Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Editorial
. 2008 Nov;64(5):485-91.
doi: 10.1002/ana.21541.

A critical evaluation of the Braak staging scheme for Parkinson's disease

Robert E Burke  1 , William T Dauer, Jean Paul G Vonsattel
Affiliations
Editorial

A critical evaluation of the Braak staging scheme for Parkinson's disease

Robert E Burke et al. Ann Neurol. 2008 Nov.

Abstract

Braak and colleagues have proposed that, within the central nervous system, Parkinson's disease (PD) begins as a synucleinopathy in nondopaminergic structures of the lower brainstem or in the olfactory bulb. The brainstem synucleinopathy is postulated to progress rostrally to affect the substantia nigra and cause parkinsonism at a later stage of the disease. In the context of a diagnosis of PD, made from current clinical criteria, the pattern of lower brainstem involvement accompanying mesencephalic synucleinopathy is often observed. However, outside of that context, the patterns of synucleinopathy that Braak described are often not observed, particularly in dementia with Lewy bodies and when synucleinopathy occurs in the absence of neurological manifestations. The concept that lower brainstem synucleinopathy represents "early PD" rests on the supposition that it has a substantial likelihood of progressing within the human lifetime to involve the mesencephalon, and thereby cause the substantia nigra pathology and clinical parkinsonism that have heretofore defined the disease. However, the predictive validity of this concept is doubtful, based on numerous observations made in populations of aged individuals who, despite the absence of neurological signs, have brain synucleinopathy ranging up to Braak stages 4 to 6 at postmortem. Furthermore, there is no relation between Braak stage and the clinical severity of PD. We conclude that the relation between patterns of abnormal synuclein immunostaining in the human brain and the disease entity now recognized as PD remains to be determined.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Patterns of abnormal immunostaining for α-synuclein identified by Braak and colleagues (adapted from Figures 1c and d, Braak et al, 2006). Six patterns of immunostaining were observed. In the pattern with the least extent of abnormal staining, involvement was observed only in region #1, which contains the dorsal motor nucleus of the vagus. In the pattern with the next most limited distribution, staining was observed, in addition to region #1, in region #2, which included the locus ceruleus and other “gain setting nuclei”. In the pattern with the next most involvement, abnormal staining was observed not only in regions #1 and #2, but also region #3, which included the SN and the amygdala. Since each succeeding pattern of increased rostral involvement 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 so on. Clinical signs of parkinsonism and Lewy pathology in the mesencephalon, both of which are now required for a definitive diagnosis of PD, are hypothesized to occur late in the disease, at Stage 3.
Fig. 2
Fig. 2
Relationship between subject age at time of death and Braak PD Stage in 116 individuals without dementia or parkinsonism. The data presented are from Braak, Parkkinen, and Bloch. There is no relationship between age at death and Braak Stage (r = 0.09, NS). Braak Stage 1 to 6 synuclein pathology is observed in neurologically unimpaired individuals who live decades beyond the average life expectancy at birth for industrialized nations.
Fig. 3
Fig. 3
Relationship between Braak PD Stage and Hoehn and Yahr PD score at the time of death in 96 individuals. The data presented are from Braak, 2003. The 68 individuals with a Hoehn and Yahr score of 0 are the same individuals as shown in Fig. 2, with the single exception that Braak Case 105, with a diagnosis of Alzheimer’s, is excluded in Fig. 2. Among 29 patients with PD (Hoehn and Yahr 1 or more), there is no relationship between Hoehn and Yahr score and Braak Stage (r = - 0.2, NS). The data appears to be clustered into two populations: those with PD and those without.
Fig. 4
Fig. 4
Patterns of expression of α-synuclein mRNA in rat brain. The Figure is adapted from Maroteaux and Scheller, 1991, Figure 4. The images are darkfield micrographs of in situ hybridization for mRNA, so intense hybridization appears white on a black background. Different brain sections are arranged in ascending order according to the regions involved at different Braak Stages of synucleinopathy. In the bottom panels it is apparent that both the olfactory tubercle (LOT: nucleus of the lateral olfactory tract) and the DMN of the vagus (“10”) express high levels of α-synuclein mRNA (red arrows). In the middle panel, it can be seen that the locus ceruleus (LC) also expresses high levels. In the top panels, the amygdala (Am), and the SNpc express high levels.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the α-synuclein gene identified in families with Parkinson’s Disease. Science. 1997;276:2045–2047. - PubMed
    1. Spillantini MG, Schmidt ML, Lee VMY, et al. α-Synuclein in Lewy bodies. Nature. 1997;388:839–840. - PubMed
    1. Singleton AB, Farrer M, Johnson J, et al. alpha-Synuclein locus triplication causes Parkinson’s disease. Science. 2003;302:841. - PubMed
    1. Braak H, Del Tredici K, Rub U, et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24:197–211. - PubMed
    1. Braak H, Sastre M, Bohl JR, et al. Parkinson’s disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons. Acta Neuropathol. 2007;113:421–429. - PubMed

Publication types

-