Can Imaging Separate Multiple System Atrophy from Parkinson’sDisease?

David J. Brooks, MD, DSc, FRCP*

Centre for Neuroscience, Department of Medicine, Imperial College London, London, United Kingdom

Multiple system atrophy (MSA) includes Shy-Dragersyndrome, striatonigral degeneration (SND, or MSA-P),and sporadic olivopontocerebellar atrophy (sOPCA, orMSA-C) within its spectrum. It is characterized patho-logically by argyrophilic, a-synuclein-positive inclu-sions in the glia and neurons in the substantia nigra,striatum, brain stem, and cerebellar nuclei and inter-mediolateral columns of the cord. Parkinson’s diseaseis associated with a-synuclein-positive Lewy bodyinclusions targeting the substantia nigra, brain stemnuclei, and cortex. Both MSA-P and PD are associatedclinically with asymmetrical parkinsonism and patho-logically with asymmetrical loss of dopaminergic pro-jections from the nigra to the striatum targeting theposterior putamen. However, as striatal degenerationis a feature of MSA-P but not PD, it should in princi-ple be possible to discriminate these conditions bydetecting striatal structural and functional changeswith imaging in MSA-P. In addition, although the lat-eral nigra is targeted in both MSA-P and PD, patho-logically series suggest there is greater involvement ofthe medial nigra in MSA. One would therefore expectto see lower levels of dopamine terminal function inthe anterior putamen and head of the caudate inMSA-P relative to PD. The potential value and role ofneuroimaging in supporting a diagnosis of MSA hasbeen recognized in revised consensus criteria, whichnow include neuroimaging criteria for the diagnosticcategory of possible MSA.1

A number of studies on the diagnostic accuracy ofstructural imaging methods in MSA have now been pub-lished, although the standard of truth has invariablybeen clinical impression.2 Patients with MSA showputaminal atrophy, T2 hypointensity, and ‘‘slitlike’’ lat-

eral hyperintensity on conventional MRI and also atro-phy of the lower brain stem, middle cerebellarpeduncles, and cerebellum. Signal hyperintensities canbe seen in the pons and middle cerebellar peduncles, andthe ‘‘hot cross bun’’ sign results from visualization of thetransverse pontine fibers.3 However, these features pro-vide low sensitivity in practice and a hyperintense puta-minal rim is a nonspecific, normal finding with 3T MRI.Sensitivity can be improved by reducing slice thicknessand the use of T2*-weighted gradient echo sequences.

MRI volumetry (MRV) can detect volume loss ofstriatum, brain stem, and cerebellum in MSA-P andhelp to separate this condition from PD. Voxel-basedmorphometry (VBM) reveals early degeneration of thebasal ganglia, followed by later-onset cortical atrophyin MSA, but is not practical for routine diagnosticworkup of individual patients. The average MCP widthis significantly smaller in patients with MSA than inthose with PD or control subjects without any overlapbetween MSA patients and PD patients or healthy sub-jects when a cutoff value of 8.0 mm is applied. Thearea of the pons measured on midsagittal T1-weightedMR images is also significant smaller in MSA-P patientscompared with patients with PD and healthy controlsthough individual ranges overlap. Diffusion-weightedimaging (DWI) may represent the most sensitive diag-nostic tool for supporting a diagnosis of MSA-P. DWIat 1.5T is able to discriminate patients with MSA-Pfrom patients with PD on the basis of putaminal ADCand Trace(D) values.4 In line with the known underly-ing neuropathology, more severe involvement posteriorin the MCP has been shown to be higher in patientswith MSA compared with PD or PSP, allowing a gooddiscrimination between these disease entities. Whenstudied with magnetization transfer imaging (MTI),MSA-P patients have been shown to have a significantMT reduction in the putamen and the white matter ofthe precentral gyrus compared with controls.

Transcranial sonography (TCS) detects ultrasoundechoes from brain parenchyma through the intactskull. Around 90% of patients with PD but only 10%of MSA cases show midbrain hyperechogenicity. Con-versely, hyperechogenicity of the lentiform nucleus

------------------------------------------------------------*Correspondence to: Prof. David J. Brooks, Du Cane Road, LondonW12 0NN, UK; david.brooks@csc.mrc.ac.uk

Relevant conflicts of interest/financial disclosures: Nothing to report.Full financial disclosures and author roles may be found in the onlineversion of this article.

Received: 12 October 2011; Accepted: 23 October 2011Published online in Wiley Online Library (wileyonlinelibrary.com).DOI: 10.1002/mds.24046

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(LN) can be detected in more than 70% of MSApatients compared with one quarter of patients withPD. Combining the finding of a hyperechogenic LNwith a normal echogenic SN is highly specific forMSA, but in practice, the sensitivity of this approachis only around 59%.5

The function of the presynaptic dopaminergic systemis severely impaired in patients with both clinicallyprobable MSA-P and PD—putamen 18F-dopa uptakeand DAT binding are reduced by at least 30% of nor-mal levels at symptom onset. It has been reported thatloss of striatal DAT binding is more asymmetrical in PDthan in MSA-P and that caudate 18F-dopa uptake is sig-nificantly more depressed in MSA-P than in PD.6 Thishas led to the suggestion that imaging presynaptic dopa-minergic function may have utility for discriminatingMSA-P from PD. However, when discriminant analysiswas applied to putamen and caudate 18F-dopa uptakein patients with parkinsonian syndromes, patients wereassigned to MSA and IPD groupings with equal fre-quency.7 A problem with these dopaminergic imagingseries was that as for the MRI studies reviewed above,the standard of truth was clinical impression. It is nowknown from clinicopathological studies that, at best,clinic impression in life only concords with subsequentpathology in around 90% of cases labeled as PD and86% labeled as MSA. In early disease concordance waseven lower, as not all characteristic clinical featureswere evident. In addition, most cases of parkinsonismshowed mixed pathology at postmortem.In this issue of Movement Disorders, Perju-Dumb-

rava and colleagues8 have compared 123I-beta-CITSPECT findings in 8 PD and 6 MSA cases who subse-quently had pathological validation of their antemor-tem clinical diagnoses. Clinical disease duration wason average around 4 years in both groups at the timeof imaging, and visual inspection detected bilaterallyreduced striatal DAT binding in all patients. Meanstriatal binding was reduced by 53% in MSA-P and52% in PD, and, unexpectedly, there was a trend to-ward greater asymmetry of striatal binding in MSAthan in PD. In contrast to previous reports, putamen/caudate binding ratios did not differ between the 2groups. These authors concluded that MSA and PDcannot be differentiated by subregional analysis or vis-ual inspection of striatal DAT binding.This report is valuable as it is the first imaging study

of DAT binding in MSA-P with pathological valida-tion. However, its conclusion that imaging striatal do-pamine terminal function poorly discriminates MSAand PD is already widely accepted. 123I-FP-CITSPECT is a DAT imaging agent licensed in Europeand the United States to discriminate parkinsonianpatients from those with benign tremors via detectionof loss of functional nigrostriatal dopaminergic neu-rons. This agent, however, makes no claim to be able

to discriminate the various parkinsonian conditionsassociated with striatal dopamine deficiency. Interest-ingly, recently it has been suggested that relativelyreduced midbrain DAT binding may aid discrimina-tion of MSA from PD.9

Although the Perju-Dumbrava series is valuable, it is

a small series and so subject to ascertainment bias.

The PD cases died a few years after imaging and sohad relatively severe disease. In addition, the finding

that the MSA group showed greater asymmetry of

striatal DAT binding than did the PD group almost

certainly reflects the inclusion of 3 highly asymmetric

clinical cases in the series of 6. In a previous study of

a much larger series, the same group reported that PDcases showed greater asymmetry of striatal DAT bind-

ing than MSA cases. At autopsy the MSA and PD

cases showed a high prevalence of mixed pathology in

the Perju-Dumbrava series, with small-vessel disease

present in a majority of both groups and tangle dis-

ease in 4 of the 8 PD cases. Given this, one cannotnecessarily generalize the DAT imaging findings to all

MSA and PD cases.As MSA is associated with striatal pathology, imag-

ing postsynaptic dopaminergic function or striatal me-tabolism might be expected to provide betterdiscrimination of MSA-P from PD. Studies of D2 do-pamine receptor binding in PD with 11C-raclopridePET and 123I-IBZM SPECT, have shown normal ormildly increased D2 binding in PD, whereas in atypi-cal parkinsonian syndromes, D2 receptor density maybe reduced from the onset of clinical symptoms. How-ever, D2 imaging shows poor sensitivity for discrimi-nating PD and MSA—29% of established MSA-Pcases have been reported to have normal striatal123I-IBF binding.10

Striatal metabolic imaging is currently the most ro-bust biomarker for separating atypical from typicalPD. Striatal levels of glucose metabolism measuredwith FDG PET show 80%–100% sensitivity acrossdifferent series for discriminating MSA from PD, asthe former shows reduced levels and PD patients showpreserved or raised lentiform metabolism. If computer-aided statistical parametric mapping (SPM) isemployed then blinded assessment of SPMs agreeswith clinical diagnosis in 92% of subjects followedclinically for 2 years.11

In summary, based on the best current knowledge,the revised MSA consensus criteria include atrophy onconventional MRI of the putamen, middle cerebellarpeduncle, pons, or cerebellum or hypometabolism onFDG-PET in the putamen, brain stem, or cerebellumas supportive features when differentiating possibleMSA-P from PD. Although imaging presynaptic dopa-mine terminal function has value for separating par-kinsonian conditions associated with a striataldopamine–deficiency state from those without, the

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general consensus, reinforced by the report fromPerju-Dumbrava in this journal, suggests that DATimaging currently lacks specificity to discriminatebetween the degenerative parkinsonian syndromes.

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8. Perju-Dumbrava LD, Kovacs GG, Pirker S, et al. Dopamine trans-porter imaging in autopsy-confirmed Parkinson’s disease and multi-ple system atrophy. Mov Disord. 2012;27:65–71.

9. Goebel G, Seppi K, Donnemiller E, et al. A novel computer-assisted image analysis of [123I]beta-CIT SPECT images improvesthe diagnostic accuracy of parkinsonian disorders. Eur J Nucl MedMol Imaging. 2011;38:702–710.

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