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Critical evaluation of the Braak staging scheme for Parkinson's disease.

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Critical Evaluation of the Braak Staging Scheme
for Parkinson’s Disease
Kurt A. Jellinger, MD
Drs Burke and coauthors’1 critical review of Braak’s staging
scheme of Lewy pathology, in general, is well documented and
highly welcome, although the authors did not consider several
important comments about this staging system.
First, the concept that lower brainstem synucleinopathy
represents “early” Parkinson’s disease (PD) is well documented
by recent studies on “incidental Lewy body [LB] disease” showing that the distribution of LBs is similar to that in PD, but
with lower average Braak stage (2.7 ⫾ 0.3 vs 4.4 ⫾ 0.3), associated with decreased tyrosine hydroxylase immunoreactivity in
both the striatum and sympathetic epicardial nerve fibers compared with healthy subjects but not in the same extent as in PD
patients.2– 4
Second, it is unclear whether the accumulation of pathological ␣-synuclein (aSyn) in substantia nigra correlates with the
dopaminergic deficit in the striatum as the major cause of motor
symptoms in PD. According to recent studies, dopamine transporter immunoreactivity in the striatum is inversely correlated
with the total aSyn burden in substantia nigra but not with LB
counts alone, and nigral tyrosine hydroxylase immunoreactivity
did not correlate with aSyn immunoreactivity, because it can be
preserved in neurons aggregating aSyn.5 These data support the
concept of axonal transport impairment5 and/or synaptic dysfunction causing aSyn aggregation (R. L. Kramer, personal communication, 2008).
Third, the predictive concept is doubtful1 because recent
retrospective clinicopathological studies have shown that between 6.3 and 43% of clinically manifested cases of PD did not
follow the proposed caudorostral progression pattern of LB pathology, and there was sparing of medullary nuclei in 7 to 8.3%
of PD cases with aSyn-positive inclusions in midbrain and even
cortex corresponding to Braak stages 4 and 5,6 – 8 whereas parkinsonian symptoms were already observed in stages 2 and 3,7
or even in single cases with restricted occurrence of LBs in the
dorsal vagal nucleus without involvement of other brain regions.9
Fourth, keeping these and other pros and cons in mind,
one has to conclude that if robust correlations between clinical
course and morphological changes, not definitely validated using
the currently available Braak staging scheme of LB pathology,
will be confirmed by future prospective clinicopathological studies, this and other staging systems must be revised accordingly.
In accordance with recent critical reappraisals of this staging system,1,6,7 the relation between patterns of aSyn immunostaining
in the human brain and the disease entities now recognized as
sporadic PD and dementia with LBs remains to be reevaluated.
Because the causes and molecular basis of rather frequent deviations from the proposed caudorostral progression of aSyn pa-
© 2010 American Neurological Association
thology in PD, its relation to the onset of classic parkinsonian
symptoms, the causes for the lack of clinical symptoms despite
widespread aSyn pathology in the nervous system,6,7 their relations to frequent coincidental Alzheimer’s-type lesions,7 and the
pathophysiological impact of these pathologies are currently far
from being understood, the resolution of these questions will
require further studies.
Potential Conflicts of Interest
Nothing to report.
Burke RE, Dauer WT, Vonsattel JP. A critical evaluation of the
Braak staging scheme for Parkinson’s disease. Ann Neurol 2008;
64:485– 491.
Beach TG, Adler CH, Sue LI, et al. Reduced striatal tyrosine
hydroxylase in incidental Lewy body disease. Acta Neuropathol
2008;115:445– 451.
Dickson DW, Fujishiro H, DelleDonne A, et al. Evidence that
incidental Lewy body disease is pre-symptomatic Parkinson’s disease. Acta Neuropathol 2008;115:437– 444.
DelleDonne A, Klos KJ, Fujishiro H, et al. Incidental Lewy body
disease and preclinical Parkinson disease. Arch Neurol 2008;65:
1074 –1080.
Kovacs GG, Milenkovic IJ, Preusser M, Budka H. Nigral burden
of alpha-synuclein correlates with striatal dopamine deficit. Mov
Disord 2008;23:1608 –1612.
Parkkinen L, Pirttila T, Alafuzoff I. Applicability of current staging/
categorization of alpha-synuclein pathology and their clinical relevance. Acta Neuropathol 2008;115:399 – 407.
Jellinger KA. A critical reappraisal of current staging of Lewyrelated pathology in human brain. Acta Neuropathol 2008;116:
Kalaitzakis ME, Graeber MB, Gentleman SM, Pearce RK. Controversies over the staging of alpha-synuclein pathology in Parkinson’s disease. Acta Neuropathol 2008;116:125–128; author reply
129 –131.
Wakabayashi K, Toyoshima Y, Awamori K, et al. Restricted occurrence of Lewy bodies in the dorsal vagal nucleus in a patient
with late-onset parkinsonism. J Neurol Sci 1999;165:188 –191.
DOI: 10.1002/ana.21638
Comments on “Neuroplasticity Predicts Outcome
of Optic Neuritis Independent of Tissue Damage”
Sylvie Chokron, PhD
Jenkins et al1 recorded cortical activation with functional magnetic resonance imaging (fMRI) in optic neuritis (ON) patients
and healthy volunteers over 12 months and proposed that lateral
occipital complex (LOC) activation predicts visual outcome after
clinically isolated ON.
A few methodological points should be addressed regard-
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braak, scheme, evaluation, critical, disease, parkinson, staging
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