SPECT Molecular Imaging in Atypical Parkinsonism

CHAPTER TWO

SPECT Molecular Imaging in Atypical Parkinsonism Joachim Brumberg, Ioannis U. Isaias1 University Hospital and Julius-Maximilians University, W€ urzburg, Germany 1 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. SPECT Molecular Imaging 2.1 Dopaminergic System 2.2 Brain Perfusion Imaging 2.3 Cardiac Imaging 3. SPECT Imaging in Atypical Parkinsonism 3.1 Multiple System Atrophy 3.2 Progressive Supranuclear Palsy 3.3 Corticobasal Syndrome 4. Clinical Utility of SPECT Imaging 4.1 Differentiating Atypical Parkinsonisms 4.2 Imaging Levodopa Responsiveness 5. Conclusions References

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Abstract Atypical parkinsonism is the second most common diagnosis for patients with hypokinetic movement disorders. Beside common parkinsonian symptoms (i.e. bradykinesia and muscular rigidity) patients may also present a variety of additional motor and non-motor symptoms, such as oculomotor abnormalities, postural instability, ataxia, limb apraxia, autonomic dysfunctions, etc. Clinical heterogeneity and gradual manifestation during the disease course often hamper the diagnosis and adequate treatment. This chapter provides an overview of the contribution of single photon emission computed tomography (SPECT) in the differential diagnosis of atypical parkinsonism.

International Review of Neurobiology, Volume 142 ISSN 0074-7742 https://doi.org/10.1016/bs.irn.2018.08.006

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1. INTRODUCTION Parkinsonism is a syndrome manifested by a combination of several motor and non-motor symptoms. All individuals with parkinsonism display bradykinesia (slowness of initiation of voluntary movement, with progressive reduction in speed and amplitude of repetitive movements) as well as muscular rigidity, tremor and postural instability. The most common form of parkinsonism is idiopathic Parkinson’s disease (PD). Atypical parkinsonism usually refers to multisystem degenerations (parkinsonism-plus) and include: multiple system atrophy (MSA) (striatonigral degeneration [MSA-P], olivopontocerebellar atrophy [MSA-C], Shy–Drager syndrome); Steele–Richardson–Olszewski syndrome (progressive supranuclear palsy [PSP], PSP-Richardson syndrome [PSP-RS]) and other “brainstem” (pure akinesia with gait freezing [PSP-PAGF]) or “cortical” variants (PSPparkinsonism [PSP-P]; progressive non-fluent aphasia [PSP-PNFA]); corticobasal degeneration (CBD) and syndromes (CBS); parkinsonism-dementia complex; primary pallidal system atrophy; and pallidopyramidal syndromes (Fahn & Jankovic, 2007; Kara, Hardy, & Houlden, 2013). Until parkinsonian disorders can be differentiated, either by disease-specific biologic or by etiologic markers, the separation of the different parkinsonisms depends largely on clinical–pathological correlations. Diagnostic criteria help in standardizing case definition between studies but do not reliably overcome the problem of phenotypic variability. False-negative clinical misdiagnosis is not uncommon. For example, in one study 6% of patients who died with a clinical diagnosis of PD were found to have PSP at post-mortem (Hughes, Daniel, Kilford, & Lees, 1992). Conversely, there are pathologically confirmed cases of CBD, MSA and dementia with Lewy bodies (LBD), among others, that were clinically misdiagnosed as PSP (false-positive clinical diagnoses) (Fearnley, Revesz, Brooks, Frackowiak, & Lees, 1991; Litvan et al., 1996; Nath et al., 2001). Post-mortem evaluation of patients with atypical parkinsonism showed that the clinical diagnosis can be confirmed by the histopathological examination only in <90% of cases (Turcano et al., 2017). There is a growing body of evidence to support the emerging classification of neurodegenerative disorders according to pathogenetic mechanisms. Recent positron emission tomography (PET) studies significantly favored the understanding, advances and refinements of this classification (Barthel et al., 2011; Cho et al., 2016; Klunk et al., 2004; Lohith et al., 2018; Shimada et al., 2009). Presently, these studies are limited to selected cases

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and research purposes. Many established radioligands for single photon emission computed tomography (SPECT) imaging are therefore still in use for the differential diagnosis of parkinsonism. Atypical parkinsonisms are rare diseases with no cure currently available. A correct diagnosis is fundamental to provide support and information, to estimate medical survival and to plan provision of services. It is also of great value to advance our understanding of these disorders to test new and specific therapies.

2. SPECT MOLECULAR IMAGING 2.1 Dopaminergic System In many cases, atypical parkinsonisms share the common histopathological hallmark of a loss of dopamine-producing nerve bodies in the substantia nigra and the subsequent impairment of dopamine-related neurotransmission in the striatum (Isaias & Antonini, 2010; Isaias, Marotta, Pezzoli, Sabri, & Hesse, 2012; Kish, Shannak, & Hornykiewicz, 1988; Piggott et al., 1999). This striatal dopaminergic deficit is directly responsible for two of the main motor symptoms, i.e. bradykinesia and muscular rigidity (Kojovic et al., 2014; Parr-Brownlie & Hyland, 2005; Spiegel et al., 2007). Consequently, the first radioligands developed for PD and related disorders focused mainly on the dopaminergic system. Two targets were identified, the dopamine reuptake transporter (DAT) and the dopamine receptors. 2.1.1 Dopamine Transporters The DAT is expressed on the nerve terminals of dopamine-producing neurons, which are mainly located in the pars compacta of the substantia nigra but also in the midbrain ventral tegmental area (Uhl, 2003). It reuptakes free dopamine from the intrasynaptic cleft into presynaptic nerve bodies and terminates dopaminergic neurotransmission in the striatum. A reduction of striatal DAT levels indirectly indicates a loss of the expressing neurons in the substantia nigra, and thus qualifies the quantification of DAT binding to measure the integrity of dopaminergic neurons in the substantia nigra. Histopathological studies confirmed that the loss of dopamineproducing cells in the substantia nigra correlates with nuclear imaging findings of the nigrostriatal pathway in patients with PD and atypical parkinsonism (Colloby, McParland, O’Brien, & Attems, 2012; Kraemmer et al., 2014; Snow et al., 1993). Radiotracers for SPECT targeting the DAT

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belong to the group of tropane derivatives, with a molecule structure similar to cocaine. The first SPECT studies on DAT density in the 1990s used [123I](1R)-2β-carbomethoxy-3β-(4-iodophenyl)tropane ([123I]β-CIT) and reported a decrease of [123I]β-CIT striatal uptake with an excellent test/retest reproducibility and a correlation with clinical symptoms in PD patients (Innis et al., 1993; Seibyl et al., 1995, 1997). Subsequently, several 123I-labeled radioligands have been developed to target the DAT (Abi-Dargham et al., 1996; Booij et al., 1997; Fischman et al., 1998; Tatsch et al., 1997); among them, the [123I]N-ω-fluoropropyl-2βcarbomethoxy-3β-(4-iodophenyl)nortropane ([123I]FP-CIT) was shown to be the most successful and is now widely used in clinical practice. The two radioligands mainly differ for the washout period, which leads to stable binding values for [123I]β-CIT after 18–27 h and for [123I]FP-CIT after 3–6 h post-injection (Seibyl et al., 1998). They also slightly differ for nonspecific uptake values, e.g. the affinity to the serotonin transporter (SERT), which is located on the presynaptic membrane of serotonergic neurons, predominantly in extrastriatal regions (Koopman, la Fleur, Fliers, Serlie, & Booij, 2012; Torres, Gainetdinov, & Caron, 2003). Besides a visual interpretation of striatal and extrastriatal binding, the evaluation of DAT binding should also contain a semiquantitative assessment in the striatum and striatal subregions (i.e. caudate nucleus, putamen) (S€ oderlund et al., 2013). Region of interest (ROI) may be outlined individually, based on morphologic magnetic resonance imaging (MRI) or by using predefined, standardized ROIs (Darcourt et al., 2010). Specific binding ratios or non-displaceable binding potential (BP; BP ¼ specific binding ratio-1) can be estimated using the occipital cortex as a reference region [(mean counts of the striatal ROI  mean counts of occipital ROI)/(mean counts of the background ROI)] (Innis et al., 2007). Further measures are the caudate to putamen (C/P) specific binding ratio and the asymmetry index, which is expressed as a percentage and can be calculated as the striatal specific binding ratio difference (striatumipsilateral – striatumcontralateral) relative to the mean value of both striatal regions. If available, the comparison of semiquantitative ratios with control values, obtained with the same technique or from published datasets (Varrone et al., 2013), can improve the inter-individual comparison. To overcome some disadvantages of 123I-labeled radiopharmaceuticals (i.e. cost expensive delivery from production sites to nuclear imaging facilities), 99mTc-labeled tropane derivatives have been also investigated (Kung et al., 1996; Meegalla et al., 1996) and [99mTc]TRODAT-1 proved to be suitable for clinical use (Mozley et al., 2000; Weng et al., 2004).

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However, this ligand could not consistently compete with [123I]FP-CIT and [123I]β-CIT due to an inferior accuracy for early differential diagnosis of PD and nondegenerative diseases and a lower sensitivity for disease progression (Van Laere et al., 2004). 2.1.2 Dopamine Receptors Dopamine receptors are widespread, expressed throughout the brain, and can be divided into five subtypes (i.e. D1–D5). Striatal regions have a high density of D2 receptors, acting either as presynaptic autoreceptors or located on the postsynaptic cell membrane (De Mei, Ramos, Iitaka, & Borrelli, 2009; George, Kern, Smith, & Franco, 2014; Usiello et al., 2000). Autopsy-based autoradiography studies showed that striatal D2 receptors are largely preserved in PD subjects, even in advanced stages of the disease (Rinne, Laihinen, L€ onnberg, Marjam€aki, & Rinne, 1991; Ryoo, Pierrotti, & Joyce, 1998). Several 123I-labeled SPECT radioligands have been proposed for D2 quantification: idolisuride and the benzamide derivatives epidepride, iodobenzamide ([123I]IBZM) and iodobenzofuran ([123I] IBF). Of these, the commercially available tracer [123I]IBZM (Costa et al., 1990) has been used most often for clinical and research purposes. Unlike [123I]FP-CIT, which is regularly used in clinical practice, postsynaptic SPECT imaging has been replaced by more accurate and easily applicable PET diagnostics. However, it can still be of value in a clinical or scientific setting where cyclotron-based PET radiopharmaceuticals are not available. The analysis of D2 receptors should comprise visual and ROI-based semiquantitative assessment of the striatum. Reference regions with absent or low D2 density, such as the frontal or occipital cortex and the cerebellum can be used to calculate the specific binding ratio. The subdivision of the striatum into the head of caudate, anterior and posterior putamen enables the estimation of anteroposterior gradients and should be compared with data from age-matched normal subjects, if available (Van Laere et al., 2010).

2.2 Brain Perfusion Imaging In general, neurodegenerative diseases impair cerebral activity in different brain regions, which can be evaluated by metabolic or perfusion molecular imaging studies. Cerebral perfusion, measured by means of tracer uptake, can serve as a surrogate marker of neuronal integrity. Agents for brain perfusion imaging need to pass through the blood–brain barrier and they should have a high first-pass extraction, prolonged retention in the brain, and very limited or no metabolism (Kung, Ohmomo, & Kung, 1990).

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The first iodinated monoamine, N-isopropyl-4-iodo-amphetamine ([123I] IMP), was developed based on a series of amphetamine analogs (Kuhl et al., 1982). Presently, the most widely available SPECT radioligands measuring the regional cerebral blood flow (rCBF) are the [99mTc]-labeled compounds ethyl cysteine dimer ([99mTc]ECD) and hexamethyl propylene amine oxime ([99mTc]HMPAO). These tracers cross the blood–brain barrier due to their lipophilic nature and are extracted proportional to the rCBF. They are retained within the neuronal cells in their initial distribution until they convert into hydrophilic compounds (Kapucu et al., 2009). Both tracers are reliable, but differences have been described regarding in vitro stability, uptake mechanism and cerebral distribution (e.g. depending on age) (Inoue et al., 2003). Of relevance, SPECT studies do not allow an absolute quantification of cerebral blood flow if not combined with complex data assessment, such as arterial input sampling. Therefore, its application in clinical practice is largely restricted to a visual and semiquantitative analysis of relative regional flow differences. ROI techniques can be applied to measure the rCBF of a predefined reference region (e.g. cerebellum, global brain) or to compare homologous structures in the two hemispheres. For comparison with data of age-matched healthy controls, a stereotactic normalization and statistical subtraction is needed (Bartenstein et al., 1997). Different atypical parkinsonisms develop specific brain metabolic pattern abnormalities. These patterns have been developed mainly for PET studies, but can be also applied to SPECT imaging investigations (Isaias et al., 2010).

2.3 Cardiac Imaging Myocardial sympathetic activity can be evaluated by means of [123I] metaiodobenzylguanidine ([123I]MIBG). [123I]MIBG is an analog of guanethidine, which is up taken by the postganglionic presynaptic nerve terminals, mediated by the noradrenaline reuptake transporter. Although this ligand is preferably used to identify high-risk patients in the context of congestive heart failure ( Jacobson et al., 2010; Verberne, Habraken, van Eck-Smit, Agostini, & Jacobson, 2008), it has been also used to assess the peripheral autonomous involvement in neurodegenerative disorders. Histopathological evaluations of tyrosine hydroxylase immunoreactive fibers in the epicardium of patients with LBD and healthy controls revealed that cardiac sympathetic nerve fibers were significantly reduced in PD patients and negatively correlated with PD stage and disease duration (Fujishiro et al., 2008; Orimo et al., 2007). Myocardial [123I]MIBG uptake

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also correlated with sympathetic axons loss in cardiac tissue samples of autopsy-confirmed cases of patients with LBD (Takahashi et al., 2015). The outcome measure of [123I]MIBG scintigraphy is the heart to mediastinum ratio, which can be estimated using early and late anterior planar images (15 min and 4 h after injection, respectively).

3. SPECT IMAGING IN ATYPICAL PARKINSONISM Reduced nigrostriatal dopaminergic innervation occurs in idiopathic PD, as well as in several atypical parkinsonisms. In particular, presynaptic dopaminergic imaging enables subjects with neuronal damage (e.g. neurodegenerative, post-ischemic, post-traumatic, etc.) or preserved dopaminergic innervation (e.g. tremor syndromes or secondary parkinsonisms) to be distinguished (Fig. 1) (Benamer et al., 2000; Catafau et al., 2004; Marek et al., 2000; Tinazzi et al., 2008). The confirmation of a dopamine deficit is of great value for clinicians to define appropriate symptomatic treatments (e.g. with levodopa). To this end, many radioligands can be used. [123I]βCIT and [123I]FP-CIT SPECT are the most widely used and showed similar reductions in striatal DAT binding when comparing parkinsonian patients with healthy controls (Seibyl et al., 1998).

Fig. 1 Exemplary images of presynaptic dopamine transporter binding, measured by means of [123I]FP-CIT SPECT in a healthy control (A) and five patients with different forms of neurodegenerative parkinsonism: idiopathic Parkinson’s disease (B), multiple system atrophy with predominant cerebellar ataxia (C) and with predominant parkinsonism (D), progressive supranuclear palsy (E) and with corticobasal syndrome (F) Color bar at the right indicates specific binding ratios, scaled to occipital tracer uptake.

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3.1 Multiple System Atrophy Neurodegeneration in the substantia nigra of patients with MSA is reflected by a significant decrease in presynaptic striatal innervation compared to healthy subjects (Kim, Kim, & Lee, 2000; Mun˜oz et al., 2011; Pirker et al., 2000; Scherfler et al., 2005; Seppi et al., 2006; Varrone, Marek, Jennings, Innis, & Seibyl, 2001). In line with the usually symmetric motor impairment, several studies have described a more symmetric striatal DAT binding loss in subjects with MSA when compared to PD patients (El Fakhri et al., 2006; Knudsen et al., 2004; Pirker et al., 2000; Varrone et al., 2001). In contrast, one study on autopsy-defined cases of PD and MSA showed a greater asymmetry of striatal [123I]FP-CIT uptake in MSA than PD patients (Perju-Dumbrava et al., 2012). A lower DAT density in the caudate nucleus and a less marked difference between caudate nucleus and putamen was described in people with MSA than with PD (Badoud et al., 2016; Br€ ucke et al., 1997; Stoffers et al., 2005). When directly compared, MSA-P revealed lower tracer uptake in the striatum than MSA-C, especially with [123I]FP-CIT (Nicastro, Garibotto, & Burkhard, 2018) and [99mTc] TRODAT-1 (Lu et al., 2004) than [123I]β-CIT (Kim et al., 2000). In MSA-C, a negative linear correlation between striatal [123I]β-CIT uptake and cerebellar functioning was reported (Kim et al., 2000), whereas disease duration, disease severity and age did not correlate with imaging findings (Mun˜oz et al., 2011). Rapid disease progression is a key clinical feature of MSA and can also be monitored using SPECT imaging. The decline of striatal DAT binding capacity in longitudinal observation showed a significantly faster decline in MSA-P than in PD (Nocker et al., 2012; Pirker et al., 2002). [123I]β-CIT and [123I]FP-CIT also bind to SERT, although with a lower affinity than DAT (Abi-Dargham et al., 1996) and enable the evaluation of extrastriatal SERT-rich brain regions (i.e. diencephalon, midbrain and pons) (Booij et al., 2007; Joling et al., 2017). Hypothalamic monoaminergic transporter availability was reported to be lower in patients with MSA-P compared to MSA-C, PD and healthy subjects ( Joling et al., 2017; Nocker et al., 2012; Scherfler et al., 2005; Seppi et al., 2006). Histopathological profiles of both variants of MSA showed neuronal cell loss in the striatum (Ozawa et al., 2004). Accordingly, several imaging studies described a reduced binding of D2-receptor on postsynaptic neurons using either [123I]IBF (Buck et al., 1995; Kim et al., 2002), [123I]epidepride (Pirker et al., 1997) or [123I]IBZM (Seppi et al., 2004; Van Royen et al., 1993) in patients with MSA compared to healthy controls and PD patients (Fig. 2).

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Fig. 2 Representative images of one subject with idiopathic Parkinson’s disease (upper row) and one patient with multiple system atrophy with parkinsonism (lower row). (A) and (D) depict DAT binding, (B) + (E) indicate D2-receptor binding and (E) + (F) show [123I]MIBG uptake. Color bars indicate specific binding ratios, scaled to occipital tracer uptake (A, B, D, E) and to minimal and maximal counts (C, F).

The density of D2-receptors decreases during the disease course (Hierholzer et al., 1998). One study comparing postsynaptic neuronal integrity between MSA subtypes reported no difference in D2-receptor binding by means of [123I]IBZM SPECT (Schulz et al., 1994). In contrast, Plotkin and colleagues described a D2-receptor deficiency in six out of eight patients with MSA-P, but only in one out of five patients with MSA-C (Plotkin et al., 2005). Several brain areas, particularly the putamen (Bosman, Van Laere, & Santens, 2003; El Fakhri et al., 2006; Matsui et al., 2005; Sakurai et al., 2015; Van Laere et al., 2004), cerebellum (Kimura et al., 2011; Matsui et al., 2005; Sakurai et al., 2015) and frontal cortical regions, such as the left prefrontal cortex (Bosman et al., 2003; Song, Yoo, Chung, & Jeong, 2015), showed hypoperfusion in patients with MSA-P when compared to PD patients and healthy controls. A severe hypoperfusion was also reported in the posterior associative cortex and was associated with longer disease duration, higher Hoehn and Yahr stage, and poor cognitive performance (Van Laere et al., 2004). Two studies investigated perfusion abnormalities specifically in MSA-C and detected a decreased perfusion in the whole cerebellum (Matsuda et al., 2010; Nanri et al., 2010), which parallels the clinical phenotype and autopsy reports (Ozawa et al., 2004). The involvement of the autonomous nervous system (e.g. orthostatic hypotension and urinary incontinence) is a clinical feature of MSA. Sakakibara and colleagues used

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perfusion SPECT to evaluate brain activity specifically in MSA patients with micturition (Sakakibara, Uchida, Uchiyama, Yamanishi, & Hattori, 2004). They showed that in the storage phase and during micturition, patients had decreased activity in the cerebellar vermis; in the resting state with an empty bladder, no differences were observed between the brain perfusion of MSA patients and healthy controls. Myocardial [123I]MIBG imaging has proven to differentiate MSA from PD and LBD (Fig. 2) (King, Mintz, & Royall, 2011). Some studies reported a significant decrease of cardiac tracer accumulation in MSA, which still differs from PD patients (Druschky et al., 2000; Yoshita, 1998), whereas others showed a non-significant reduction (Chung, Lee, Yoon, Kim, & Lee, 2009; K€ ollensperger et al., 2007; Takatsu et al., 2000). The extent of cardiac involvement seems to depend on the variant of MSA, patients with MSA-P showing a significantly lower cardiac [123I]MIBG uptake than patients with MSA-C (Kikuchi et al., 2011). However, the pathophysiologic correlates of these partially inconclusive findings are not clear and further studies on the involvement of the peripheral autonomous nervous system are needed.

3.2 Progressive Supranuclear Palsy Both [123I]β-CIT and [123I]FP-CIT binding in the striatum are significantly reduced in patients with PSP compared to healthy subjects and patients suffering from nondegenerative parkinsonism (Antonini et al., 2003; Br€ ucke et al., 1997; Filippi et al., 2006; Joling et al., 2017; Pirker et al., 2000; Seppi et al., 2006). Several studies detected significant differences of binding values between PSP and PD, with a more severe and symmetric (Pirker et al., 2000) striatal DAT loss in people with PSP, involving the putamen but also the caudate nucleus (Antonini et al., 2003; Badoud et al., 2016; Filippi et al., 2006; Joling et al., 2017; Messa et al., 1998). Midbrain evaluation of [123I]β-CIT and [123I]FP-CIT binding showed a clear reduction of SERT levels in PSP ( Joling et al., 2017; Roselli et al., 2010; Seppi et al., 2006). SPECT studies with [123I]IBF (Buck et al., 1995; Oyanagi et al., 2002) and [123I]IBZM (Plotkin et al., 2005; Schwarz et al., 1993; Van Royen et al., 1993) also showed a severe loss of D2-receptors in patients with PSP, which aggravates during the disease course (Hierholzer et al., 1998). Of interest, Plotkin and colleagues described one patient with initially normal

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D2-receptor binding, followed by a severe decrease in D2-receptor binding at the 2-year follow-up. As pathological DAT binding was observed at baseline, the authors suggested a delayed sequential involvement of preand postsynaptic neurons (Plotkin et al., 2005). Mild differences have been reported concerning [123I]IBZM in PSP-RS compared with PSP-P: a significant decrease was observed in PSP-RS patients, whereas PSP-P had a mild increase in D2-receptor binding (Lin et al., 2010). One study with [123I]IBZM showed that D2-receptor binding correlated significantly to midbrain atrophy in PSP-RS, measured as maximal anteroposterior diameter in T2-weighted MR images (Arnold, Tatsch, Kraft, Oertel, & Schwarz, 2002). The neurodegenerative processes in cortical areas in PSP paralleled a reduction in global brain perfusion, especially involving parietal and frontal areas and the basal ganglia ( Johnson, Sperling, Holman, Nagel, & Growdon, 1992). A reduced uptake of [99mTc]ECD was shown in PSP patients in the anterior cingulate and medial frontal cortex, which extended to the presupplementary motor area and prefrontal cortex (Varrone et al., 2007), respectively, the cingulate gyrus and the thalamus (Kimura et al., 2011). It is unclear whether cardiac sympathetic innervation is affected in patients with PSP. The heart to mediastinum ratio of [123I]MIBG clearly differentiates patients with PSP from patients with LBD, but data are inconclusive in comparison with healthy controls (Kashihara, Ohno, Kawada, & Okumura, 2006; Miyamoto et al., 2008; Nagayama, Hamamoto, Ueda, Nagashima, & Katayama, 2005; Yoshita, 1998). In people with PSP, two studies described rather normal uptake values (Kashihara et al., 2006; Miyamoto et al., 2008), whereas Nagayama and colleagues observed a modest reduction in the heart to mediastinum ratio (Nagayama et al., 2005). Yoshita and colleagues, in turn, reported significantly reduced values in PSP patients compared with controls (Yoshita, 1998). As these reductions could clearly be linked to medications (e.g. antihypertensives, neuroleptics and antidepressants) or comorbidities (e.g. heart failure and diabetic neuropathy), the involvement of the cardiac sympathetic innervation in PSP is still debatable.

3.3 Corticobasal Syndrome Difficulties in establishing a correct diagnosis of CBS at a clinical level should always be considered when interpreting brain imaging studies. The majority

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of studies with SPECT enrolled patients that had been clinically classified with probable CBD or CBS, based on different consensus criteria (Armstrong et al., 2013; Lang, Bergeron, Pollanen, & Ashby, 1994; Litvan et al., 2003; Litvan, Cummings, & Mega, 1998; Mahapatra, Edwards, Schott, & Bhatia, 2004). Heterogenic autopsy findings (e.g. Alzheimer pathology, frontotemporal lobar degeneration) are known in patients with CBS (Lee et al., 2011). As for other atypical parkinsonisms, the neuronal loss of the substantia nigra is often also present in CBS and results in reduced [123I]β-CIT and [123I]FP-CIT binding (Badoud et al., 2016; Pirker et al., 2000). The striatal DAT binding usually shows a distinct asymmetry of reduction in CBD, which is comparable to that described in PD patients (Klaffke et al., 2006; Lai et al., 2004; Pirker et al., 2000), but with a much larger variability that also falls within the normal range (Badoud et al., 2016; Cilia et al., 2011; Nicastro, Burkhard, & Garibotto, 2018). No significant correlation between DAT binding and clinical characteristics (e.g. disease duration and severity) were observed in CBS (Cilia et al., 2011). In two cases with post-mortem confirmation of CBD, only a mild reduction in [123I]FP-CIT uptake within 1.5 years after symptom onset was observed; at 3–4 years later, the striatal binding had decreased by 37% (Pirker, Perju-Dumbrava, Kovacs, TraubWeidinger, & Pirker, 2015). Unlike patients with MSA and PSP, patients with CBS did not show significantly reduced striatal [123I]IBZM uptake (Klaffke et al., 2006; Pirker et al., 2013; Plotkin et al., 2005). Furthermore, D2 density results vary greatly; two autopsy-confirmed cases of CBD showed either normal [123I]IBZM uptake in the striatum or reduced D2 density contralateral to the clinically most affected hemisphere (Pirker et al., 2013). Subjects with CBD demonstrate global hypoperfusion involving parietal, temporal and frontal cortical areas and the basal ganglia, which is typically more pronounced in the hemisphere contralateral to the clinically most affected side (Hossain et al., 2003; Kreisler et al., 2005; Okuda, Tachibana, Kawabata, Takeda, & Sugita, 2001). Asymmetry is stronger in CBD patients than in PSP (Zhang et al., 2001), but the less affected hemisphere shows a similar pattern of hypoperfusion to the basal ganglia and parietal cortical regions (Markus, Lees, Lennox, Marsden, & Costa, 1995). Hypoperfusion in the right superior frontal gyrus and left middle frontal gyrus was also described in subjects with CBS in comparison to healthy controls (Misch et al., 2014). Very few data are available on cardiac [123I]-MIBG uptake in patients with CBD; of 12 patients overall, all cases showed normal uptake values (Kashihara et al., 2006; Shin, Lee, Bang, Joo, & Huh, 2006).

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4. CLINICAL UTILITY OF SPECT IMAGING 4.1 Differentiating Atypical Parkinsonisms Several studies have examined the diagnostic performance of SPECT and [123I]β-CIT, [123I]FP-CIT, [99mTc]TRODAT-1 or [123I]PE21 to distinguish degenerative from nondegenerative parkinsonism (e.g. vascular parkinsonism) and other diseases with preserved nigrostriatal innervation (e.g. essential tremor) (Table 1). Two different types of image analysis were applied: (i) visual assessment by rating the scan as “normal” or “pathological” and (ii) ROI-based semiquantitative evaluation by calculating the specific binding ratio or the BP within the caudate, putamen and/or striatum. Visual assessment alone delivers an overall sensitivity of 96–98% and a specificity of 80–83% to describe a dopaminergic deficit ( Jennings et al., 2004; Marek et al., 2000). ROI-based analysis can reach a sensitivity and specificity of 81–98% and 87–100%, respectively, using either the putaminal or the striatal uptake ratios as a predictor variable ( Jennings et al., 2004; Marek et al., 2000; Mo et al., 2010; Swanson et al., 2005; Ziebell et al., 2012). The combination of visual assessment and ROI analysis increases both sensitivity and specificity up to 98% (Borghammer et al., 2014; Lokkegard et al., 2002). The positive predictive value for the rating of the scan as “pathological” using combined analysis was reported to be 99% (Borghammer et al., 2014). Ideally, the ROI-based measurement should not only comprise striatal-tobackground ratios, but also asymmetry index, C/P ratios and—if available—the age-adjusted relative loss of DAT availability compared to healthy controls (Varrone et al., 2013). SPECT imaging may further contribute to the differential diagnosis between idiopathic PD and atypical parkinsonism (W€ ullner et al., 2007) (Table 2). The visual assessment of striatal [123I]FP-CIT uptake exhibits two patterns, predominantly associated with atypical parkinsonism (burst striatum) and idiopathic PD (egg shape). The “burst striatum,” a severe bilateral DAT binding reduction with almost no striatal uptake, showed good specificity for atypical parkinsonism but only a poor sensitivity (Davidsson et al., 2014; Kahraman et al., 2012). Likewise, the “egg shape” pattern, which is defined as bilateral reduction with almost no uptake in the putamen on either side and normal or almost normal uptake in the caudate, did not show sufficient sensitivity or specificity (Davidsson et al., 2014; Kahraman et al., 2012). Of note, an ROI-based evaluation (S€ udmeyer et al., 2011; Vlaar et al., 2008; Ziebell et al., 2012), a voxel-wise analysis of striatal or whole brain uptake (Badoud et al., 2016) and the combination of visual

Table 1 Studies on the Diagnostic Accuracy for the Differentiation Between Healthy Subjects, Tremor Syndromes and Non-Neurodegenerative Parkinsonism and Neurodegenerative Parkinsonism Number of Subjects Results Predictor Author (Year) Country Study Design Non-PS PS Tracer Analysis Variable SN SP PPV NPV

Marek et al. (2000)

United States

Prospective multicenter

36

60

[123I]β-CIT

Visual assessment “Abnormal” ROI analysis

0.98

0.83

nr

nr

Contralateral 0.96 P/O

0.94

nr

nr

Denmark Retrospective 29 Løkkegaard, Werdelin, and Friberg (2002)

60

[123I]β-CIT

Combined visual “Abnormal” and ROI analysis

0.97

0.83

nr

nr

10

25

[123I]β-CIT

Visual assessment “Abnormal”

0.96

0.80

nr

nr

ROI analysis

Age-adjusted 0.92 S/O

1.00

nr

nr

0.87

nr

nr

0.91–0.98a 0.92–0.96a nr

nr

Jennings et al. United (2004) States

Prospective

Swanson et al. United (2005) States

Retrospective 48

155 [99mTc] ROI analysis TRODAT-1

Left posterior 0.81 P/O

Mo et al. (2010)

Sweden

Prospective

128 [123I]FP-CIT ROI analysis

P/O

Ziebell et al. (2012)

Denmark Retrospective 65

124 [123I]PE21

Age-adjusted 0.87 S/O

Borghammer et al. (2014)

Denmark Prospective

88

38

65

ROI analysis

[123I]FP-CIT Combined visual “Abnormal” and ROI analysis

0.98

0.91

0.95 0.80

0.98

0.99 0.95

a Range for two different SPECT cameras. Abbreviations: non-PS, neurodegenerative parkinsonism; PS, neurodegenerative parkinsonism; NPV, negative predictive value; nr, not reported; O, occipital cortex; P, putamen; PPV, positive predictive value; S, striatum; SN, sensitivity; SP, specificity.

Table 2 Studies on the Diagnostic Accuracy for the Differentiation Between Idiopathic Parkinson’s Disease and Atypical Parkinsonism Number of Subjects Author (Year)

Country

Study Design

PD

aPS

Tracer

Analysis

Seppi et al. (2006)

Austria

Prospective

17

29

[123I]β-CIT

Combined ROI Midbrain/OβCIT and voxel-wise analysis

0.90 0.94 0.96 0.84

Vlaar et al. (2008)

Netherlands Retrospective 154b 27a

[123I]FP-CIT

ROI analysis

P/OFPCIT

0.80 0.24 0.87 0.15

S/OIBZM

0.80 0.24 0.87 0.15

P/OFPCIT and S/OIBZM

0.79 0.62 0.91 0.44

123

[

Mo et al. (2010)

Sweden

S€ udmeyer et al. (2011) Germany

Kahraman, Eggers, Schicha, Timmermann, and Schmidt (2012)

Germany

SP

PPV NPV

97

18

[123I]FP-CIT [123I]IBZM

ROI analysis

Contralateral P/OFPCIT and S/OIBZM

0.50 0.89 nr

Prospective

31

17

[123I]FP-CIT

ROI analysis

S/OFPCIT

0.76 0.71 0.59 0.85

Prospective

34

Retrospective 120

44 45

nr

123

I]IBZM

S/OIBZM

0.53 0.94 0.82 0.78

123

I]MIBG

Delayed H/MMIBG

0.88 0.65 0.58 0.91

Combined (all 3)

0.94 0.94 0.89 0.97

S/FCIBZM

0.25 0.91 0.79 0.48

[

Germany

SN

Prospective

[

Hellwig et al. (2012)

I]IBZM

Predictor Variable

Results

123

I]IBZM

ROI analysis

123

I]-FP-CIT

Visual assessment “Burst striatum”

0.29 0.93 0.62 0.78

ROI analysis

0.73 0.51 0.80 0.41

[ [

“Egg-shaped”

Continued

Table 2 Studies on the Diagnostic Accuracy for the Differentiation Between Idiopathic Parkinson’s Disease and Atypical Parkinsonism—cont’d Number of Subjects Results Author (Year)

Country

Study Design

PD

aPS

Tracer

Analysis

Predictor Variable

SN

SP

PPV NPV

Orimo, Suzuki, Inaba, 13 studies and Mizusawa (2012)

Meta-analysis 450

182

[123I]MIBG

ROI analysis

Delayed H/MMIBG

0.90 0.83 nr

nr

Ziebell et al. (2012)

Denmark

Retrospective 82a

35

[123I]PE21

ROI analysis

C/PPE21

0.84 0.63 nr

nr

Denmark

a

Borghammer et al. (2014)

Davidsson, Sweden Georgiopoulos, Dizdar, Granerus, and Zachrisson (2014) Badoud et al. (2016)

Takaya et al. (2018)

a

Prospective

71

Retrospective 73

Switzerland Retrospective 306

Japan

Retrospective 46

a

123

15

[

I]FP-CIT

Combined visual “Abnormal” and and ROI analysis olfactory test Olfactory test

0.85 0.60 0.91 0.45

18a

[123I]FP-CIT

Visual assessment “Burst striatum”

0.61 0.90 0.61 0.90

ROI analysis

“Egg-shaped”

0.74 0.90 0.92 0.41

Voxel-wise analysis

Striatal uptake

0.45 0.84 nr

Whole brain uptake

0.28 0.90

ROI analysis

Combined S/OFPCIT, 0.76 0.71 0.59 0.85 and perfusion (LFP, MF, LN)

86

23

[123I]FP-CIT 123

[ I]FP-CIT [123I]IMP

nr

Group also contained subjects with dementia with Lewy bodies. Group also contained subjects with essential tremor and drug-induced parkinsonism. Abbreviations: aPS, atypical parkinsonism; FC, frontal cortex; H, heart; LFP, lateral frontoparietal cortex; LN, lenticular nucleus; M, mediastinum; MF, midline frontal region; NP, negative predictive value; nr, not reported; O, occipital cortex; P, putamen; PD, Parkinson’s disease; PPV, positive predictive value; S, striatum; SN, sensitivity; SP, specificity.

b

SPECT and Parkinsonism

53

and ROI analysis with additional olfactory testing (Borghammer et al., 2014), cannot increase the diagnostic performance of presynaptic SPECT to an acceptable level. Midbrain tracer uptake instead seems to be the best measure; Seppi and colleagues reported a positive predicted value of 96% and a negative predictive value of 84% for the differentiation between PD and patients with MSA and PSP (Seppi et al., 2006). However, this measure has not been described in other studies, and its validation is still lacking. Postsynaptic and cardiac imaging might be also of some value; striatal [123I]IBZM binding showed acceptable sensitivity (25–80%) and specificity (24–91%) to distinguish between idiopathic PD and atypical parkinsonism (Hellwig et al., 2012; Seppi et al., 2004; S€ udmeyer et al., 2011; Vlaar et al., 2008). A meta-analysis on the discrimination power of cardiac [123I]MIBG imaging included 13 studies with 450 PD patients and 182 subjects with atypical parkinsonism; in the pooled analysis, the delayed heart to mediastinum ratio was estimated to differentiate these two groups with a sensitivity of 90% and a specificity of 83% (Orimo et al., 2012). Finally, beside single tracer studies a combination of two or more radioligands have been evaluated for the differential diagnosis of idiopathic PD and atypical parkinsonism. Combined [123I]FP-CIT and [123I]IBZM SPECT imaging reached 50–79% sensitivity and 62–89% specificity (Mo et al., 2010; Vlaar et al., 2008), whereas the combination of striatal DAT binding and perfusion measures in the lateral frontoparietal cortex, the midline frontal region and the lenticular nucleus showed a 76% sensitivity and 71% specificity (Takaya et al., 2018). Only one study combined three tracers, namely [123I]FP-CIT, [123I]IBZM and [123I]MIBG (S€ udmeyer et al., 2011): pre- and postsynaptic striatal uptake and delayed cardiac heart to mediastinum ratios resulted in high diagnostic accuracy (sensitivity 94%, specificity 94%, positive predictive value 89%, negative predictive value 97%). However, time and cost factors may hamper a wide application of three scans. Despite all efforts with transporters and receptors binding ligands, SPECT studies suggest that brain perfusion (and even more PET measures of glucose ([18F]FDG) uptake) is a more reliable tool to differentiate between atypical parkinsonisms (Takaya et al., 2018) (Fig. 3).

4.2 Imaging Levodopa Responsiveness Besides distinguishing idiopathic PD from atypical parkinsonisms, postsynaptic imaging has also been used to assess the responsiveness to dopaminergic therapies. Patients with a good response to dopaminergic therapy showed a

54

Joachim Brumberg and Ioannis U. Isaias

SPECT

Coregistration onto MRI

Reference

Regions of interest

Occipital lobe

Striatum (Str)

Whole cerebrum

Lenticular nucleus (LN)

DAT

Cerebellum (Cbl)

Midline frontal Lateral frontoparietal region (MF) (LFP)

IMP

Fig. 3 Regions of interest for dopamine transporter (DAT) and cerebral perfusion (IMP) SPECT in a representative patient (Takaya et al., 2018).

significantly higher binding of [123I]IBZM than non-responders (Schelosky, Hierholzer, Wissel, Cordes, & Poewe, 1993; Schwarz et al., 1998). [123I] IBZM uptake predicted a positive or negative response to apomorphine and to oral treatment with levodopa, with a high sensitivity (>96%) and specificity between 64% and 75% in patients with prior questionable response to dopaminomimetic drugs (Hellwig et al., 2013; Schwarz, Tatsch, Gasser, Arnold, & Oertel, 1997). Still, Hellwig and colleagues revealed that [123I]IBZM binding is not an independent predictor for levodopa responsiveness and does not provide additional predictive information on the effect of dopaminomimetics beyond other clinical variables (Hellwig et al., 2013).

5. CONCLUSIONS The gradual manifestation of parkinsonian syndromes and the manifold clinical presentation of atypical parkinsonisms require the use of additional diagnostic tools. Brain molecular imaging can provide valuable information to optimize available treatments. Presynaptic dopaminergic imaging, i.e. [123I]β-CIT or [123I]FP-CIT SPECT, should be applied to confirm the neurodegenerative origin of motor symptoms and the involvement of the nigrostriatal dopaminergic system. [123I]MIBG SPECT can display cardiac sympathetic denervation and thus distinguish atypical parkinsonism from idiopathic PD. Brain perfusion measurement is the only technique that can further differentiate atypical parkinsonisms. Diseasespecific perfusion patterns are indicative for MSA, PSP and CBS. The assessment of postsynaptic D2-receptor availability has lost much of its clinical

SPECT and Parkinsonism

55

relevance, since evidence has emerged that postsynaptic radiotracer binding is not an independent predictor of levodopa responsiveness. Due to scientific advances in the field of metabolic and pathology-specific PET imaging, the use of SPECT molecular imaging has been displaced in the differential diagnosis of idiopathic and atypical parkinsonism, but it is still a valuable tool when healthcare infrastructure or resources do not allow PET diagnostics.

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