gait disturbance in the early stages of the disease than Parkinson’s disease patients. Cholinesterase activity has also been studied in a small series of patients with MSA-C (Hirano et al., 2008). This study has found that MSA-C patients have reduced acetylcholinesterase activity in the thalamus and posterior lobe of the cerebellar cortex compared with healthy controls, suggesting that pharmacological modulation of the cholinergic system may have a role in the treatment of MSA-C. Cognitive function in Multiple System Atrophy has not yet been evaluated with these radioligands.

2.4 Sympathetic Imaging [123I]metaiodobenzylguanidine (MIBG) cardiac scintigraphy and myocardial [18F]fluorodopamine PET has been suggested to be helpful in the differentiation of Parkinson’s disease with autonomic failure from Multiple System Atrophy. Several studies have reported that Parkinson’s disease patients show a reduced tracer uptake due to the occurrence of myocardial postganglionic sympathetic dysfunction, but not Multiple System Atrophy

MSA (Eckert et al., 2008; Poston et al., 2012)

Anterior cingulate area, brainstem, caudate, frontal eye fields, medial thalamus, medial prefrontal cortex, and ventrolateral prefrontal cortex

PSP (Eckert et al., 2008; Ge et al., 2018)

Relative hypermetabolism Hippocampus, insula, of frontal and superior parieto-occipital regions parietal cortex and thalamus

Hypometabolism in the Bilateral hypometabolism premotor cortex, in the putamen, supplementary motor area, cerebellum, and brainstem and parietal association regions

Brain areas Pallido-thalamic and pontine with covarying hypermetabolism metabolic increases

Brain regions with covarying metabolic reductions

PD (Hirano, Eckert, Flanagan, & Eidelberg, 2009)

Relative bilateral increases in occipital regions

Asymmetrical reductions (worse in the hemisphere, contralateral to the more affected body side) in the cerebrum, lateral parietal and frontal regions, and thalamus

CBD (Niethammer et al., 2014)

Table 1 Overview of the Different Disease-Related Covariance Patterns Identified From [18F]FDG PET Studies Performed in Parkinson’s Disease (PD), Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP), and Corticobasal Degeneration (CBD) Patients Spatial Covariance Analysis of [18F]FDG PET Scans

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and the other atypical parkinsonisms where preganglionic dysfunction occurs, and MIBG binding is typically normal. Using myocardial [18F] fluorodopamine PET, patients with Parkinson’s disease could be distinguished from Multiple System Atrophy with 83% sensitivity at 80% sensitivity and 100% sensitivity among patients with neurogenic orthostatic hypotension (Goldstein et al., 2008). However in one study, decreased MIBG binding has been reported in up to 1/3 of patients with Multiple System Atrophy (Nagayama et al., 2010). However, the dose of radioactive tracer used was lower than typical doses used in such studies. A PET study with the sympathetic nerve tracer [11C]meta-hydroxyephedrine ([11C]HED) also showed that substantial cardiac denervation can occur in some patients with Multiple System Atrophy and Progressive Supranuclear Palsy (Raffel et al., 2006). Interestingly, no correlation was found between cardiac [11C]HED retention and striatal [11C]DTBZ binding suggesting that cardiac denervation and striatal denervation occur independently in patients with parkinsonian syndromes.

2.5 Serotonergic Imaging So far, serotoninergic PET ligands have not been used in patients with Multiple System Atrophy. Using [18F]DOPA PET, that in the midbrain region reflects the activity of the aromatic amino acid decarboxylase, similar [18F]DOPA uptake was found in the raphe of MSA-P and Parkinson’s disease patients compared to controls (Lewis et al., 2012). Similar results were seen in SPECT studies. [123I]betaCIT and [123I]FP-CIT binding in the midbrain was found not to be different in Multiple System Atrophy and Parkinson’s disease patients at the early stage of disease (Suwijn, Berendse, Verschuur, de Bie, & Booij, 2014), although it was found to be significantly reduced in established MSA-P patients compared to Parkinson’s disease patients (Scherfler et al., 2005).

2.6 Other Systems Opioid receptor binding has been studied using [11C]diprenorphine-PET in Multiple System Atrophy. MSA-P patients showed reduced opioid receptor binding in the putamen, but preserved binding in the caudate compared with normal controls (Burn et al., 1995). Conversely, in MSA-C patients, reduced binding was observed in both the caudate and putamen (Rinne et al., 1995).

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2.7 Microglial Activation Imaging Microglial activation occurs in a regulated fashion in response to both acute and chronic brain insults and is thought to allow tissue repair and regeneration to occur. However, there is evidence to suggest that in disorders where extensive chronic microglial activation occurs, excessive immune cytokines and neurotoxic factors are released which can cause death of the surrounding healthy neurons and promote a cascade of further neurodegeneration (Smith, Das, Ray, & Banik, 2012). The role of microglial activation and neuroinflammation in the pathogenesis of Multiple System Atrophy has been studied using [11C](R)-PK11195 PET, a selective in vivo marker of microglial activation that binds to the mitochondrial translocater protein 18 kDa (TSPO). In a small number of patients with probable Multiple System Atrophy, [11C](R)-PK11195 PET showed increased binding in the dorsolateral prefrontal cortex, putamen, pallidum, pons, and substantia nigra, which correspond to the areas of known pathology in Multiple System Atrophy (Gerhard et al., 2003). These findings would suggest that the neuroinflammatory process triggered by activated microglial might contribute to the neurodegenerative process in Multiple System Atrophy. Within a prospective 48-week, randomized double blind clinical trial investigating the efficacy of minocycline in inhibiting microglial activation in MSA-P, three patients were evaluated with [11C](R)-PK11195 PET to determine the effect of minocycline on microglial activation (Dodel et al., 2010). Although the trial failed to demonstrate a clinical effect of minocycline on motor function in the entire cohort, the three patients studied with PET had an attenuated mean increase in microglial activation compared to the placebo group and in two of them, [11C](R)-PK11195 PET binding effectively decreased, suggesting that minocycline could interfere with microglial activation.

2.8 Tau and Alpha-Synuclein Imaging Since Multiple System Atrophy is an alpha-synucleinopathy and tau pathology should be absent in this condition, the use of tau-PET imaging could potentially be helpful in the differentiation of Multiple System Atrophy from tauopathies that can clinically mimic Multiple System Atrophy. However, in Multiple System Atrophy patients with significant glia cytoplasmic inclusion burden, false positives on tau-PET imaging could occur. Significant retention of the tau ligand [18F]AV-1541 has been described in the posterior putamen in Multiple System Atrophy (Cho, Choi, Lee, et al., 2017). The mechanisms of this off-target binding remain unclear. One hypothesis is that

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off-target binding results as a potential interaction between iron deposition in the putamen and the radioligand (Choi et al., 2018). Another tau ligand, [11C]PBB3, was shown to bind to the cortical and subcortical regions in Multiple System Atrophy (Perez-Soriano et al., 2017). The development of PET ligands targeting alpha-synuclein, which would allow for in vivo assessment of alpha-synuclein deposition, has been an area of active research in recent years. [11C]BF-227 has been evaluated in a small number of Multiple System Atrophy patients, showing increased binding in the subcortical white matter, putamen, posterior cingulate cortex, globus pallidus, primary motor cortex, anterior cingulate cortex, and substantia nigra in these patients compared with normal controls (Kikuchi et al., 2010). However, this ligand is non-selective, as it binds with high affinity to amyloid beta and low affinity to alpha-synuclein within Lewy Bodies.

3. PROGRESSIVE SUPRANUCLEAR PALSY Progressive Supranuclear Palsy is an important cause of atypical parkinsonism. Disease onset typically occurs after the 6th decade of life. Richardson’s syndrome (PSP-RS) is the classically described phenotype of Progressive Supranuclear Palsy characterized by the combination of parkinsonian features, supranuclear vertical gaze palsy, dementia of subcortical type, and pseudobulbar signs, including dysphagia, dysarthria, and emotional incontinence. Bradykinesia, rigidity affecting axial muscles more than the limbs, postural instability, and gait disturbances are commonly seen (Williams & Lees, 2009). In the past decade, there has been an increasing recognition of the variability and broad spectrum of different clinical phenotypes that could exist within Progressive Supranuclear Palsy. These clinical variants can make the ante mortem diagnosis challenging (Respondek et al., 2013), with many patients subsequently developing features of PSP-RS with disease progression (Respondek et al., 2014). Considerable overlap exists with the other neurodegenerative disorders including other atypical parkinsonian disorders. These clinical variants are classified according to their main clinical phenotype and include Progressive Supranuclear Palsy with predominant parkinsonism (PSP-P), Progressive Supranuclear Palsy with progressive gait freezing (PSP-PGF), corticobasal syndrome (PSP-CBS), Progressive Supranuclear Palsy with predominant speech of language disorder (PSP-SL), Progressive Supranuclear Palsy with predominant frontal involvement (PSP-F), and Progressive Supranuclear Palsy with predominant cerebellar ataxia (PSP-C). As such, the clinical

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diagnosis of Progressive Supranuclear Palsy, particularly at the early stage of disease remains extremely challenging. In recognition of the broad clinical presentation of Progressive Supranuclear Palsy, The Movement Disorders Criteria for the clinical diagnosis of Progressive Supranuclear Palsy was revised in 2016 to improve the early diagnosis of the disorder (Hoglinger et al., 2017). The diagnosis of Progressive Supranuclear Palsy is dependent on neuropathological findings of intracerebral aggregation of tau, predominantly involving isoforms with four microtubule-binding repeats (4R-tau) (Dickson, 1999; Kovacs, 2015; Litvan et al., 1996). These neurofibrillary tangles are present in the striatal structures, globus pallidus, brainstem, cerebellum, and cerebral cortex. Other pathological changes include decreased pigment in the substantia nigra and locus coeruleus and loss of neurons in the basal ganglia, brainstem, and cerebellum. Brain atrophy is also common. There has been much interest in developing radiological biomarkers for the diagnosis of Progressive Supranuclear Palsy, which has been the subject of a recent review (Whitwell, Hoglinger, et al., 2017). At present, [18F]FDG PET imaging can support the early clinical diagnosis of PSP-RS. However, its utility for the diagnosis of other clinical variants of Progressive Supranuclear Palsy remains limited.

3.1 Dopaminergic Imaging Evaluation of presynaptic dopaminergic function in Progressive Supranuclear Palsy patients with [18F]DOPA PET has revealed equally severe reductions of uptake in the caudate and the anterior and posterior putamen (Brooks et al., 1990). Subsequent SPECT studies with DAT ligands have confirmed these findings, showing more symmetrical and severe reductions in binding within the striatum of Progressive Supranuclear Palsy patients compared with Parkinson’s disease patients (Filippi et al., 2006). However, there is a considerable overlap of individual findings between the two groups of patients to allow discrimination between Parkinson’s disease and Progressive Supranuclear Palsy in clinical practice (Kim et al., 2002). Using a voxel-by-voxel analysis approach, reductions of 18F-DOPA uptake were seen in the orbitofrontal cortex in patients with familial Progressive Supranuclear Palsy suggesting a cortical dopaminergic deficiency in these patients (Tai et al., 2007). Similarly to Multiple System Atrophy, [11C]raclopride-PET binding is reduced in Progressive Supranuclear Palsy patients in comparison with

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normal subjects and untreated Parkinson’s disease patients, suggesting a degeneration of D2 receptors in Progressive Supranuclear Palsy (Brooks et al., 1992). This finding has been confirmed in subsequent SPECT studies (Plotkin et al., 2005; Schwarz et al., 1993).

3.2 Glucose Metabolism Perfusion SPECT studies in Progressive Supranuclear Palsy patients have shown hypoperfusion in the frontal cortex and midbrain ( Johnson, Sperling, Holman, Nagel, & Growdon, 1992; Van Laere et al., 2006). In line with these perfusion SPECT studies, [18F]FDG PET has demonstrated areas of reduced glucose metabolism in the frontal cortex, midbrain, and striatum in these patients (Karbe et al., 1992; Piccini et al., 2001) (see Fig. 2). These abnormalities have also been detected in cases of familial Progressive Supranuclear Palsy, as well as in up to one-third of subclinical cases of familial Progressive Supranuclear Palsy (Piccini et al., 2001). In a series of seven cases of autopsy-confirmed Progressive Supranuclear Palsy who underwent ante mortem [18F]FDG PET, imaging findings reported mild asymmetric thalamic hypometabolism (n ¼ 7), bilateral caudate hypometabolism (n ¼ 6), midbrain hypometabolism (n ¼ 6), and bilateral hypometabolism in the supplementary motor area (n ¼ 4) (Zalewski et al., 2014). Multivariate brain network analysis (spatial covariance analysis with bootstrapping) using a whole-brain approach has been able to identify a reliable Progressive Supranuclear Palsy-related pattern across two different populations (see Table 1). The Progressive Supranuclear Palsy-related pattern is characterized by hypometabolism in the middle prefrontal cortex, ventrolateral prefrontal cortex, striatum, thalamus, and midbrain and increased metabolism in the hippocampus, insula, and parieto-temporal regions (Ge et al., 2018). [18F]FDG PET findings have also been associated with clinical symptoms in Progressive Supranuclear Palsy. Hypometabolism in the thalamus and increased metabolism in the precentral gyrus were shown to be associated with worsening postural instability and increased falls, implicating the role of the thalamo-cortical circuits in the control of postural reflexes in Progressive Supranuclear Palsy (Zwergal et al., 2011). Hypometabolism in the prefrontal cortex and subthalamic nucleus were shown to be associated with the severity of gait dysfunction. During walking, Progressive Supranuclear Palsy patients showed reduced [18F]FDG uptake in the indirect locomotor pathway involving the prefrontal

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cortex–subthalamamic nucleus–pedunculopontine/cuneiform nucleus loops, and increased 18F-FDG uptake in the direct locomotor pathway linking the primary motor cortex to the spinal cord (Zwergal et al., 2013). Metabolism of different brain regions has been associated with the ocular motor abnormalities seen in Progressive Supranuclear Palsy. Hypometabolism in the bilateral anterior cingulate gyrus and right lingual gyrus was found to be associated with downward gaze palsy (Amtage, Maurer, et al., 2014). Finally, hypometabolism in the left medial and dorsolateral frontal lobe was associated with non-fluent aphasia (Roh et al., 2010). [18F]FDG PET could be useful to differentiate Progressive Supranuclear Palsy from Parkinson’s disease and other parkinsonisms. More severe medial frontal hypometabolism is seen in Progressive Supranuclear Palsy compared to Parkinson’s disease (Klein, de Jong, de Vries, & Leenders, 2005). In a series of Progressive Supranuclear Palsy patients who underwent [18F]FDG PET, a 76.6% concordance of visual assessment of medial frontal cortices hypometabolism with the clinical diagnosis of Progressive Supranuclear Palsy was obtained. Remarkably, concordance with clinical diagnosis was achieved in 93.3% of Progressive Supranuclear Palsy cases investigated when a computer-supported statistical parametric reading method was used to evaluate the [18F]FDG-PET images (Tripathi et al., 2013). However, frontal hypometabolism has not been consistently observed in Progressive Supranuclear Palsy (Park et al., 2009). Overall, the metabolic abnormalities seen in Progressive Supranuclear Palsy resemble those seen in Multiple System Atrophy and a number of different computer-assisted technologies have been employed to increase the sensitivity and diagnosis of Progressive Supranuclear Palsy. In a large series of patients with parkinsonian features but uncertain clinical diagnosis, an automated image-based classification procedure allowed Progressive Supranuclear Palsy to be distinguished from idiopathic Parkinson’s disease and MSA with 88% sensitivity and 94% specificity (Tang et al., 2010). [18F]FDG-PET findings may be potentially useful in differentiating PSP-RS, PSP-P, and idiopathic Parkinson’s disease. In a series of patients diagnosed according to clinical criteria, PSP-RS patients demonstrated prominent thalamic hypometabolism and PSP-P patients demonstrated prominent putaminal hypometabolism on [18F]FDG-PET. The putamen/thalamus uptake ratio was found to differentiate PSP-P from PSP-RS and from Parkinson’s disease with acceptable accuracy (Srulijes et al., 2012). [18F]FDG-PET may also be useful in the early diagnosis of patients presenting with Primary Progressive Aphasia. Patients with a metabolic pattern

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involving the parietal, subcortical, and frontal structures were found to be more likely to progress to Progressive Supranuclear Palsy or Corticobasal Degeneration, rather than Alzheimer ‘s disease or Frontotemporal Dementia (Cerami et al., 2017; Roh et al., 2010).

3.3 Cholinergic Imaging Cholinergic function has also been studied in Progressive Supranuclear Palsy. Compared with Parkinson’s disease patients, [11C]MP4A PET in Progressive Supranuclear Palsy patients showed a severe reduction in acetylcholinesterase activity in the thalamus (Shinotoh et al., 1999) and other subcortical structures (Gilman et al., 2010). These changes are likely to reflect cholinergic neuronal loss from the pedunculopontine nucleus and other brainstem structures. Dysfunction of these systems may underlie the gait impairment that is observed in Progressive Supranuclear Palsy. The ratio of the thalamic to cortical [11C]MP4A binding might potentially allow Progressive Supranuclear Palsy to be differentiated from Parkinson’s disease. In agreement with PET studies, [123I]IBVM SPECT in Progressive Supranuclear Palsy patients have also shown reductions in presynaptic vesicular acetylcholine expression in the thalamus compared to healthy controls. Milder reductions of [123I]IBVM binding were also observed in the anterior cingulate cortex when compared with normal controls. Vesicular acetylcholine expression in the striatum of Progressive Supranuclear Palsy patients was unaffected. [123I]IBVM binding in the thalamus and peduncolopontine nucleus was found to be inversely correlated to disease duration and could potentially serve as a biomarker of disease progression (Mazere et al., 2012). The cholinergic system has also been studied via the muscarinic acetylcholine receptors using [11C]N-methyl-4-piperidyl benzilate-PET in Progressive Supranuclear Palsy patients with dementia (Asahina et al., 1998). No differences in binding were observed in these patients compared with healthy controls, which would suggest that the cerebral cholinergic system might not have a significant role in mediating cognitive dysfunction in Progressive Supranuclear Palsy.

3.4 Other Systems Opioid receptors have been studied using [11C]diprenorphine-PET in a small number of PSP-RS patients, showing reduced opioid receptor binding in the caudate and putamen of these patients compared with Parkinson’s disease and healthy controls (Burn et al., 1995).

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GABA-A receptors have been studied using [11C]flumazenil-PET. Compared with healthy controls, Progressive Supranuclear Palsy patients showed a 13% reduction in [11C]flumazenil binding in the cerebral cortex (Foster et al., 2000).

3.5 Microglial Activation Imaging Microglial action has been studied using [11C](R)-PK11195 PET in four patients with Progressive Supranuclear Palsy. Increased binding was seen in the basal ganglia, midbrain, frontal lobe, and cerebellum (Gerhard et al., 2006). Two of these patients were rescanned after 6–10 months and showed stable levels of microglial activation over that short period.

3.6 Tau and Amyloid PET Imaging Recent advances in tau-PET imaging have been an exciting development in the field, offering the potential of visualizing tau pathology in vivo, which could serve as a useful biomarker of the disease. [18F]AV-1451 ligand (Flortaucipir) has been the most widely used so far. Compared with controls, PSP-RS patients show consistent patterns of increased uptake in subcortical structures, including the globus pallidus, putamen, caudate, thalamus, subthalamus nucleus, midbrain, and dentate nucleus (see Fig. 3). Cortical uptake also occurs but is less prominent (Cho, Choi, Hwang, et al., 2017; Hammes et al., 2017; Passamonti et al., 2017; Smith, Schain, et al., 2017; Whitwell, Lowe, et al., 2017). Different patterns of [18F]AV 1451 uptake have been demonstrated in PSP-RS, Parkinson’s disease, and Alzhiemer’s disease (Passamonti et al., 2017). PSP-RS patients have increased uptake in the midbrain and reduced uptake in the cortex and hippocampus when compared with Alzhiemer’s disease patients, and increased uptake in the globus pallidus, putamen, subthalamic nucleus, midbrain, and dentate nucleus when compared with Parkinson’s disease patients (Schonhaut et al., 2017). In the same study, differences in uptake were seen in the clinical variants of Progressive Supranuclear Palsy, with sparing of the dentate in PSP-PAGF and asymmetrical uptake in PSP-Corticobasal Degeneration. Another tau-radioligand, [11C]PBB3 has been compared with [18F]AV1451 in post mortem samples of Progressive Supranuclear Palsy brains and has shown better tracer uptake compared to [18F]AV-1451 (Ono et al., 2017). While these findings look promising, it should be acknowledged that important limitations persist with the use of tau-PET imaging techniques,

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Fig. 3 (A) Averaged [18F]AV-1451 PET images in healthy controls, Parkinson’s disease, and Progressive Supranuclear Palsy. (B) Voxel-by-voxel analysis of [18F]AV-1451 PET across the diagnostic groups. Progressive Supranuclear Palsy patients show increased [18F]AV-1451 binding in the globus pallidus and midbrain compared with healthy controls and Parkinson’s disease patients. Reprinted from Cho, H., Choi, J. Y., Hwang, M. S., Lee, S. H., Ryu, Y. H., Lee, M. S., & Lyoo, C. H. (2017). Subcortical (18) F-AV-1451 binding patterns in progressive supranuclear palsy. Movement Disorders, 32(1), p. 139. https://doi.org/ 10.1002/mds.26844. Copyright (2017), with permission from John Wiley and Sons.

which need to be addressed in order to use this approach as a clinical biomarker in Progressive Supranuclear Palsy. [18F]AV-1541 was originally developed to detect tau in the form of paired helical filaments in Alzhiemer’s disease. Therefore, its utility in non-Alzhiemer’s disease tauopathies, where the tau inclusions are composed of straight filaments, remains controversial. In contrast to Alzhiemer’s disease where strong binding of [18F]AV-1541 occurs, non-Alzhiemer’s disease tauopathies show inconsistent binding in autoradiography studies (Lowe et al., 2016; Marquie et al., 2015). In a Progressive Supranuclear Palsy autopsy case, tau neuropathology was found to correlate with [18F]FDG-PET, but not [18F]AV-1451-PET (Smith, Scholl, Honer, et al., 2017). Finally, increased tracer retention is observed also in

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cognitively normal older adults in the medial temporal lobes, and off-target binding, which increases with age, occurs in the brainstem, basal ganglia, and choroid plexus (Scholl et al., 2016). The cause of this off-target binding remains unresolved and is thought to be due to binding to neuromelanin and melanin containing cells, and areas of brain hemorrhage (Marquie et al., 2015). The occurrence of off-target complicates tracer quantification, particularly in the brainstem and basal ganglia, which are sites of increased tracer binding in PSP-RS syndrome. Furthermore, retention of [18F]AV1541 in the basal ganglia increases with age in both healthy older adults and Progressive Supranuclear Palsy patients, with an overlap between the control and Progressive Supranuclear Palsy groups which may not allow Progressive Supranuclear Palsy patients to be distinguished from healthy controls (Smith, Schain, et al., 2017). Amyloid deposition has been studied in Progressive Supranuclear Palsy patients using Pittsburgh compound B (PiB) PET. In a series of clinically probable Progressive Supranuclear Palsy patients, evidence of amyloid deposition was seen in 40% of the patients. However, amyloid deposition was not found to be correlated with clinical severity, MRI patterns of atrophy, or tau deposition as measured by [18F]AV-1541 uptake and is thought to be an agerelated phenomenon rather than being associated with neurodegeneration (Whitwell et al., 2018).

4. CORTICOBASAL DEGENERATION Corticobasal Degeneration is a progressive neurodegenerative disease involving basal ganglia and cerebral cortex. Clinically, Corticobasal Degeneration is a very heterogeneous disorder and is now recognized as both a movement and cognitive disorder. The classical presentation of Corticobasal Degeneration is the “corticobasal syndrome,” characterized by a progressive asymmetric akinetic-rigid syndrome with apraxia, limb dystonia, and myoclonus, and other features indicative of cortical dysfunction, such as cortical sensory loss, alien limb phenomena, and mirror movements. However, this classical presentation accounts for only 40% of autopsy-confirmed cases of Corticobasal Degeneration (Armstrong et al., 2013). In this study, motor features such as dystonia and myoclonus were surprisingly less common and were found in only one-third of autopsy proven cases of Corticobasal Degeneration (Armstrong et al., 2013). The broad spectrum of clinical phenotypes now recognized within Corticobasal Degeneration include corticobasal syndrome (CBS), frontal behavioral-spatial syndrome (FBS),

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non-fluent variant of primary progressive aphasia (NAV), and Progressive Supranuclear Palsy syndrome (PSPS). Clinical accuracy of ante mortem diagnosis is extremely poor with only half to two-thirds of patients correctly diagnosed (Burrell, Hornberger, Villemagne, Rowe, & Hodges, 2013; Grimes, Lang, & Bergeron, 1999; Hughes, Daniel, Ben-Shlomo, & Lees, 2002). In fact, Corticobasal Degeneration is often confused with other Corticobasal Degeneration mimickers including Alzhiemer’s disease, Progressive Supranuclear Palsy, and Frontotemporal Dementia which can also present with a corticobasal syndrome. Corticobasal Degeneration patients presenting initially with cognitive complaints are particularly difficult to distinguish from Alzhiemer’s disease patients, as Corticobasal Degeneration specific signs only emerge later in the disease course (Day et al., 2017). The Armstrong criteria for the diagnosis of Corticobasal Degeneration were published in 2013 based on clinical data from existing autopsy-confirmed cases (Armstrong et al., 2013). Neuroimaging markers were not included in the diagnostic criteria. Unfortunately, the accuracy of the Armstrong clinical criteria remains poor, and the application of these criteria in an autopsyconfirmed series of Corticobasal Degeneration was unable to correctly diagnose one-third of cases, even when the diagnostic criteria were applied late in the disease course (Alexander et al., 2014). The diagnosis of Corticobasal Degeneration thus rests heavily on neuropathological confirmation. Neuropathological hallmarks of Corticobasal Degeneration include mild atrophy of the cortical gyri with pale, swollen neurons with eccentric nuclei scattered throughout the cerebrum, particularly in the medial frontal area, and severe neuronal loss within the substantia nigra with achromasia of the surviving neurons. Both Corticobasal Degeneration and Progressive Supranuclear Palsy are 4R tauopathies, but differ in the size of the tau cleavage fragment (Feany & Dickson, 1995; Yamada, McGeer, & McGeer, 1992). Abnormal tau accumulation in both neurons and glial cells is extensive in gray and white matter, basal ganglia, diencephalon, and the rostral part of the brainstem. Abnormal tau accumulation within astrocytes forms pathognomonic astrocytic plaques (Kouri, Whitwell, Josephs, Rademakers, & Dickson, 2011).

4.1 Dopaminergic Imaging Striatal [18F]DOPA uptake is asymmetrically reduced in Corticobasal Degeneration patients, with the caudate and putamen being equally

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impaired (Sawle, Brooks, Marsden, & Frackowiak, 1991). These early PET findings have been confirmed by subsequent SPECT studies, which have shown asymmetrical reductions in presynaptic DAT availability in these patients (Plotkin et al., 2005), which has been confirmed in autopsy cases (Pirker et al., 2013). In contrast with Parkinson’s disease patients, Corticobasal Degeneration patients show more asymmetry and a more uniform reduction in striatal uptake (Cilia et al., 2011). However, it has to be acknowledged that presynaptic DAT imaging appears to be normal in 10–40% of patients with clinically probable corticobasal syndrome, particularly in early stages of the disease (Cilia et al., 2011).

4.2 Glucose Metabolism [18F]FDG PET studies have shown a characteristic pattern of reduced glucose metabolism in striatum, thalamus, and parietal cortex contralateral to the most affected side (Niethammer et al., 2014; Zalewski et al., 2014) (see Fig. 2). This specific pattern could be helpful for the diagnosis of Corticobasal Degeneration. In Progressive Supranuclear Palsy, typically, a more diffuse fronto-occipito-striatal hypoperfusion is reported (Slawek, Lass, Derejko, & Dubaniewicz, 2001). However, asymmetrical hypometabolism on [18F]FDG PET can also be observed in Progressive Supranuclear Palsy (Amtage, Hellwig, et al., 2014). Interestingly, [18F]FDG PET abnormalities can be observed months to years before the occurrence of DAT SPECT abnormalities. When computer-assisted methodologies are applied together with trained readers, [18F]FDG PET has been reported to have 91% sensitivity and 99% specificity for the diagnosis of Corticobasal Degeneration (Eckert et al., 2005). Automated approaches using spatial covariance analysis have identify a Corticobasal Degeneration-related pattern that allowed Corticobasal Degeneration to be differentiated from other Atypical Parkinsonian disorders, including Progressive Supranuclear Palsy (Niethammer et al., 2014) (see Table 1). A 92.7% specificity for the diagnosis of Corticobasal Degeneration has been reported by these authors. In patients presenting with Corticobasal syndrome where differentiation between Corticobasal Degeneration and Alzhiemer’s disease was difficult, the use of [18F]FDG PET was superior to MRI brain imaging. Additionally, [18F]FDG PET showed 91% specificity for predicting amyloid status with good inter-rater reliability, although specificity was low at only 50% (Eckert et al., 2005).

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4.3 Other Systems Cholinergic function has been studied in a small series of Corticobasal Degeneration patients using [11C]N-methylpiperidin-4-yl acetate (Hirano et al., 2010). This study has shown decreased levels of acetylcholinesterase in cortical regions, including the paracentral regions, frontal, parietal, and occipital cortex in Corticobasal Degeneration compared with healthy controls.

4.4 Microglial Activation Imaging Microglial activation has been studied using [11C](R)-PK11195 PET in four patients with a clinical diagnosis of Corticobasal Degeneration. Increased binding was found in the caudate nucleus, putamen, substantia nigra, pons, pre-, and post-central gyrus and the frontal lobe, corresponding to the regions of known pathology in Corticobasal Degeneration (Gerhard et al., 2004).

4.5 Tau and Amyloid Imaging A small number of studies have assessed tau ligands in Corticobasal Degeneration. Increased [18F]AV-1451 binding is observed in the precentral gray and white matter, midbrain, putamen, globus pallidus, thalamus, and corticospinal tract of Corticobasal Degeneration patients compared with healthy controls. Asymmetrically increased binding is observed on the side contralateral to the clinically affected side, allowing differentiation from Corticobasal Degeneration–Alzhiemer’s disease (CBS-AD) and Progressive Supranuclear Palsy (Cho, Baek, et al., 2017; Smith, Scholl, Widner, et al., 2017). However, [18F]AV-1451 binding in one study did not correlate well with cortical thickness or glucose hypometabolism (Smith, Scholl, Widner, et al., 2017). Increased [18F]AV-1451 uptake has also been observed in pathologically proven cases of Corticobasal Degeneration initially presenting with other clinical variants, including Primary Progressive Apraxia of Speech which is often difficult to differentiate from those occurring as a result of amyloid pathology ( Josephs et al., 2016) and also PSP-RS syndrome (McMillan et al., 2016). In the early reported cases of patients presenting with Primary Progressive Apraxia of Speech, ante mortem [18F]AV-1541 PET binding was shown to be correlated with tau protein deposition determined by post mortem autoradiography ( Josephs et al., 2016). Increased [18F]AV-1451 binding in the precentral white matter has been found to be correlated with increased motor disability (Cho, Baek, et al., 2017).

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Overall, [18F]AV-1451 is emerging as a promising imaging for Corticobasal Degeneration but will need further confirmation. In an autoradiographic study, [18F]THK5351, another novel tau ligand, was shown to have high binding affinity in the superior frontal, superior parietal, pre-, and post-central gyri compared with normal controls, and higher binding in the globus pallidus and precentral gyrus compared to Alzheimer’s disease immunochemistry (Kikuchi et al., 2016). [18F]THK5351 has also been studied in a series of clinically probable Progressive Supranuclear Palsy patients. Increased binding of this ligand was observed in the midbrain, globus pallidus, frontal cortex, and medulla compared with healthy controls. Additionally radioligand binding correlated well with disease severity (Brendel et al., 2017). Amyloid PET imaging may have a role in the differentiation of Corticobasal Degeneration from Alzheimer’s disease. The prevalence of amyloid positivity was 38% in Corticobasal Degeneration which decreased with age, in contrast to Alzheimer’s disease where the mean amyloid positivity was 88% (Ossenkoppele et al., 2015). However, the absence of neuropathological confirmation of Corticobasal Degeneration in many of these imaging studies and the relative rarity of Corticobasal Degeneration cases compared to the other Atypical Parkinsonisms limit the interpretation of the findings of these studies.

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