REVIEW URRENT C OPINION
Update on SPECT and PET in parkinsonism – part 1: imaging for differential diagnosis Philipp T. Meyer a and Sabine Hellwig b,c
Purpose of review To give an update on recent findings concerning the use of single-photon emission computed tomography (SPECT) and positron emission tomography (PET) for differential diagnosis and prognosis of neurodegenerative parkinsonism and related disorders. Recent findings Several studies confirmed the very high diagnostic accuracy and clinical impact of imaging nigrostriatal function (most notably with [123I]FP-CIT-SPECT) for diagnosing neurodegenerative parkinsonism and dementia with Lewy bodies. Accurate differential diagnosis of neurodegenerative parkinsonism can be achieved by imaging disease-specific patterns of cerebral glucose metabolism with [18F]fluorodeoxyglucose-PET, which surpasses the diagnostic accuracy of other currently available radionuclide imaging techniques. Summary SPECT and PET are established methods for the differential diagnosis of parkinsonism with significant therapeutic and prognostic impact. Given the limited accuracy of the clinical diagnosis as the reference standard, future studies with post-mortem verification are needed for validation of diagnostic imaging pattern, particularly in tauopathies. Keywords cerebral glucose metabolism, corticobasal degeneration, dopamine receptor, dopamine transporter, multiple system atrophy, parkinsonism, Parkinson’s disease, positron emission tomography, progressive supranuclear palsy, single-photon emission computed tomography
INTRODUCTION Radionuclide imaging techniques, such as singlephoton emission computed tomography (SPECT) and positron emission tomography (PET), allow for a quantitative visualization of functional and molecular processes in the living human brain. By virtue of disclosing disease-specific alterations early in the disease course (e.g., of cerebral glucose metabolism, dopaminergic neurotransmission or pathological depositions), molecular neuroimaging has become an essential part in the diagnostic work-up of patients with neurodegenerative disorders, in particular parkinsonism. Clinicopathological studies suggest that the clinical diagnosis of Parkinson’s disease (PD), as the most frequent cause of parkinsonism, is incorrect in about 25% of patients [1]. Frequent misdiagnoses include essential tremor (ET), vascular parkinsonism (VP), druginduced parkinsonism (DiP) and the atypical parkinsonian syndromes (APS) multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and www.co-neurology.com
corticobasal degeneration (CBD). As typical clinical hallmarks are often missing at early stages, the accuracy of the clinical diagnosis improves with disease duration. Cumulative clinicopathological data from the Queen Square Brain Bank, however, suggest that still a large fraction of patients with MSA and PSP (about 30%) and, in particular, CBD (up to 74%) are not correctly diagnosed even at late stage [2]. Against this background, SPECT and PET are used with two aims. The first aim is to identify patients with progressive nigrostriatal degeneration, a
Department of Nuclear Medicine, bDepartment of Neurology and Department of Psychiatry and Psychotherapy, University Hospital Freiburg, Freiburg, Germany
c
Correspondence to Philipp T. Meyer, MD, PhD, Department of Nuclear Medicine, University Hospital Freiburg, Hugstetter Straße 55, 79106 Freiburg, Germany. Tel: +49 761 270 39160; fax: +49 761 270 39300; e-mail: [email protected] Curr Opin Neurol 2014, 27:390–397 DOI:10.1097/WCO.0000000000000106 Volume 27 Number 4 August 2014
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Update on SPECT and PET in parkinsonism: part 1 Meyer and Hellwig
KEY POINTS Accurate differential diagnosis of parkinsonism is of paramount therapeutic and prognostic importance. Imaging of nigrostriatal integrity, most notably with [123I]FP-CIT-SPECT, is well established and highly accurate for diagnosing neurodegenerative parkinsonism and DLB. Imaging disease-specific patterns of cerebral glucose metabolism with [18F]FDG-PET does not only allow for an accurate distinction between LBD and APS, but also supports the differentiation between APS subgroups (MSA, PSP and CBD) with high specificity. Studies with post-mortem verification are needed for further validation of diagnostic imaging pattern, particularly in tauopathies.
which is the common pathological feature in PD, MSA, PSP and CBD. The second aim is to differentiate between the latter patient groups. Both decisions are of paramount therapeutic and prognostic importance given the possible excellent treatment options and prognosis in patients without nigrostriatal degeneration and the limited responsiveness to levodopa and faster progression to disability and death in patients with APS compared with PD [3,4]. Thus, the present review will give an overview of most recent SPECT and PET findings regarding the following subjects of interest: (1) imaging nigrostriatal degeneration in parkinsonism, (2) differential diagnosis of neurodegenerative parkinsonism. From clinicians’ perspective, we will mainly focus on methods and radiotracers that are established and broadly available in clinical routine. Finally, because of the high prevalence and clinical importance of cognitive impairment in Lewy-body diseases [including PD, PD with dementia (PDD) and dementia with Lewy-bodies (DLB)] [5,6], an update on biomarker imaging of cognitive impairment in Lewy-body diseases (LBD) will be given in a companion paper of this review [7].
IMAGING NIGROSTRIATAL DEGENERATION IN PARKINSONISM Assessment of nigrostriatal integrity is performed using radiotracers of three distinct presynaptic molecular targets: aromatic amino acid decarboxylase (e.g., [18F]fluorodopa, dopamine synthesis and
storage), vesicular monoamine transporter type 2 (VMAT2, e.g., [11C]DTBZ) and the plasma membrane dopamine transporter (DAT). Although these radiotracers provide similar diagnostic results, a recent longitudinal multitracer study provided evidence that underlying targets are differentially regulated in PD. At symptom onset, dopamine synthesis seems to be upregulated, whereas DAT expression appears to be downregulated (relative to VMAT2). At later stages, measures of nigrostriatal integrity approach each other, suggesting a breakdown of initial compensatory mechanisms [8]. Numerous different radiotracers have been proposed for DAT imaging. [123I]FP-CIT gained most widespread acceptance as an approved SPECT tracer in Europe and the United States (Fig. 1). Two multicenter trials demonstrated that [123I]FP-CIT-SPECT offers excellent diagnostic specificity for identifying neurodegenerative parkinsonism (>95%). Diagnostic sensitivity depended on the inclusion of either patients with clinically well established diagnosis (97%, ET vs. neurodegenerative parkinsonism) [10] or patients with ‘uncertain’ tremor or parkinsonism or both (78%, final diagnosis after 3-year follow-up) [11]. The lower sensitivity in the latter study was because of patients with scans without evidence of dopaminergic deficit (SWEDDs), who were clinically diagnosed with neurodegenerative parkinsonism. Lower rates of SWEDDs (10%) have also been observed in clinical therapy trials including clinically certain cases, but accumulating evidence (e.g., stable clinical and imaging follow-up, no response to dopaminergic treatment) suggests that SWEDDs do not suffer from neurodegenerative parkinsonism [11,12]. In fact, a sufficient sensitivity of [123I]FP-CITSPECT for presymptomatic detection of nigrostriatal degeneration in PD is supported by a commonly observed ipsilateral DAT loss in hemi-parkinsonism (e.g., [13]) and a significant and progressive decline of DAT availability in patients with idiopathic rapid eye movement (REM) sleep behaviour disorder (RBD), which may precede classical LBD symptoms for a decade [14]. Two recent larger studies underline the diagnostic value of [123I]FP-CIT-SPECT in secondary parkinsonism (Fig. 1). In a 2-year follow-up multicenter trial including patients with schizophrenia and possible DiP, Tinazzi et al. [15 ] found that SPECT at baseline was the only significant predictor of motor disability progression and response to levodopa. This is in line with the ability of [123I]FPCIT-SPECT to detect underlying nigrostriatal degeneration. In a large sample of patients with VP (N ¼ 80) and PD (N ¼ 171), Benı´tez-Rivero et al. [16 ] demonstrated a very high accuracy of [123I]FPCIT-SPECT to distinguish between VP and PD (94%).
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Neuroimaging
NC
ET
DiP
PD H&Y 1
PD
PD
H&Y II-III
H&Y IV
VP
NPH
PSP
CBD
DVR
6.0
0.3
FIGURE 1. Dopamine transporter imaging with [123I]FP-CIT-SPECT. Normal SPECT findings in a normal control (NC) and patients with essential tremor (ET) and drug-induced parkinsonism (DiP). A focal lesion may be observed in patients with vascular parkinsonism (VP). Extent and intensity of dopamine transporter (DAT) binding may appear decreased in normalpressure hydrocephalus (NPH), primarily because of partial volume effects. DAT binding decreases with clinical severity [e.g., assessed by Hoehn & Yahr scale (H&Y)] and duration of Parkinson’s disease (PD). Patients with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) may show a fairly homogenous DAT loss in caudate and putamen, whereas patients with PD typically exhibit a strong rostro-caudal gradient. Patterns of regional cerebral glucose metabolism of the latter patients are depicted in Fig. 2. The distribution volume ratio (DVR) images acquired 3 h after [123I]FP-CIT injection are shown [9].
On visual inspection, patients with PD showed a typical pattern of DAT loss with a clear caudate-toputamen gradient, whereas DAT binding in VP was either normal, homogenously reduced (mild to moderate) or affected by focal defects. The actual clinical impact of DAT imaging on management of patients with clinically uncertain parkinsonian syndromes (CUPS) was underlined by an earlier multicenter study [17]. Thirty-six percent of patients with the initial suspected diagnosis of presynaptic degeneration showed a normal [123I]FPCIT-SPECT, whereas 54% of patients with suspected nonpresynaptic parkinsonism showed a pathological scan. Consecutive changes in diagnosis and diagnostic confidence led to a change in clinical management in 72% of cases. These results were confirmed by a recent prospective open-label controlled study with 1-year follow-up. Significantly more patients with CUPS in the [123I]FP-CIT-SPECT group compared with the control group had at least one change in clinical management because of more frequent changes in diagnosis associated with higher confidence. Quality of life and health resource use were, however, not significantly affected by DAT scanning, possibly because of the rather short follow-up [18 ]. It is well known that striatal DAT binding in PD is correlated with symptom severity (bradykinesia, in particular) and disease duration at time of imaging (e.g., [19,20]) (Fig. 1). To explore the prognostic relevance of DAT imaging, a large cohort of patients &&
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with de-novo PD (N ¼ 491) was followed for 5.5 years, undergoing DAT-SPECT ([123I]b-CIT) at inclusion and after 22 months. A lower DAT availability at baseline and a higher subsequent DAT loss were demonstrated to be predictors of higher motor disability, cognitive impairment, psychosis and depression [21 ]. Imaging of nigrostriatal integrity is also a valuable method for diagnosing DLB. In a recent metaanalysis (419 patients in total), the estimated pool sensitivity and specificity of [123I]FP-CIT-SPECT was 87 and 94%, respectively [22 ]. Moreover, a study with post-mortem verification showed that striatal [123I]FP-CIT binding in PDD and DLB is correlated with density of dopaminergic neurons of the substantia nigra (R ¼ 0.65) and not with nigral or striatal a-synuclein, Ab or tau pathology[23 ]. Interestingly, two out of seven patients with DLB showed a normal [123I]FP-CIT scan and relatively preserved nigral neuronal density. Furthermore, another SPECT study (using [123I]PE2I) in newly diagnosed DLB found no correlation between striatal DAT availability and severity of cognitive or motor impairment, fluctuations or hallucinations [24 ]. Taken together, this suggests that the typical clinical picture in DLB is driven by cortical, not nigrostriatal pathology. Finally, as a clinical pitfall it has to be kept in mind that a considerable fraction of patients with frontotemporal dementia may also show nigrostriatal degeneration, which correlates with severity of extrapyramidal symptoms [25,26]. &&
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Update on SPECT and PET in parkinsonism: part 1 Meyer and Hellwig Table 1. Typical SPECT and PET imaging findings in parkinsonism
Disease
Striatal DAT [123I]FP-CIT-SPECT
Striatal dopamine D2/D3 receptor [123I]IBZM-SPECT
Cardiac sympathetic innervation [123I]MIBG scintigraphy
Regional glucose metabolism [18F]FDG-PETb
PD
Reduced in putamen and (less) caudate nucleus, usually markedly asymmetrica
Normal, in early stages upregulated
Reduced, in early stages often still normal (>30% of cases)
Increased in putamen/ pallidum, sensorimotor cortex, pons and cerebellum reduced in posterior temporoparietal, occipital and possibly frontal cortices (esp. in PD-MCI, typical in PDD and DLB)
MSA
Markedly reduced, more pronounced in MSA-P than MSA-C, usually symmetric
Reduced, more pronounced in MSA-P than MSA-C
Normal, in later stages possibly reduced (20–30% of cases)
Reduced in striatum (posterior putamen; especially in MSA-P), pons and cerebellum (esp. in MSA-C)
PSP
Markedly reduced in putamen and caudate nucleus (small rostrocaudal gradient), usually symmetric
Often reduced
Normal, borderline low to reduced findings have also been reported (sparse data)
Reduced in medial, dorsoand ventrolateral frontal areas (pronounced in anterior cingulate gyrus, supplementary motor and premotor areas), caudate nucleus, (medial) thalamus and upper brain stem
CBD
Reduced in putamen and caudate nucleus (small rostro-caudal gradient), markedly asymmetrica
Variably reduced, asymmetrica
Normal, borderline low to reduced findings have also been reported (sparse data)
Reduced in frontoparietal areas (pronounced parietal), motor cortex, middle cingulate gyrus, thalamus, striatum, markedly asymmetrica
ET and DiP
Normal
Normal (caveat: possible receptor blockade by neuroleptics)
Normal (caveat: possible drug interferences)
(no major findings on visual inspection)
VP
Variable, often normal, but also homogenously reduced or focal defects (depending on vascular lesion pattern)
Variable, often normal, but also reduced (depending on vascular lesion pattern) (sparse data)
Variable, may be reduced because of comorbidities (coronary heart disease, diabetes, drugs, etc.) (sparse data)
Reduced, homogenously reduced with or without focal defects (depending on vascular lesion pattern)
CBD, corticobasal degeneration; DAT, dopamine transporter; DiP, drug-induced parkinsonism; DLB, dementia with Lewy bodies; MCI, mild cognitive impairment; MSA, multisystem atrophy; PD, Parkinson’s disease; PDD, PD with dementia; PSP, progressive supranuclear palsy. a Findings are pronounced contralateral to most affected body side. b Without absolute quantification, findings primarily refer to relative changes of regional cerebral glucose metabolism.
DIFFERENTIAL DIAGNOSIS OF NEURODEGENERATIVE PARKINSONISM When using imaging of nigrostriatal integrity, several features apparently distinguish PD from APS as summarized in Table 1, for example, more pronounced degeneration in APS than PD at comparable disease duration [27,30,31 ], homogenous involvement of caudate and putamen in PSP and CBD (leading to differences in rostrocaudal or ventrodorsal imaging gradients e.g., [20,27,31 ]), and markedly asymmetric findings in PD and, in particular, CBD compared with PSP and MSA [20,28,31 ] &
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(Fig. 1). These observations were, however, usually made in more or less selected patient populations (i.e., clinically ‘typical’ cases, two-group comparisons) and do not allow a reliable differential diagnosis in clinically realistic populations (i.e., uncertain cases, multiple groups) (accuracy 90%) of [18F]FDG-PET for the distinction between PD and APS, which was largely independent of analysis methods, patient groups (CBD, PDD/DLB) and symptom duration [36 ,42,43,55–57]. Furthermore, sensitivity and specificity of the PET diagnoses of MSA, PSP and CBD usually exceeded 75 and &&
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Update on SPECT and PET in parkinsonism: part 1 Meyer and Hellwig
PD H&Y II–III
z
max
7 PD H&Y IV
6
[18F]FDG uptake
5
PSP
4 3 2
CBD
1 0
0.0 MSA
right
lateral left
right
mesial left
FIGURE 2. Imaging regional cerebral glucose metabolism with fluorodeoxyglucose ([18F]FDG)-PET. Disease-specific patterns of regional cerebral glucose metabolism in PD, PSP, CBD (same patients as in Fig. 1) and multiple system atrophy (MSA). The transaxial images of cerebral [18F]FDG uptake (left) and three-dimensional stereotactic surface projections (3D-SSP) of voxel-wise Z-score values in comparison with healthy volunteers (right; decreases are shown; datasets were analysed with Neurostat/3D-SSP [45]) are given. The typical findings listed in Table 1 are illustrated. (For additional abbreviations, see Fig. 1.)
90% (as requested for a confirmatory test), respectively [36 ,42,43,55]. Given the clinical and imaging ambiguity, it may, however, be advisable to use a combined PSP/CBD tauopathy category for PET readings at the moment, which reaches a sensitivity and specificity of 87 and 100% [36 ].
Acknowledgements None.
CONCLUSION
REFERENCES AND RECOMMENDED READING
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Accurate diagnosis of neurodegenerative parkinsonism can be achieved by imaging nigrostriatal function (most notably [123I]FP-CIT-SPECT), whereas [18F]FDG-PET allows for an accurate differential diagnosis between PD, MSA, PSP and CBD. Given the limited accuracy of the clinical diagnosis as the reference standard, future studies with post-mortem verification are needed for validation of diagnostic imaging pattern, particularly in tauopathies.
Conflicts of interest PTM and SH receive financial support for an ongoing clinical study by GE. No other potential conflicts of interest.
Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Tolosa E, Wenning G, Poewe W. The diagnosis of Parkinson’s disease. Lancet Neurol 2006; 5:75–86. 2. Ling H, O’Sullivan SS, Holton JL, et al. Does corticobasal degeneration exist? A clinicopathological re-evaluation. Brain 2010; 133:2045–2057. 3. Kempster PA, Williams DR, Selikhova M, et al. Patterns of levodopa response in Parkinson’s disease: a clinico-pathological study. Brain 2007; 130:2123– 2128.
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Neuroimaging 4. O’Sullivan SS, Massey LA, Williams DR, et al. Clinical outcomes of progressive supranuclear palsy and multiple system atrophy. Brain 2008; 131:1362– 1372. 5. Aarsland D, Kurz MW. The epidemiology of dementia associated with Parkinson disease. J Neurol Sci 2010; 289:18–22. 6. Litvan I, Aarsland D, Adler CH, et al. MDS Task Force on mild cognitive impairment in Parkinson’s disease: critical review of PD-MCI. Mov Disord 2011; 26:1814–1824. 7. Meyer PT, Frings L, Hellwig S. Update on SPECT and PET in parkinsonism – part 2: biomarker imaging of cognitive impairment in Lewy-body diseases. Curr Opin Neurol 2014; 27:398–404. 8. Nandhagopal R, Kuramoto L, Schulzer M, et al. Longitudinal evolution of compensatory changes in striatal dopamine processing in Parkinson’s disease. Brain 2011; 134:3290–3298. 9. Meyer PT, Winz OH, Dafotakis M, et al. Improved visual [(123)I]FP-CIT SPECT interpretation for evaluation of parkinsonism by visual rating of parametric distribution volume ratio images. Q J Nucl Med Mol Imaging 2011; 55:301–309. 10. Benamer TS, Patterson J, Grosset DG, et al. Accurate differentiation of parkinsonism and essential tremor using visual assessment of [123I]-FPCIT SPECT imaging: the [123I]-FP-CIT study group. Mov Disord 2000; 15:503–510. 11. Marshall VL, Reininger CB, Marquardt M, et al. Parkinson’s disease is overdiagnosed clinically at baseline in diagnostically uncertain cases: a 3-year European multicenter study with repeat [123I]FP-CIT SPECT. Mov Disord 2009; 24:500–508. 12. Tatsch K, Poepperl G. Nigrostriatal dopamine terminal imaging with dopamine transporter SPECT: an update. J Nucl Med 2013; 54:1331– 1338. 13. Tissingh G, Booij J, Bergmans P, et al. Iodine-123-N-omega-fluoropropyl2beta-carbomethoxy-3beta-(4-iodophenyl)tropane SPECT in healthy controls and early-stage, drug-naive Parkinson’s disease. J Nucl Med 1998; 39:1143–1148. 14. Iranzo A, Valldeoriola F, Lomena F, et al. Serial dopamine transporter imaging of nigrostriatal function in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study. Lancet Neurol 2011; 10:797– 805. 15. Tinazzi M, Morgante F, Matinella A, et al. Imaging of the dopamine transporter && predicts pattern of disease progression and response to levodopa in patients with schizophrenia and parkinsonism: a 2-year follow-up multicenter study. Schizophr Res 2014; 152:344–349. Tinazzi et al. performed a 2-year follow-up in 60 patients with schizophrenia and possible drug-induced parkinsonism who underwent [123I]FP-CIT-SPECT. SPECT at baseline was the only independent predictor of unified Parkinson’s disease rating scale score worsening and improvement on levodopa treatment. In fact, the latter was only observed in those with an abnormal scan. Thus, SPECT can identify those patients who most likely also suffer from neurodegenerative parkinsonism and may benefit from levodopa. 16. Benitez-Rivero S, Marin-Oyaga VA, Garcia-Solis D, et al. Clinical features and && 123I-FP-CIT SPECT imaging in vascular parkinsonism and Parkinson’s disease. J Neurol Neurosurg Psychiatry 2013; 84:122–129. DAT-SPECT findings have been controversial in VP. Some investigators reported focal, some global and others no changes at all. This article on a very large cohort nicely illustrates that SPECT findings in VP may be heterogeneous, in line with the heterogeneity of underlying vascular lesions. Accurate differentiating of VP from PD can, however, be achieved by visual readings using a few simple rules. Independent confirmation is warranted. 17. Catafau AM, Tolosa E. Impact of dopamine transporter SPECT using 123IIoflupane on diagnosis and management of patients with clinically uncertain Parkinsonian syndromes. Mov Disord 2004; 19:1175–1182. 18. Kupsch AR, Bajaj N, Weiland F, et al. Impact of DaTscan SPECT imaging on && clinical management, diagnosis, confidence of diagnosis, quality of life, health resource use and safety in patients with clinically uncertain parkinsonian syndromes: a prospective 1-year follow-up of an open-label controlled study. J Neurol Neurosurg Psychiatry 2012; 83:620–628. Kupsch et al. investigated the clinical impact of [123I]FP-CIT-SPECT in a randomized multicenter trial enrolling patients with uncertain parkinsonism. Compared with a control group, patients who underwent SPECT had significantly more changes in diagnosis and management during a 1-year follow-up. Further follow-up is needed to explore how SPECT affects quality of life and survival as most relevant clinical outcomes. 19. Benamer HT, Patterson J, Wyper DJ, et al. Correlation of Parkinson’s disease severity and duration with 123I-FP-CIT SPECT striatal uptake. Mov Disord 2000; 15:692–698. 20. Cilia R, Rossi C, Frosini D, et al. Dopamine transporter SPECT imaging in corticobasal syndrome. PLoS One 2011; 6:e18301. 21. Ravina B, Marek K, Eberly S, et al. Dopamine transporter imaging is asso&& ciated with long-term outcomes in Parkinson’s disease. Mov Disord 2012; 27:1392–1397. This large (n ¼ 491 included) prospective study employing longitudinal DAT-SPECT and long-term (5.5 years) follow-up underscores the prognostic value of DATSPECT: Lower baseline DAT binding was associated with higher disease severity, disability, falling, cognitive impairment, psychosis and depressive symptoms.
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22. Papathanasiou ND, Boutsiadis A, Dickson J, et al. Diagnostic accuracy of 123I-FP-CIT (DaTSCAN) in dementia with Lewy bodies: a metaanalysis of published studies. Parkinsonism Relat Disord 2012; 18:225– 229. By conducting a meta-analysis on four studies with a total of 419 patients, the authors calculated a sensitivity of 87% and a specificity of 94% of [123I]FP-CITSPECT for differentiating between DLB and no DLB (non-Alzheimer’s disease or normalcy). The high, but not perfect, sensitivity agrees with the neuropathological finding that some DLB cases may, in fact, show normal DAT-SPECT. To maintain such high specificity in clinical routine, it is, however, necessary to be aware of other causes of pathological scans, for example, APS, frontotemporal dementia and vascular lesions. 23. Colloby SJ, McParland S, O’Brien JT, et al. Neuropathological correlates of && dopaminergic imaging in Alzheimer’s disease and Lewy body dementias. Brain 2012; 135:2798–2808. This is an important study as it demonstrates by post-mortem analyses that DATSPECT is a valid in-vivo marker of nigral dopaminergic neuronal density. In turn, DAT binding did not correlate with markers of underlying Lewy-type or Alzheimer’s disease -type pathologies. Moreover, some patients with pathologically proven DLB exhibited normal striatal DAT binding (‘false negative scan’), an important clinical pitfall. 24. Ziebell M, Andersen BB, Pinborg LH, et al. Striatal dopamine transporter && binding does not correlate with clinical severity in dementia with Lewy bodies. J Nucl Med 2013; 54:1072–1076. Data on possible correlations between DAT imaging and clinical features in DLB are conflicting. This study considerably adds to our knowledge. Despite employing a large patient sample (n ¼ 51) and sophisticated quantitative analyses, no correlation between DAT availability and minimental status examination, H&Y score, fluctuations or hallucinations could be established. This underlines the current perception that the clinical manifestation of DLB is governed by cortical, not nigrostriatal pathology. 25. Rinne JO, Laine M, Kaasinen V, et al. Striatal dopamine transporter and extrapyramidal symptoms in frontotemporal dementia. Neurology 2002; 58:1489– 1493. 26. Morgan S, Kemp P, Booij J, et al. Differentiation of frontotemporal dementia from dementia with Lewy bodies using FP-CIT SPECT. J Neurol Neurosurg Psychiatry 2012; 83:1063–1070. 27. Antonini A, Benti R, De Notaris R, et al. 123I-Ioflupane/SPECT binding to striatal dopamine transporter (DAT) uptake in patients with Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. Neurol Sci 2003; 24:149–150. 28. Knudsen GM, Karlsborg M, Thomsen G, et al. Imaging of dopamine transporters and D2 receptors in patients with Parkinson’s disease and multiple system atrophy. Eur J Nucl Med Mol Imaging 2004; 31:1631– 1638. 29. Su¨dmeyer M, Antke C, Zizek T, et al. Diagnostic accuracy of combined FPCIT, IBZM, and MIBG scintigraphy in the differential diagnosis of degenerative parkinsonism: a multidimensional statistical approach. J Nucl Med 2011; 52:733–740. 30. Kahraman D, Eggers C, Schicha H, et al. Visual assessment of dopaminergic degeneration pattern in 123I-FP-CIT SPECT differentiates patients with atypical parkinsonian syndromes and idiopathic Parkinson’s disease. J Neurol 2012; 259:251–260. 31. Oh M, Kim JS, Kim JY, et al. Subregional patterns of preferential striatal & dopamine transporter loss differ in Parkinson disease, progressive supranuclear palsy, and multiple-system atrophy. J Nucl Med 2012; 53:399– 406. Although DAT imaging is most widely done by SPECT, this study impressively shows what wealth of detailed anatomical and pathophysiological data can be gained from subregional striatal analyses with higher-resolution DAT-PET. Subregional patterns of DAT loss were found to differentiate between PD, MSA and PSP. Prospective, multigroup analyses are, however, needed to explore how these patterns perform in clinical routine. 32. Plotkin M, Amthauer H, Klaffke S, et al. Combined 123I-FP-CIT and 123IIBZM SPECT for the diagnosis of parkinsonian syndromes: study on 72 patients. J Neural Transm 2005; 112:677–692. 33. Koch W, Hamann C, Radau PE, et al. Does combined imaging of the pre and postsynaptic dopaminergic system increase the diagnostic accuracy in the differential diagnosis of parkinsonism? Eur J Nucl Med Mol Imaging 2007; 34:1265–1273. 34. Vlaar AM, de Nijs T, Kessels AG, et al. Diagnostic value of 123I-ioflupane and 123I-iodobenzamide SPECT scans in 248 patients with parkinsonian syndromes. Eur Neurol 2008; 59:258–266. 35. Perju-Dumbrava LD, Kovacs GG, Pirker S, et al. Dopamine transporter & imaging in autopsy-confirmed Parkinson’s disease and multiple system atrophy. Mov Disord 2012; 27:65–71. This article illustrates how urgently studies with post-mortem verification are needed for validation of imaging methods in parkinsonism. Opposed to the often cited ‘rule of thumb’, three out of six patients with autopsy-verified MSA show a more asymmetric striatal DAT binding than eight patients with PD. Thus, asymmetry of striatal DAT binding does not enable a reliable differentiation between PD and MSA. &
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Update on SPECT and PET in parkinsonism: part 1 Meyer and Hellwig 36. Hellwig S, Amtage F, Kreft A, et al. [18F]FDG-PET is superior to [123I]IBZMSPECT for the differential diagnosis of parkinsonism. Neurology 2012; 79:1314–1322. Dopamine D2/D3 receptor (D2R) SPECT has been frequently used for differentiation between PD and APS in Europe, albeit being controversial. This large prospective study clearly demonstrates that [18F]FDG-PET does not only provide a much higher accuracy than [123I]IBZM-SPECT for differentiation between PD and APS but also allows for a highly specific identification of APS subgroups (MSA, PSP, CBD). 37. Hellwig S, Kreft A, Amtage F, et al. 123I-iodobenzamide SPECT is not an & independent predictor of dopaminergic responsiveness in patients with suspected atypical parkinsonian syndromes. J Nucl Med 2013; 54:2081–2086. Striatal D2R availability assessed by SPECT has been reported to be predictive of dopaminergic responsiveness by earlier studies. This study, however, demonstrates that D2R-SPECT is not an independent predictor of treatment response if one accounts for clinical diagnosis and other clinical variables. Thus, the clinical utility of D2R-SPECT in parkinsonism is very questionable. 38. Nagayama H, Hamamoto M, Ueda M, et al. Reliability of MIBG myocardial scintigraphy in the diagnosis of Parkinson’s disease. J Neurol Neurosurg Psychiatry 2005; 76:249–251. 39. Ishibashi K, Saito Y, Murayama S, et al. Validation of cardiac (123)I-MIBG scintigraphy in patients with Parkinson’s disease who were diagnosed with dopamine PET. Eur J Nucl Med Mol Imaging 2010; 37:3–11. 40. Nagayama H, Ueda M, Yamazaki M, et al. Abnormal cardiac [(123)I]-metaiodobenzylguanidine uptake in multiple system atrophy. Mov Disord 2010; 25:1744–1747. 41. Eckert T, Van Laere K, Tang C, et al. Quantification of Parkinson’s diseaserelated network expression with ECD SPECT. Eur J Nucl Med Mol Imaging 2007; 34:496–501. 42. Juh R, Kim J, Moon D, et al. Different metabolic patterns analysis of Parkinsonism on the 18F-FDG PET. Eur J Radiol 2004; 51:223–233. 43. Eckert T, Barnes A, Dhawan V, et al. FDG PET in the differential diagnosis of parkinsonian disorders. Neuroimage 2005; 26:912–921. 44. Teune LK, Bartels AL, de Jong BM, et al. Typical cerebral metabolic patterns in neurodegenerative brain diseases. Mov Disord 2010; 25:2395–2404. 45. Minoshima S, Frey KA, Koeppe RA, et al. A diagnostic approach in Alzheimer’s disease using three-dimensional stereotactic surface projections of fluorine18-FDG PET. J Nucl Med 1995; 36:1238–1248. 46. Ma Y, Tang C, Spetsieris PG, et al. Abnormal metabolic network activity in Parkinson’s disease: test-retest reproducibility. J Cereb Blood Flow Metab 2007; 27:597–605. 47. Eckert T, Tang C, Ma Y, et al. Abnormal metabolic networks in atypical parkinsonism. Mov Disord 2008; 23:727–733.
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48. Poston KL, Tang CC, Eckert T, et al. Network correlates of disease severity in multiple system atrophy. Neurology 2012; 78:1237–1244. 49. Tang CC, Poston KL, Dhawan V, et al. Abnormalities in metabolic network activity precede the onset of motor symptoms in Parkinson’s disease. J Neurosci 2010; 30:1049–1056. 50. Holtbernd F, Gagnon JF, Postuma RB, et al. Abnormal metabolic network && activity in REM sleep behavior disorder. Neurology 2014; 82:620–627. This study underscores the value of PDRP expression as a versatile prognostic and diagnostic biomarker in LBD: PDRP expression, assessed by [18F]FDG-PET and CBF-SPECT, was elevated in patients with RBD, as a possible prodromal manifestation of LBD. One of the two cohorts underwent long-term follow-up, during which eight of the 17 patients phenoconverted to PD or DLB. Phenoconversion could be predicted by a combination of PDRP expression and age (r2 ¼ 0.64). 51. Kouri N, Whitwell JL, Josephs KA, et al. Corticobasal degeneration: a pathologically distinct 4R tauopathy. Nat Rev Neurol 2011; 7:263–272. 52. Wadia PM, Lang AE. The many faces of corticobasal degeneration. Parkinsonism Relat Disord 2007; 13 (Suppl 3):S336–340. 53. Amtage F, Hellwig S, Kreft A, et al. Neuronal correlates of clinical asymmetry in & progressive supranuclear palsy. Clin Nucl Med 2014; 39:319–325. Asymmetry of imaging and clinical findings represents a hallmark of CBD, often seen as a discriminant feature from PSP. This article stresses the fact that clinical and imaging asymmetry may also be observed in PSP, whereby clinical asymmetry correlates with asymmetric involvement of thalamus, middle cingulate gyrus and sensorimotor cortex. Parietal involvement was found to be suggestive of CBD. 54. Zalewski N, Botha H, Whitwell JL, et al. FDG-PET in pathologically confirmed && spontaneous 4R-tauopathy variants. J Neurol 2014; 261:710–716. This is one of the very few studies to date that correlated in-vivo imaging findings with autopsy data. In 10 patients with tauopathies (seven PSP, one CBD, one globular glial tauopathy), predominant imaging findings on [18F]FDG-PET were hypometabolism of caudate nucleus, thalamus, midbrain and supplementary motor area. Of note, only the patient with CBD showed asymmetric parietal hypometabolism. 55. Tang CC, Poston KL, Eckert T, et al. Differential diagnosis of parkinsonism: a metabolic imaging study using pattern analysis. Lancet Neurol 2010; 9:149– 158. 56. Tripathi M, Dhawan V, Peng S, et al. Differential diagnosis of parkinsonian syndromes using F-18 fluorodeoxyglucose positron emission tomography. Neuroradiology 2013; 55:483–492. 57. Garraux G, Phillips C, Schrouff J, et al. Multiclass classification of FDG PET scans for the distinction between Parkinson’s disease and atypical parkinsonian syndromes. Neuroimage Clin 2013; 2:883–893.
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Update on SPECT and PET in parkinsonism – part 1: imaging for differential diagnosis Philipp T. Meyer a and Sabine Hellwig b,c
Purpose of review To give an update on recent findings concerning the use of single-photon emission computed tomography (SPECT) and positron emission tomography (PET) for differential diagnosis and prognosis of neurodegenerative parkinsonism and related disorders. Recent findings Several studies confirmed the very high diagnostic accuracy and clinical impact of imaging nigrostriatal function (most notably with [123I]FP-CIT-SPECT) for diagnosing neurodegenerative parkinsonism and dementia with Lewy bodies. Accurate differential diagnosis of neurodegenerative parkinsonism can be achieved by imaging disease-specific patterns of cerebral glucose metabolism with [18F]fluorodeoxyglucose-PET, which surpasses the diagnostic accuracy of other currently available radionuclide imaging techniques. Summary SPECT and PET are established methods for the differential diagnosis of parkinsonism with significant therapeutic and prognostic impact. Given the limited accuracy of the clinical diagnosis as the reference standard, future studies with post-mortem verification are needed for validation of diagnostic imaging pattern, particularly in tauopathies. Keywords cerebral glucose metabolism, corticobasal degeneration, dopamine receptor, dopamine transporter, multiple system atrophy, parkinsonism, Parkinson’s disease, positron emission tomography, progressive supranuclear palsy, single-photon emission computed tomography
INTRODUCTION Radionuclide imaging techniques, such as singlephoton emission computed tomography (SPECT) and positron emission tomography (PET), allow for a quantitative visualization of functional and molecular processes in the living human brain. By virtue of disclosing disease-specific alterations early in the disease course (e.g., of cerebral glucose metabolism, dopaminergic neurotransmission or pathological depositions), molecular neuroimaging has become an essential part in the diagnostic work-up of patients with neurodegenerative disorders, in particular parkinsonism. Clinicopathological studies suggest that the clinical diagnosis of Parkinson’s disease (PD), as the most frequent cause of parkinsonism, is incorrect in about 25% of patients [1]. Frequent misdiagnoses include essential tremor (ET), vascular parkinsonism (VP), druginduced parkinsonism (DiP) and the atypical parkinsonian syndromes (APS) multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and www.co-neurology.com
corticobasal degeneration (CBD). As typical clinical hallmarks are often missing at early stages, the accuracy of the clinical diagnosis improves with disease duration. Cumulative clinicopathological data from the Queen Square Brain Bank, however, suggest that still a large fraction of patients with MSA and PSP (about 30%) and, in particular, CBD (up to 74%) are not correctly diagnosed even at late stage [2]. Against this background, SPECT and PET are used with two aims. The first aim is to identify patients with progressive nigrostriatal degeneration, a
Department of Nuclear Medicine, bDepartment of Neurology and Department of Psychiatry and Psychotherapy, University Hospital Freiburg, Freiburg, Germany
c
Correspondence to Philipp T. Meyer, MD, PhD, Department of Nuclear Medicine, University Hospital Freiburg, Hugstetter Straße 55, 79106 Freiburg, Germany. Tel: +49 761 270 39160; fax: +49 761 270 39300; e-mail: [email protected] Curr Opin Neurol 2014, 27:390–397 DOI:10.1097/WCO.0000000000000106 Volume 27 Number 4 August 2014
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Update on SPECT and PET in parkinsonism: part 1 Meyer and Hellwig
KEY POINTS Accurate differential diagnosis of parkinsonism is of paramount therapeutic and prognostic importance. Imaging of nigrostriatal integrity, most notably with [123I]FP-CIT-SPECT, is well established and highly accurate for diagnosing neurodegenerative parkinsonism and DLB. Imaging disease-specific patterns of cerebral glucose metabolism with [18F]FDG-PET does not only allow for an accurate distinction between LBD and APS, but also supports the differentiation between APS subgroups (MSA, PSP and CBD) with high specificity. Studies with post-mortem verification are needed for further validation of diagnostic imaging pattern, particularly in tauopathies.
which is the common pathological feature in PD, MSA, PSP and CBD. The second aim is to differentiate between the latter patient groups. Both decisions are of paramount therapeutic and prognostic importance given the possible excellent treatment options and prognosis in patients without nigrostriatal degeneration and the limited responsiveness to levodopa and faster progression to disability and death in patients with APS compared with PD [3,4]. Thus, the present review will give an overview of most recent SPECT and PET findings regarding the following subjects of interest: (1) imaging nigrostriatal degeneration in parkinsonism, (2) differential diagnosis of neurodegenerative parkinsonism. From clinicians’ perspective, we will mainly focus on methods and radiotracers that are established and broadly available in clinical routine. Finally, because of the high prevalence and clinical importance of cognitive impairment in Lewy-body diseases [including PD, PD with dementia (PDD) and dementia with Lewy-bodies (DLB)] [5,6], an update on biomarker imaging of cognitive impairment in Lewy-body diseases (LBD) will be given in a companion paper of this review [7].
IMAGING NIGROSTRIATAL DEGENERATION IN PARKINSONISM Assessment of nigrostriatal integrity is performed using radiotracers of three distinct presynaptic molecular targets: aromatic amino acid decarboxylase (e.g., [18F]fluorodopa, dopamine synthesis and
storage), vesicular monoamine transporter type 2 (VMAT2, e.g., [11C]DTBZ) and the plasma membrane dopamine transporter (DAT). Although these radiotracers provide similar diagnostic results, a recent longitudinal multitracer study provided evidence that underlying targets are differentially regulated in PD. At symptom onset, dopamine synthesis seems to be upregulated, whereas DAT expression appears to be downregulated (relative to VMAT2). At later stages, measures of nigrostriatal integrity approach each other, suggesting a breakdown of initial compensatory mechanisms [8]. Numerous different radiotracers have been proposed for DAT imaging. [123I]FP-CIT gained most widespread acceptance as an approved SPECT tracer in Europe and the United States (Fig. 1). Two multicenter trials demonstrated that [123I]FP-CIT-SPECT offers excellent diagnostic specificity for identifying neurodegenerative parkinsonism (>95%). Diagnostic sensitivity depended on the inclusion of either patients with clinically well established diagnosis (97%, ET vs. neurodegenerative parkinsonism) [10] or patients with ‘uncertain’ tremor or parkinsonism or both (78%, final diagnosis after 3-year follow-up) [11]. The lower sensitivity in the latter study was because of patients with scans without evidence of dopaminergic deficit (SWEDDs), who were clinically diagnosed with neurodegenerative parkinsonism. Lower rates of SWEDDs (10%) have also been observed in clinical therapy trials including clinically certain cases, but accumulating evidence (e.g., stable clinical and imaging follow-up, no response to dopaminergic treatment) suggests that SWEDDs do not suffer from neurodegenerative parkinsonism [11,12]. In fact, a sufficient sensitivity of [123I]FP-CITSPECT for presymptomatic detection of nigrostriatal degeneration in PD is supported by a commonly observed ipsilateral DAT loss in hemi-parkinsonism (e.g., [13]) and a significant and progressive decline of DAT availability in patients with idiopathic rapid eye movement (REM) sleep behaviour disorder (RBD), which may precede classical LBD symptoms for a decade [14]. Two recent larger studies underline the diagnostic value of [123I]FP-CIT-SPECT in secondary parkinsonism (Fig. 1). In a 2-year follow-up multicenter trial including patients with schizophrenia and possible DiP, Tinazzi et al. [15 ] found that SPECT at baseline was the only significant predictor of motor disability progression and response to levodopa. This is in line with the ability of [123I]FPCIT-SPECT to detect underlying nigrostriatal degeneration. In a large sample of patients with VP (N ¼ 80) and PD (N ¼ 171), Benı´tez-Rivero et al. [16 ] demonstrated a very high accuracy of [123I]FPCIT-SPECT to distinguish between VP and PD (94%).
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Neuroimaging
NC
ET
DiP
PD H&Y 1
PD
PD
H&Y II-III
H&Y IV
VP
NPH
PSP
CBD
DVR
6.0
0.3
FIGURE 1. Dopamine transporter imaging with [123I]FP-CIT-SPECT. Normal SPECT findings in a normal control (NC) and patients with essential tremor (ET) and drug-induced parkinsonism (DiP). A focal lesion may be observed in patients with vascular parkinsonism (VP). Extent and intensity of dopamine transporter (DAT) binding may appear decreased in normalpressure hydrocephalus (NPH), primarily because of partial volume effects. DAT binding decreases with clinical severity [e.g., assessed by Hoehn & Yahr scale (H&Y)] and duration of Parkinson’s disease (PD). Patients with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) may show a fairly homogenous DAT loss in caudate and putamen, whereas patients with PD typically exhibit a strong rostro-caudal gradient. Patterns of regional cerebral glucose metabolism of the latter patients are depicted in Fig. 2. The distribution volume ratio (DVR) images acquired 3 h after [123I]FP-CIT injection are shown [9].
On visual inspection, patients with PD showed a typical pattern of DAT loss with a clear caudate-toputamen gradient, whereas DAT binding in VP was either normal, homogenously reduced (mild to moderate) or affected by focal defects. The actual clinical impact of DAT imaging on management of patients with clinically uncertain parkinsonian syndromes (CUPS) was underlined by an earlier multicenter study [17]. Thirty-six percent of patients with the initial suspected diagnosis of presynaptic degeneration showed a normal [123I]FPCIT-SPECT, whereas 54% of patients with suspected nonpresynaptic parkinsonism showed a pathological scan. Consecutive changes in diagnosis and diagnostic confidence led to a change in clinical management in 72% of cases. These results were confirmed by a recent prospective open-label controlled study with 1-year follow-up. Significantly more patients with CUPS in the [123I]FP-CIT-SPECT group compared with the control group had at least one change in clinical management because of more frequent changes in diagnosis associated with higher confidence. Quality of life and health resource use were, however, not significantly affected by DAT scanning, possibly because of the rather short follow-up [18 ]. It is well known that striatal DAT binding in PD is correlated with symptom severity (bradykinesia, in particular) and disease duration at time of imaging (e.g., [19,20]) (Fig. 1). To explore the prognostic relevance of DAT imaging, a large cohort of patients &&
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with de-novo PD (N ¼ 491) was followed for 5.5 years, undergoing DAT-SPECT ([123I]b-CIT) at inclusion and after 22 months. A lower DAT availability at baseline and a higher subsequent DAT loss were demonstrated to be predictors of higher motor disability, cognitive impairment, psychosis and depression [21 ]. Imaging of nigrostriatal integrity is also a valuable method for diagnosing DLB. In a recent metaanalysis (419 patients in total), the estimated pool sensitivity and specificity of [123I]FP-CIT-SPECT was 87 and 94%, respectively [22 ]. Moreover, a study with post-mortem verification showed that striatal [123I]FP-CIT binding in PDD and DLB is correlated with density of dopaminergic neurons of the substantia nigra (R ¼ 0.65) and not with nigral or striatal a-synuclein, Ab or tau pathology[23 ]. Interestingly, two out of seven patients with DLB showed a normal [123I]FP-CIT scan and relatively preserved nigral neuronal density. Furthermore, another SPECT study (using [123I]PE2I) in newly diagnosed DLB found no correlation between striatal DAT availability and severity of cognitive or motor impairment, fluctuations or hallucinations [24 ]. Taken together, this suggests that the typical clinical picture in DLB is driven by cortical, not nigrostriatal pathology. Finally, as a clinical pitfall it has to be kept in mind that a considerable fraction of patients with frontotemporal dementia may also show nigrostriatal degeneration, which correlates with severity of extrapyramidal symptoms [25,26]. &&
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Update on SPECT and PET in parkinsonism: part 1 Meyer and Hellwig Table 1. Typical SPECT and PET imaging findings in parkinsonism
Disease
Striatal DAT [123I]FP-CIT-SPECT
Striatal dopamine D2/D3 receptor [123I]IBZM-SPECT
Cardiac sympathetic innervation [123I]MIBG scintigraphy
Regional glucose metabolism [18F]FDG-PETb
PD
Reduced in putamen and (less) caudate nucleus, usually markedly asymmetrica
Normal, in early stages upregulated
Reduced, in early stages often still normal (>30% of cases)
Increased in putamen/ pallidum, sensorimotor cortex, pons and cerebellum reduced in posterior temporoparietal, occipital and possibly frontal cortices (esp. in PD-MCI, typical in PDD and DLB)
MSA
Markedly reduced, more pronounced in MSA-P than MSA-C, usually symmetric
Reduced, more pronounced in MSA-P than MSA-C
Normal, in later stages possibly reduced (20–30% of cases)
Reduced in striatum (posterior putamen; especially in MSA-P), pons and cerebellum (esp. in MSA-C)
PSP
Markedly reduced in putamen and caudate nucleus (small rostrocaudal gradient), usually symmetric
Often reduced
Normal, borderline low to reduced findings have also been reported (sparse data)
Reduced in medial, dorsoand ventrolateral frontal areas (pronounced in anterior cingulate gyrus, supplementary motor and premotor areas), caudate nucleus, (medial) thalamus and upper brain stem
CBD
Reduced in putamen and caudate nucleus (small rostro-caudal gradient), markedly asymmetrica
Variably reduced, asymmetrica
Normal, borderline low to reduced findings have also been reported (sparse data)
Reduced in frontoparietal areas (pronounced parietal), motor cortex, middle cingulate gyrus, thalamus, striatum, markedly asymmetrica
ET and DiP
Normal
Normal (caveat: possible receptor blockade by neuroleptics)
Normal (caveat: possible drug interferences)
(no major findings on visual inspection)
VP
Variable, often normal, but also homogenously reduced or focal defects (depending on vascular lesion pattern)
Variable, often normal, but also reduced (depending on vascular lesion pattern) (sparse data)
Variable, may be reduced because of comorbidities (coronary heart disease, diabetes, drugs, etc.) (sparse data)
Reduced, homogenously reduced with or without focal defects (depending on vascular lesion pattern)
CBD, corticobasal degeneration; DAT, dopamine transporter; DiP, drug-induced parkinsonism; DLB, dementia with Lewy bodies; MCI, mild cognitive impairment; MSA, multisystem atrophy; PD, Parkinson’s disease; PDD, PD with dementia; PSP, progressive supranuclear palsy. a Findings are pronounced contralateral to most affected body side. b Without absolute quantification, findings primarily refer to relative changes of regional cerebral glucose metabolism.
DIFFERENTIAL DIAGNOSIS OF NEURODEGENERATIVE PARKINSONISM When using imaging of nigrostriatal integrity, several features apparently distinguish PD from APS as summarized in Table 1, for example, more pronounced degeneration in APS than PD at comparable disease duration [27,30,31 ], homogenous involvement of caudate and putamen in PSP and CBD (leading to differences in rostrocaudal or ventrodorsal imaging gradients e.g., [20,27,31 ]), and markedly asymmetric findings in PD and, in particular, CBD compared with PSP and MSA [20,28,31 ] &
&
&
(Fig. 1). These observations were, however, usually made in more or less selected patient populations (i.e., clinically ‘typical’ cases, two-group comparisons) and do not allow a reliable differential diagnosis in clinically realistic populations (i.e., uncertain cases, multiple groups) (accuracy 90%) of [18F]FDG-PET for the distinction between PD and APS, which was largely independent of analysis methods, patient groups (CBD, PDD/DLB) and symptom duration [36 ,42,43,55–57]. Furthermore, sensitivity and specificity of the PET diagnoses of MSA, PSP and CBD usually exceeded 75 and &&
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Update on SPECT and PET in parkinsonism: part 1 Meyer and Hellwig
PD H&Y II–III
z
max
7 PD H&Y IV
6
[18F]FDG uptake
5
PSP
4 3 2
CBD
1 0
0.0 MSA
right
lateral left
right
mesial left
FIGURE 2. Imaging regional cerebral glucose metabolism with fluorodeoxyglucose ([18F]FDG)-PET. Disease-specific patterns of regional cerebral glucose metabolism in PD, PSP, CBD (same patients as in Fig. 1) and multiple system atrophy (MSA). The transaxial images of cerebral [18F]FDG uptake (left) and three-dimensional stereotactic surface projections (3D-SSP) of voxel-wise Z-score values in comparison with healthy volunteers (right; decreases are shown; datasets were analysed with Neurostat/3D-SSP [45]) are given. The typical findings listed in Table 1 are illustrated. (For additional abbreviations, see Fig. 1.)
90% (as requested for a confirmatory test), respectively [36 ,42,43,55]. Given the clinical and imaging ambiguity, it may, however, be advisable to use a combined PSP/CBD tauopathy category for PET readings at the moment, which reaches a sensitivity and specificity of 87 and 100% [36 ].
Acknowledgements None.
CONCLUSION
REFERENCES AND RECOMMENDED READING
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Accurate diagnosis of neurodegenerative parkinsonism can be achieved by imaging nigrostriatal function (most notably [123I]FP-CIT-SPECT), whereas [18F]FDG-PET allows for an accurate differential diagnosis between PD, MSA, PSP and CBD. Given the limited accuracy of the clinical diagnosis as the reference standard, future studies with post-mortem verification are needed for validation of diagnostic imaging pattern, particularly in tauopathies.
Conflicts of interest PTM and SH receive financial support for an ongoing clinical study by GE. No other potential conflicts of interest.
Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Tolosa E, Wenning G, Poewe W. The diagnosis of Parkinson’s disease. Lancet Neurol 2006; 5:75–86. 2. Ling H, O’Sullivan SS, Holton JL, et al. Does corticobasal degeneration exist? A clinicopathological re-evaluation. Brain 2010; 133:2045–2057. 3. Kempster PA, Williams DR, Selikhova M, et al. Patterns of levodopa response in Parkinson’s disease: a clinico-pathological study. Brain 2007; 130:2123– 2128.
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Neuroimaging 4. O’Sullivan SS, Massey LA, Williams DR, et al. Clinical outcomes of progressive supranuclear palsy and multiple system atrophy. Brain 2008; 131:1362– 1372. 5. Aarsland D, Kurz MW. The epidemiology of dementia associated with Parkinson disease. J Neurol Sci 2010; 289:18–22. 6. Litvan I, Aarsland D, Adler CH, et al. MDS Task Force on mild cognitive impairment in Parkinson’s disease: critical review of PD-MCI. Mov Disord 2011; 26:1814–1824. 7. Meyer PT, Frings L, Hellwig S. Update on SPECT and PET in parkinsonism – part 2: biomarker imaging of cognitive impairment in Lewy-body diseases. Curr Opin Neurol 2014; 27:398–404. 8. Nandhagopal R, Kuramoto L, Schulzer M, et al. Longitudinal evolution of compensatory changes in striatal dopamine processing in Parkinson’s disease. Brain 2011; 134:3290–3298. 9. Meyer PT, Winz OH, Dafotakis M, et al. Improved visual [(123)I]FP-CIT SPECT interpretation for evaluation of parkinsonism by visual rating of parametric distribution volume ratio images. Q J Nucl Med Mol Imaging 2011; 55:301–309. 10. Benamer TS, Patterson J, Grosset DG, et al. Accurate differentiation of parkinsonism and essential tremor using visual assessment of [123I]-FPCIT SPECT imaging: the [123I]-FP-CIT study group. Mov Disord 2000; 15:503–510. 11. Marshall VL, Reininger CB, Marquardt M, et al. Parkinson’s disease is overdiagnosed clinically at baseline in diagnostically uncertain cases: a 3-year European multicenter study with repeat [123I]FP-CIT SPECT. Mov Disord 2009; 24:500–508. 12. Tatsch K, Poepperl G. Nigrostriatal dopamine terminal imaging with dopamine transporter SPECT: an update. J Nucl Med 2013; 54:1331– 1338. 13. Tissingh G, Booij J, Bergmans P, et al. Iodine-123-N-omega-fluoropropyl2beta-carbomethoxy-3beta-(4-iodophenyl)tropane SPECT in healthy controls and early-stage, drug-naive Parkinson’s disease. J Nucl Med 1998; 39:1143–1148. 14. Iranzo A, Valldeoriola F, Lomena F, et al. Serial dopamine transporter imaging of nigrostriatal function in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study. Lancet Neurol 2011; 10:797– 805. 15. Tinazzi M, Morgante F, Matinella A, et al. Imaging of the dopamine transporter && predicts pattern of disease progression and response to levodopa in patients with schizophrenia and parkinsonism: a 2-year follow-up multicenter study. Schizophr Res 2014; 152:344–349. Tinazzi et al. performed a 2-year follow-up in 60 patients with schizophrenia and possible drug-induced parkinsonism who underwent [123I]FP-CIT-SPECT. SPECT at baseline was the only independent predictor of unified Parkinson’s disease rating scale score worsening and improvement on levodopa treatment. In fact, the latter was only observed in those with an abnormal scan. Thus, SPECT can identify those patients who most likely also suffer from neurodegenerative parkinsonism and may benefit from levodopa. 16. Benitez-Rivero S, Marin-Oyaga VA, Garcia-Solis D, et al. Clinical features and && 123I-FP-CIT SPECT imaging in vascular parkinsonism and Parkinson’s disease. J Neurol Neurosurg Psychiatry 2013; 84:122–129. DAT-SPECT findings have been controversial in VP. Some investigators reported focal, some global and others no changes at all. This article on a very large cohort nicely illustrates that SPECT findings in VP may be heterogeneous, in line with the heterogeneity of underlying vascular lesions. Accurate differentiating of VP from PD can, however, be achieved by visual readings using a few simple rules. Independent confirmation is warranted. 17. Catafau AM, Tolosa E. Impact of dopamine transporter SPECT using 123IIoflupane on diagnosis and management of patients with clinically uncertain Parkinsonian syndromes. Mov Disord 2004; 19:1175–1182. 18. Kupsch AR, Bajaj N, Weiland F, et al. Impact of DaTscan SPECT imaging on && clinical management, diagnosis, confidence of diagnosis, quality of life, health resource use and safety in patients with clinically uncertain parkinsonian syndromes: a prospective 1-year follow-up of an open-label controlled study. J Neurol Neurosurg Psychiatry 2012; 83:620–628. Kupsch et al. investigated the clinical impact of [123I]FP-CIT-SPECT in a randomized multicenter trial enrolling patients with uncertain parkinsonism. Compared with a control group, patients who underwent SPECT had significantly more changes in diagnosis and management during a 1-year follow-up. Further follow-up is needed to explore how SPECT affects quality of life and survival as most relevant clinical outcomes. 19. Benamer HT, Patterson J, Wyper DJ, et al. Correlation of Parkinson’s disease severity and duration with 123I-FP-CIT SPECT striatal uptake. Mov Disord 2000; 15:692–698. 20. Cilia R, Rossi C, Frosini D, et al. Dopamine transporter SPECT imaging in corticobasal syndrome. PLoS One 2011; 6:e18301. 21. Ravina B, Marek K, Eberly S, et al. Dopamine transporter imaging is asso&& ciated with long-term outcomes in Parkinson’s disease. Mov Disord 2012; 27:1392–1397. This large (n ¼ 491 included) prospective study employing longitudinal DAT-SPECT and long-term (5.5 years) follow-up underscores the prognostic value of DATSPECT: Lower baseline DAT binding was associated with higher disease severity, disability, falling, cognitive impairment, psychosis and depressive symptoms.
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22. Papathanasiou ND, Boutsiadis A, Dickson J, et al. Diagnostic accuracy of 123I-FP-CIT (DaTSCAN) in dementia with Lewy bodies: a metaanalysis of published studies. Parkinsonism Relat Disord 2012; 18:225– 229. By conducting a meta-analysis on four studies with a total of 419 patients, the authors calculated a sensitivity of 87% and a specificity of 94% of [123I]FP-CITSPECT for differentiating between DLB and no DLB (non-Alzheimer’s disease or normalcy). The high, but not perfect, sensitivity agrees with the neuropathological finding that some DLB cases may, in fact, show normal DAT-SPECT. To maintain such high specificity in clinical routine, it is, however, necessary to be aware of other causes of pathological scans, for example, APS, frontotemporal dementia and vascular lesions. 23. Colloby SJ, McParland S, O’Brien JT, et al. Neuropathological correlates of && dopaminergic imaging in Alzheimer’s disease and Lewy body dementias. Brain 2012; 135:2798–2808. This is an important study as it demonstrates by post-mortem analyses that DATSPECT is a valid in-vivo marker of nigral dopaminergic neuronal density. In turn, DAT binding did not correlate with markers of underlying Lewy-type or Alzheimer’s disease -type pathologies. Moreover, some patients with pathologically proven DLB exhibited normal striatal DAT binding (‘false negative scan’), an important clinical pitfall. 24. Ziebell M, Andersen BB, Pinborg LH, et al. Striatal dopamine transporter && binding does not correlate with clinical severity in dementia with Lewy bodies. J Nucl Med 2013; 54:1072–1076. Data on possible correlations between DAT imaging and clinical features in DLB are conflicting. This study considerably adds to our knowledge. Despite employing a large patient sample (n ¼ 51) and sophisticated quantitative analyses, no correlation between DAT availability and minimental status examination, H&Y score, fluctuations or hallucinations could be established. This underlines the current perception that the clinical manifestation of DLB is governed by cortical, not nigrostriatal pathology. 25. Rinne JO, Laine M, Kaasinen V, et al. Striatal dopamine transporter and extrapyramidal symptoms in frontotemporal dementia. Neurology 2002; 58:1489– 1493. 26. Morgan S, Kemp P, Booij J, et al. Differentiation of frontotemporal dementia from dementia with Lewy bodies using FP-CIT SPECT. J Neurol Neurosurg Psychiatry 2012; 83:1063–1070. 27. Antonini A, Benti R, De Notaris R, et al. 123I-Ioflupane/SPECT binding to striatal dopamine transporter (DAT) uptake in patients with Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. Neurol Sci 2003; 24:149–150. 28. Knudsen GM, Karlsborg M, Thomsen G, et al. Imaging of dopamine transporters and D2 receptors in patients with Parkinson’s disease and multiple system atrophy. Eur J Nucl Med Mol Imaging 2004; 31:1631– 1638. 29. Su¨dmeyer M, Antke C, Zizek T, et al. Diagnostic accuracy of combined FPCIT, IBZM, and MIBG scintigraphy in the differential diagnosis of degenerative parkinsonism: a multidimensional statistical approach. J Nucl Med 2011; 52:733–740. 30. Kahraman D, Eggers C, Schicha H, et al. Visual assessment of dopaminergic degeneration pattern in 123I-FP-CIT SPECT differentiates patients with atypical parkinsonian syndromes and idiopathic Parkinson’s disease. J Neurol 2012; 259:251–260. 31. Oh M, Kim JS, Kim JY, et al. Subregional patterns of preferential striatal & dopamine transporter loss differ in Parkinson disease, progressive supranuclear palsy, and multiple-system atrophy. J Nucl Med 2012; 53:399– 406. Although DAT imaging is most widely done by SPECT, this study impressively shows what wealth of detailed anatomical and pathophysiological data can be gained from subregional striatal analyses with higher-resolution DAT-PET. Subregional patterns of DAT loss were found to differentiate between PD, MSA and PSP. Prospective, multigroup analyses are, however, needed to explore how these patterns perform in clinical routine. 32. Plotkin M, Amthauer H, Klaffke S, et al. Combined 123I-FP-CIT and 123IIBZM SPECT for the diagnosis of parkinsonian syndromes: study on 72 patients. J Neural Transm 2005; 112:677–692. 33. Koch W, Hamann C, Radau PE, et al. Does combined imaging of the pre and postsynaptic dopaminergic system increase the diagnostic accuracy in the differential diagnosis of parkinsonism? Eur J Nucl Med Mol Imaging 2007; 34:1265–1273. 34. Vlaar AM, de Nijs T, Kessels AG, et al. Diagnostic value of 123I-ioflupane and 123I-iodobenzamide SPECT scans in 248 patients with parkinsonian syndromes. Eur Neurol 2008; 59:258–266. 35. Perju-Dumbrava LD, Kovacs GG, Pirker S, et al. Dopamine transporter & imaging in autopsy-confirmed Parkinson’s disease and multiple system atrophy. Mov Disord 2012; 27:65–71. This article illustrates how urgently studies with post-mortem verification are needed for validation of imaging methods in parkinsonism. Opposed to the often cited ‘rule of thumb’, three out of six patients with autopsy-verified MSA show a more asymmetric striatal DAT binding than eight patients with PD. Thus, asymmetry of striatal DAT binding does not enable a reliable differentiation between PD and MSA. &
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Update on SPECT and PET in parkinsonism: part 1 Meyer and Hellwig 36. Hellwig S, Amtage F, Kreft A, et al. [18F]FDG-PET is superior to [123I]IBZMSPECT for the differential diagnosis of parkinsonism. Neurology 2012; 79:1314–1322. Dopamine D2/D3 receptor (D2R) SPECT has been frequently used for differentiation between PD and APS in Europe, albeit being controversial. This large prospective study clearly demonstrates that [18F]FDG-PET does not only provide a much higher accuracy than [123I]IBZM-SPECT for differentiation between PD and APS but also allows for a highly specific identification of APS subgroups (MSA, PSP, CBD). 37. Hellwig S, Kreft A, Amtage F, et al. 123I-iodobenzamide SPECT is not an & independent predictor of dopaminergic responsiveness in patients with suspected atypical parkinsonian syndromes. J Nucl Med 2013; 54:2081–2086. Striatal D2R availability assessed by SPECT has been reported to be predictive of dopaminergic responsiveness by earlier studies. This study, however, demonstrates that D2R-SPECT is not an independent predictor of treatment response if one accounts for clinical diagnosis and other clinical variables. Thus, the clinical utility of D2R-SPECT in parkinsonism is very questionable. 38. Nagayama H, Hamamoto M, Ueda M, et al. Reliability of MIBG myocardial scintigraphy in the diagnosis of Parkinson’s disease. J Neurol Neurosurg Psychiatry 2005; 76:249–251. 39. Ishibashi K, Saito Y, Murayama S, et al. Validation of cardiac (123)I-MIBG scintigraphy in patients with Parkinson’s disease who were diagnosed with dopamine PET. Eur J Nucl Med Mol Imaging 2010; 37:3–11. 40. Nagayama H, Ueda M, Yamazaki M, et al. Abnormal cardiac [(123)I]-metaiodobenzylguanidine uptake in multiple system atrophy. Mov Disord 2010; 25:1744–1747. 41. Eckert T, Van Laere K, Tang C, et al. Quantification of Parkinson’s diseaserelated network expression with ECD SPECT. Eur J Nucl Med Mol Imaging 2007; 34:496–501. 42. Juh R, Kim J, Moon D, et al. Different metabolic patterns analysis of Parkinsonism on the 18F-FDG PET. Eur J Radiol 2004; 51:223–233. 43. Eckert T, Barnes A, Dhawan V, et al. FDG PET in the differential diagnosis of parkinsonian disorders. Neuroimage 2005; 26:912–921. 44. Teune LK, Bartels AL, de Jong BM, et al. Typical cerebral metabolic patterns in neurodegenerative brain diseases. Mov Disord 2010; 25:2395–2404. 45. Minoshima S, Frey KA, Koeppe RA, et al. A diagnostic approach in Alzheimer’s disease using three-dimensional stereotactic surface projections of fluorine18-FDG PET. J Nucl Med 1995; 36:1238–1248. 46. Ma Y, Tang C, Spetsieris PG, et al. Abnormal metabolic network activity in Parkinson’s disease: test-retest reproducibility. J Cereb Blood Flow Metab 2007; 27:597–605. 47. Eckert T, Tang C, Ma Y, et al. Abnormal metabolic networks in atypical parkinsonism. Mov Disord 2008; 23:727–733.
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48. Poston KL, Tang CC, Eckert T, et al. Network correlates of disease severity in multiple system atrophy. Neurology 2012; 78:1237–1244. 49. Tang CC, Poston KL, Dhawan V, et al. Abnormalities in metabolic network activity precede the onset of motor symptoms in Parkinson’s disease. J Neurosci 2010; 30:1049–1056. 50. Holtbernd F, Gagnon JF, Postuma RB, et al. Abnormal metabolic network && activity in REM sleep behavior disorder. Neurology 2014; 82:620–627. This study underscores the value of PDRP expression as a versatile prognostic and diagnostic biomarker in LBD: PDRP expression, assessed by [18F]FDG-PET and CBF-SPECT, was elevated in patients with RBD, as a possible prodromal manifestation of LBD. One of the two cohorts underwent long-term follow-up, during which eight of the 17 patients phenoconverted to PD or DLB. Phenoconversion could be predicted by a combination of PDRP expression and age (r2 ¼ 0.64). 51. Kouri N, Whitwell JL, Josephs KA, et al. Corticobasal degeneration: a pathologically distinct 4R tauopathy. Nat Rev Neurol 2011; 7:263–272. 52. Wadia PM, Lang AE. The many faces of corticobasal degeneration. Parkinsonism Relat Disord 2007; 13 (Suppl 3):S336–340. 53. Amtage F, Hellwig S, Kreft A, et al. Neuronal correlates of clinical asymmetry in & progressive supranuclear palsy. Clin Nucl Med 2014; 39:319–325. Asymmetry of imaging and clinical findings represents a hallmark of CBD, often seen as a discriminant feature from PSP. This article stresses the fact that clinical and imaging asymmetry may also be observed in PSP, whereby clinical asymmetry correlates with asymmetric involvement of thalamus, middle cingulate gyrus and sensorimotor cortex. Parietal involvement was found to be suggestive of CBD. 54. Zalewski N, Botha H, Whitwell JL, et al. FDG-PET in pathologically confirmed && spontaneous 4R-tauopathy variants. J Neurol 2014; 261:710–716. This is one of the very few studies to date that correlated in-vivo imaging findings with autopsy data. In 10 patients with tauopathies (seven PSP, one CBD, one globular glial tauopathy), predominant imaging findings on [18F]FDG-PET were hypometabolism of caudate nucleus, thalamus, midbrain and supplementary motor area. Of note, only the patient with CBD showed asymmetric parietal hypometabolism. 55. Tang CC, Poston KL, Eckert T, et al. Differential diagnosis of parkinsonism: a metabolic imaging study using pattern analysis. Lancet Neurol 2010; 9:149– 158. 56. Tripathi M, Dhawan V, Peng S, et al. Differential diagnosis of parkinsonian syndromes using F-18 fluorodeoxyglucose positron emission tomography. Neuroradiology 2013; 55:483–492. 57. Garraux G, Phillips C, Schrouff J, et al. Multiclass classification of FDG PET scans for the distinction between Parkinson’s disease and atypical parkinsonian syndromes. Neuroimage Clin 2013; 2:883–893.
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