a critical evaluation of the braak staging scheme for parkinson's disease

A Critical Evaluation of the Braak StagingScheme for Parkinson’s Disease

Robert E. Burke, MD,1,2 William T. Dauer, MD,1,3 and Jean Paul G. Vonsattel, MD2

Braak and colleagues have proposed that, within the central nervous system, Parkinson’s disease (PD) begins as a synucleinopa-thy in nondopaminergic structures of the lower brainstem or in the olfactory bulb. The brainstem synucleinopathy is postulatedto progress rostrally to affect the substantia nigra and cause parkinsonism at a later stage of the disease. In the context of adiagnosis of PD, made from current clinical criteria, the pattern of lower brainstem involvement accompanying mesencephalicsynucleinopathy is often observed. However, outside of that context, the patterns of synucleinopathy that Braak described areoften not observed, particularly in dementia with Lewy bodies and when synucleinopathy occurs in the absence of neurologicalmanifestations. The concept that lower brainstem synucleinopathy represents “early PD” rests on the supposition that it has asubstantial likelihood of progressing within the human lifetime to involve the mesencephalon, and thereby cause the substantianigra pathology and clinical parkinsonism that have heretofore defined the disease. However, the predictive validity of thisconcept is doubtful, based on numerous observations made in populations of aged individuals who, despite the absence ofneurological signs, have brain synucleinopathy ranging up to Braak stages 4 to 6 at postmortem. Furthermore, there is norelation between Braak stage and the clinical severity of PD. We conclude that the relation between patterns of abnormalsynuclein immunostaining in the human brain and the disease entity now recognized as PD remains to be determined.

Ann Neurol 2008;64:485–491

The neurobiology of �-synuclein has been central tothe study of Parkinson’s disease (PD) since the discov-ery that missense mutations in this protein cause famil-ial PD.1 The discovery that �-synuclein is a majorcomponent of Lewy bodies in idiopathic PD height-ened interest in the protein,2 as did the observationthat duplication or triplication of the �-synuclein genealso causes PD.3 Synuclein had yet another importantimpact on thinking about PD when Braak and col-leagues published elegant descriptions of abnormal pat-terns of �-synuclein immunostaining in human brainsand proposed a neuropathological staging scheme.4

They proposed that the earliest stage of PD (stage 1) ischaracterized by abnormal �-synuclein immunostain-ing confined to the medulla oblongata or the olfactorybulb, and that clinical parkinsonism and neuronal lossin the substantia nigra pars compacta (SNpc), both ofwhich are now required for a definitive diagnosis ofPD, occur late in the disease course.

This proposed staging scheme has had a profoundimpact on many aspects of current thinking about PD.The concept that the disease may begin in nondopam-inergic structures of the brainstem, or perhaps even inthe peripheral autonomic nervous system,4,5 has influ-

enced how we think about early diagnosis of PD, howwe might develop biomarkers,6 and how we thinkabout the “best” animal models for the disease.7 TheBraak staging scheme for PD has already begun to re-ceive wide acceptance.8,9 Given the significant influenceof the Braak staging scheme and its likely impact onfuture PD research directions, it appears critical to assesswhether its scientific validity has been affirmed, and toconsider issues that will require further investigation.

Braak Staging and the Clinical Manifestationsof Parkinson’s DiseaseBraak Staging of the Pathology of Parkinson’s DiseaseBraak and colleagues have outlined their concept ofstaging PD with great clarity in many publica-tions,4,5,10,11 so it will suffice here to summarize theirprincipal findings. Their observations are depictedschematically in Figure 1 (based on Braak and col-leagues11). Some brains showed abnormal synucleinimmunostaining only in the medulla oblongata (in thedorsal motor nucleus [DMN] of the vagus) or the ol-factory bulb; these regions are identified as region 1.Other brains showed not only involvement of these

From the Departments of 1Neurology, 2Pathology and Cell Biology,and 3Pharmacology, Columbia University Medical Center, NewYork, NY.

Received Jun 3, 2008, and in revised form Sep 3. Accepted forpublication Sep 5, 2008.

Published online in Wiley InterScience (www.interscience.wiley.com).DOI: 10.1002/ana.21541

Potential conflict of interest: Nothing to report.

Address correspondence to Dr Burke, Department of Neurology,Room 306, Black Building, Columbia University, 650 West 168thStreet, New York, NY 10032. E-mail: [email protected]

POINT OF VIEW

© 2008 American Neurological Association 485Published by Wiley-Liss, Inc., through Wiley Subscription Services

structures, but also rostrally adjacent structures, includ-ing the caudal raphe nuclei and the locus ceruleus (LC)(region 2 in Fig 1). Because each group of brains withmore widespread changes always included the involve-ment of the medulla oblongata and pons, as observedin the mildly involved brains, Braak and colleaguesproposed that the varying degrees of synuclein pathol-ogy depict a temporal sequence of events: involvementlimited to region 1 is the earliest phase (stage 1), in-volvement of regions 1 and 2 is the next phase (stage2), and so on. Braak and colleagues proposed that it isonly when the synuclein pathology reaches stage 3 or 4that SN neuronal loss occurs, clinical signs of parkin-sonism appear, and it becomes possible to diagnose“PD” by current criteria. Thus, the Braak hypothesisproposes that synuclein pathology in the lower brain-stem is necessary for the later appearance of PD, andfurther, that it is sufficient; that is, this synuclein pa-thology so predictably evolves to PD that it can beconsidered to represent “early PD.”

Patterns of Synuclein Pathology in Human BrainWe shall first consider the evidence that lower brain-stem synuclein pathology is necessary for the eventualoccurrence of clinical PD, as it is now recognized. InBraak’s original data,4 of the patients who had beenclinically diagnosed to have PD, all had synuclein pa-thology not only in the SNpc, but also in either theLC, the nucleus raphe, or the DMN. This observation,that in the context of a clinical diagnosis of PD,synuclein pathology is always observed caudal to themesencephalon, has been largely borne out by otherinvestigators.12,13 However, this observation is notenough to be certain that, in these instances, the clin-ical diagnosis of PD was universally preceded by lowerbrainstem synucleinopathy. In considering whethersuch may be the case, it is useful to think about pat-terns of synuclein deposition in cases of “incidentalLewy body disease,” individuals without dementia orparkinsonism who harbor synuclein pathology, includ-ing in the SN. There is substantial evidence that suchcases may represent “preclinical” PD; they have re-duced numbers of SN dopamine neurons to a slightlyless degree than that in PD patients.14 Contrary towhat would be predicted by the Braak hypothesis,many of these brains with synuclein pathology in themesencephalon, likely to represent “preclinical” PD, donot show a lower brainstem synucleinopathy. Parkki-nen and colleagues12 identified 79 brains withsynuclein pathology in the mesencephalon. Amongthese, 13 (16%) did not have synuclein pathology inthe DMN or LC.12 Most of these patients were neu-rologically normal, some had had strokes, and one hada diagnosis of dementia with Lewy bodies (DLB).

DLB is a particular problem for the Braak schemebecause such patients were excluded.4 The exclusion ofcases of DLB from the Braak series cannot be justifiedbecause there is a growing consensus that the extensiveoverlap in the clinical and pathological features of PD,PD with dementia, and DLB do not permit meaning-ful distinctions among them.15,16 These disorders aremore appropriately considered as manifestations of asingle underlying pathogenic mechanism encompassedby the terms Lewy body disorders15 or Lewy body dis-ease.16 Among 226 brains with synuclein pathologymore recently analyzed by Parkkinen and colleagues,17

there was a clinical diagnosis of dementia in 74.Among these, 28% had synuclein pathology that didnot fit the Braak scheme. Given the presence ofsynuclein pathology, many of these cases were likely tohave DLB.17

The Braak scheme also does not address the occur-rence of “amygdala-predominant” synuclein patholo-gy.18 In their series, Zaccai and colleagues18 identifiedsynuclein pathology in 39% of aged individuals fol-lowed prospectively in two population-based cohorts.Among the 76 brains with synuclein pathology, 35

Fig 1. Patterns of abnormal immunostaining for �-synucleinidentified by Braak and colleagues. Six patterns of immuno-staining were observed. In the pattern with the least extent ofabnormal staining, involvement was observed only in region 1,which contains the dorsal motor nucleus of the vagus. In thepattern with the next most limited distribution, staining wasobserved, in addition to region 1, in region 2, which includedthe locus ceruleus and other “gain setting nuclei.” In the pat-tern with the next most involvement, abnormal staining wasobserved not only in regions 1 and 2, but also region 3,which included the substantia nigra (SN) and the amygdala.Because each succeeding pattern of increased rostral involve-ment included pathology in the adjacent more caudal regions,Braak and colleagues proposed that PD begins in region 1(stage 1), then proceeds rostrally to region 2 (stage 2), and soon. Clinical signs of parkinsonism and Lewy pathology in themesencephalon, both of which are now required for a defini-tive diagnosis of PD, are hypothesized to occur late in thedisease, at stage 3. 4 � region 4 including mesocortex andthalamus; 5 � region 5 including neocortex high order associ-ation; 6 � region 6 including neocortex, primary and second-ary. (Adapted from Figs 1C and D in Braak and colleagues,11

by permission.)

486 Annals of Neurology Vol 64 No 5 November 2008

(46%) did not conform to the Braak staging scheme.Among these, 22 (29%) had amygdala-predominantsynuclein pathology. They identified no relation be-tween amygdala synuclein pathology and neurofibril-lary Alzheimer’s changes.18

Thus, although the patterns that Braak and col-leagues described usually appear to be confirmed whena clinical diagnosis of PD has been made by currentclinical criteria, they often are not confirmed outside ofthat context, particularly in clinically asymptomatic in-dividuals and in individuals with DLB. Given the evi-dence that individuals with incidental Lewy body dis-ease may represent preclinical PD, and the frequentobservation that individuals with an initial diagnosis ofDLB evolve to a condition that is indistinguishablefrom PD, it is not tenable to propose that lower brain-stem synuclein pathology is a necessary occurrence be-fore the onset of PD, as it is now recognized.

Does Braak Stage 1 (or 2) Represent “EarlyParkinson’s Disease”?The Braak hypothesis not only proposes that lowerbrainstem pathology is a necessary precondition for theoccurrence of PD, but also that it is sufficient. In otherwords, there is such a compelling likelihood that stage1 or 2 synuclein pathology will evolve to stages 3 or 4,and more importantly, evolve to manifest clinical par-kinsonism that this pathology can be considered torepresent “early PD,” as has been claimed.9 A numberof observations do not support the claim that stage 1and 2 Braak synuclein pathology can be meaningfullyconsidered to represent “early PD.” Data from elderlyindividuals without detectable neurological impairment(Fig 2) show that many harbor early Braak pathology.Given the advanced age of many of these individuals, itis not meaningful to speculate that they would haveexperienced development of PD had they lived longer.We do not know how long these individuals harboredthis pathology or how long it would take for it toevolve, if ever.

A more worrisome concern is whether the evolutionof synuclein pathology to Braak stages 4, 5, or 6, evenif it occurs, necessarily means that the individual willclinically manifest any of the motor or nonmotor dis-abilities currently recognized as clinical manifestationsof PD. In Figure 2, it is apparent that many individ-uals die harboring Braak synuclein pathology stages 4to 6 without ever having had neurological impairment,and many additional studies support this observa-tion.19–23 Therefore, we cannot be certain that earlyBraak stages will evolve to higher stages in the humanlifetime, and even when they do, they will not neces-sarily be associated with the clinical disabilities that wenow identify as PD. Thus, the relation between earlyBraak stages of abnormal synuclein staining and thedisease entity that we now identify as PD is unknown.

Is There a Relation between Braak Stages and Eitherthe Duration or the Clinical Severity ofParkinson’s Disease?If the Braak staging scheme represents the actual tem-poral evolution of PD, there should be a relation be-tween Braak stages and either the duration or the se-verity of PD. Braak and colleagues did not examineany possible relation between stages and duration ofdisease. However, their data demonstrate that there isno relation between Braak stage and Hoehn and Yahrscore (Fig 3). Many patients with Braak stages 4 andhigher did not have signs of parkinsonism. In contrast,many individuals with Braak stages 3 and 4 (whensigns of parkinsonism are predicted to first appear) hadsevere PD (Hoehn and Yahr 5). In fact, Braak’s dataappear to cluster into two distinct sets of patients:those with PD and those without.

Is REM Sleep Behavior Disorder an Early,Nondopaminergic Stage of Parkinson’s DiseaseCaused by Brainstem Synucleinopathy?In support of the Braak scheme, it has been proposedthat REM sleep behavior disorder (RBD) may be anearly nondopaminergic manifestation of PD caused bysynuclein pathology identified in stage 2.6,9,24 There isno question that RBD can precede signs of parkinson-ism in a number of neurodegenerative diseases.24,25

The question is whether such instances support theconcept that PD universally begins with nondopamin-ergic involvement of the brainstem. The proposal that

Fig 2. Relation between subject age at time of death andBraak Parkinson’s disease (PD) stage in 116 individuals with-out dementia or parkinsonism. The data presented are fromBraak and colleagues4 (circles; N � 67), Parkkinen and co-workers12 (squares; N � 32), and Bloch and researchers44

(triangles; N � 17). There is no relation between age atdeath and Braak stage (r � 0.09, not significant). Braakstages 1 to 6 synuclein pathology is observed in neurologicallyunimpaired individuals who live decades beyond the averagelife expectancy at birth for industrialized nations.

Burke et al: Braak PD Staging Scheme 487

RBD represents a clinical manifestation of stage 2synucleinopathy would depend foremost on compellingevidence that the pathology described provides a plau-sible neuropathological substrate. The neural structuresof the human brain that mediate muscle atonia duringREM sleep are not precisely known.24,25 It has beenproposed that the subceruleus region in cat, and its an-alogue in rat, the sublateral dorsal nucleus, are crucialfor atonia during REM sleep.24 Although the humanhomologue of this structure is not defined,24 we canconsider whether stage 2 Braak pathology is found ven-tromedial to the LC, the region thought important forRBD.24 Although Braak and colleagues have describedLewy pathology in the LC, they have not provided anexplicit description of the region postulated to be theanalogue of the rat sublateral dorsal nucleus. Even ifsuch Lewy pathology were found, it would not providea compelling basis for the postulated cellular dysfunc-tion. Indeed, abnormal synuclein accumulation doesnot prove cellular dysfunction (discussed further later),and it is unknown whether stage 2 Braak is accompa-nied by neuronal loss or gliosis in the medulla orpons.4 Thus, there is no compelling evidence that thesynuclein pathology described in Braak stage 2 pro-vides a neural substrate for RBD.

If RBD cannot be specifically attributed to the ab-normal synuclein staining observed in Braak stages 1

and 2, then we must evaluate other evidence thatRBD, in the setting of neurodegenerative synucle-inopathies, is, in fact, due to involvement of brainstemnondopaminergic systems. One potential source ofsupportive data would be postmortem analysis in thecontext of such diseases that RBD can occur in theabsence of SN involvement. To date, there have beenpostmortem analyses of 27 RBD brains associated withsynucleinopathies.25 Among these, the SN was exam-ined in seven brains, and these brains always exhibitedSN neuronal loss and synuclein pathology. Thus, weare unaware of a single case in which RBD was asso-ciated with a synucleinopathy without coexisting in-volvement of the SN.

An alternative source of data to evaluate the proposi-tion that RBD is a nondopaminergic manifestation ofthe synucleinopathies is to assess the relation betweenRBD and nigrostriatal dopaminergic pathways assessedby neuroimaging techniques. Eisensehr and colleagues26

examined striatal dopamine transporter binding by (N)-(3-iodopropene-2-yl)-2�-carbomethoxy-3�-(-4-chloro-phenyl)tropane ([123I]IPT)-single-photon emission com-puted tomography (SPECT) in five patients with RBDand with normal neurological examinations. The RBDpatients had reduced [123I]IPT-SPECT. Albin and col-leagues27 made similar observations using [11C]dihy-drotetrabenazine ([11C]DTBZ)-PET in six patients withRBD and no signs of parkinsonism. Gilman and co-workers28 examined the status of nigrostriatal dopami-nergic projections by use of [11C]DTBZ -PET in 13 pa-tients with RBD and a clinical diagnosis of multiplesystem atrophy (MSA). [11C]DTBZ striatal binding val-ues were diminished among these patients, and therewas a significant inverse correlation between[11C]DTBZ binding and severity of RBD.28 Eisensehrand colleagues29 identified reduced [123I]IPT-SPECTvalues even in subclinical RBD patients. Thus, there isevidence of dopaminergic dysfunction in clinical andeven subclinical RBD without other neurological mani-festations. These studies do not provide evidence to sup-port the notion that RBD is caused by nondopaminergicinvolvement in the synucleinopathies; on the contrary,they indicate that mild and even subclinical RBD is as-sociated with dopaminergic dysfunction.

It has often been pointed out that RBD may precedeparkinsonism by many years. However, if the Braakscheme is a valid and general description of diseaseprogression in PD, then it would be predicted thatRBD would always precede parkinsonism. However,more often the converse is true. In a series of 195 pa-tients referred to a PD clinic, assessed by Scaglione andcoworkers,30 64 (33%) had RBD. Of these, the signsof parkinsonism preceded RBD in 73%, and amongthese patients RBD appeared an average of 8 years afterthe onset of parkinsonism. In a series of 60 patients

Fig 3. Relation between Braak Parkinson’s disease (PD) stageand Hoehn and Yahr (H&Y) PD score at the time of deathin 96 individuals. The data presented are from Braak andcolleagues.4 The 68 individuals with a Hoehn and Yahr scoreof zero are the same individuals as shown in Figure 2, withthe single exception that Braak Case 105, with a diagnosis ofAlzheimer’s disease, is excluded in Figure 2. Among 29 pa-tients with PD (Hoehn and Yahr score � 1), there is no re-lation between Hoehn and Yahr score and Braak stage (r ��0.2, not significant). Data appear to be clustered into twopopulations: those with PD and those without.


with RBD that De Cock31 and colleagues reported, themanifestations of RBD preceded parkinsonism in only22% of patients. Thus, even if RBD in the context ofsynucleinopathies could be attributed to a specific de-generative change in the brainstem, and even if suchchange could be attributed to the synuclein pathologythat Braak described, then the aforementioned clinicalobservations would suggest that involvement of mesen-cephalic dopaminergic systems in the majority of PDcases precedes pontine involvement, contrary to theBraak scheme.

Although the occurrence of RBD before parkinson-ism in PD has often been offered as evidence that spe-cifically supports the Braak staging scheme of PD, itcannot be accepted as such. In many cases, RBD pre-cedes parkinsonism in the MSAs.32,33 Although MSAis also a synucleinopathy, characterized by synuclein-positive glial inclusions, it does not manifest intraneu-ronal synucleinopathy, and the Braak staging schemecannot be proposed to occur.

What Is the Pathophysiological Significance ofLewy Pathology?Another challenge for the Braak staging scheme is theuncertain pathophysiological significance of Lewy pa-thology. The Braak scheme assumes that Lewy pathol-ogy reliably detects neurons that are in a state of PD-related cellular dysfunction. However, synucleinpathology may not identify such neurons with sensitiv-ity; conversely, neurons with abnormal synuclein im-munostaining may not be in a state of PD-relateddysfunction. About the ability of synuclein immuno-staining to detect early PD neuronal dysfunction, pa-tients with PD-causing LRRK2 mutations are informa-tive. Although the majority of patients with the mostcommon LRRK2 mutation (G2019S) show classicLewy body pathology, some do not. And strikingly,many patients with other pathogenic mutations ofLRRK2 do not show Lewy pathology. Indeed, the ini-tial clinical report of LRRK2-related PD describes mul-tiple cases of “pure nigral degeneration.”34 Thus, in agenetically defined patient population, it is clear thatLewy pathology is not a reliable indicator of PD cellu-lar dysfunction. Therefore, the assumption thatsynuclein immunopathology will define where PD “be-gins,” as in the Braak scheme, is not tenable. Con-versely, cell biological studies of synuclein and relatedprotein aggregation disorders raise questions about thepathophysiologic significance of protein aggregates. In-creased expression of synuclein protein has been iden-tified in neurons in a variety of injury models,35–37 andin these contexts it has, in fact, been postulated to pos-sibly play a protective role. In a Drosophila model invivo, formation of synuclein inclusions correlates withreduced cellular toxicity.38 In human brain, an inverserelation has been noted between the presence of Lewy

bodies and neuron death.39 Related work in Hunting-ton’s disease demonstrates that protein inclusions marksurviving cells that are effectively sequestering mis-folded protein.40 In conclusion, the absence of abnor-mal immunostaining for synuclein in neurons cannotbe interpreted as evidence that the cell is free of PD-related dysfunction; on the other hand, the presence ofsuch staining cannot be interpreted as evidence that thecell is dysfunctional or that synuclein is responsible.

Are There Alternative Hypotheses for theRegional Patterns of Synuclein Pathology ThatBraak and Colleagues Observed?If there is a consensus that the regional patterns ofsynuclein pathology that Braak and colleagues de-scribed are, in most instances, confirmed in the contextof a clinical diagnosis of PD, and yet there is reasonalso to question the caudal-to-rostral evolution of thedisease, as proposed, then we must consider whetherthere are alternative hypotheses to account for the pat-terns observed. One alternative hypothesis is that pat-terns are due to the relative likelihood of differentbrain regions to manifest Lewy pathology. Without in-voking any assumptions about the timing of events, wemight hypothesize that the DMN is a brain regionlikely to demonstrate such pathology, the LC nextmost likely, and so on. Without any assumptions aboutwhich region, if any, was affected “first,” it would beproposed that observations made postmortem reflectthese probabilities. Such a concept would account forthe observation that it is unlikely to encounter SNLewy pathology in the absence of pathology in theDMN or LC, or both. On the other hand, this con-cept would also account for the instances in whichatypical patterns are observed. The likelihood of differ-ent brain regions to manifest Lewy pathology would bedetermined by many cellular characteristics of the neu-rons in these regions: their level of expression ofsynuclein, the likelihood that the cellular environmentwould be permissive for synuclein aggregation, the abil-ity of these neurons to clear synuclein aggregates, andso on. The DMN, LC, and the SNpc are distinguishedfor their abundant levels of expression of �-synucleinmRNA41 (Fig 4). There is, in fact, a striking correla-tion between the human brain structures identified in“early” Braak stages and structures with the greatestlevels of synuclein expression in the rodent brain: stage1 � DMN and olfactory tubercle; stage 2 � LC; andstage 3 � amygdala, SN, the pedunculopontine nu-cleus, and the nucleus of the diagonal band. In humanbrain, high levels of synuclein expression have been ob-served in the LC and SNpc.42

ConclusionsBraak and colleagues’ elegant and thorough morpho-logical investigations have demonstrated intriguing pat-


terns of synuclein pathology in the brains of patientswith a clinical diagnosis of PD. For the most part,these patterns have been confirmed by other investiga-tors. However, there has been little exploration of thesepatterns in patients with a clinical diagnosis of DLB,and the existing evidence suggests that nonconfor-mance with the Braak patterns occurs. This questionbears importantly on the meaning of the Braak pat-terns for the pathogenesis of PD, because PD and DLBare arguably variant presentations of a single entity.16

Most importantly, this assessment of the Braak stagingscheme suggests that there is insufficient evidence toclaim that human PD begins in nondopaminergicstructures of the brainstem and then evolves in acaudal-to-rostral progression over the course of the dis-ease. A number of currently unresolved questions leadto this assessment. First, the prognostic implications ofthe presence of synuclein pathology in the brainstemare unknown. There are numerous instances ofsynuclein pathology in the brainstem, and in fact, even

more widely distributed in the brain, in neurologicallyintact elderly individuals. To propose that these indi-viduals would have experienced development of PD“had they lived long enough” is speculative and mean-ingless given their advanced age. We do not know howlong these individuals harbored this pathology, or if itwould have progressed at all. Second, we do not un-derstand the relation between abnormal synuclein im-munostaining in the brain and the selective loss of neu-rons that is the cardinal manifestation of PD. There arereported individuals with only Braak stage 2 synucle-inopathy and yet who have clinical parkinsonism,17 buton the other hand, there are many individuals withBraak stage 6 who do not. Not surprisingly, in view ofthese observations, there is no relation between Braakstages and the clinical severity of PD. In conclusion,the regional patterns of synuclein pathology in PDbrains that Braak and colleagues described do not pro-vide compelling evidence for the caudal-to-rostral tem-poral progression of the disease that they postulate, be-cause these patterns may be accounted for alternativelyby considerations related to the propensity of brain re-gions to display such pathology, based on regional dif-ferences in levels of synuclein expression and other fac-tors.

The resolution of these questions will require muchmore study, including additional assessments of thepatterns of synucleinopathy in the human brain and,most importantly, how these patterns relate to vali-dated biomarkers for progression of PD.43 At a morebasic level, we need a better understanding of the neu-robiology of synuclein. Although there is much evi-dence that overexpression of synuclein can be deleteri-ous to neurons, it is unlikely to be just that simple.Although time and again the neurobiology of synucleinhas offered opportunities to understand the pathogen-esis of PD, these are as yet only opportunities, andtheir fulfillment will require much additional work andcritical analysis.

This work was supported by NIH (NS26836, NS38370) (R.E.B.)K02 NS045798) (W.T.D.), the Anne and Bernard Spitzer Centerfor Cell and Genetic Therapy For Parkinson’s Disease (W.T.D.),and the Parkinson’s Disease Foundation. (R.E.B., W.T.D.,J.P.G.V.)

Acknowledgement

We are indebted to Drs I. Alafuzoff and K. Jellinger for their reviewof the manuscript and helpful comments.

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a critical evaluation of the braak staging scheme for parkinson's disease

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