Braak staging: the disease spreads in order

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Heiko Braak, Kelly Del Tredici, Udo Rüb and colleagues at the J.W. Goethe University, Frankfurt. Funders were not checked.

What happened

Mapping Lewy pathology across autopsy brains (168 cases: 69 incidental cases with Lewy pathology but no diagnosis, 41 clinically diagnosed patients and 58 matched controls, per the authors' 2006 review), they proposed six stages. Lesions begin in the vagus nerve's motor nucleus in the lower brainstem and in the smell centre (anterior olfactory nucleus), climb to the substantia nigra in stages 3–4, and reach the cortex last. Neurobiol Aging 24:197–211. A companion paper the same year (Braak et al., J Neural Transm 2003) proposed that an unidentified pathogen could cross the gut lining and travel up the vagus nerve; the staging paper itself does not make that claim in its abstract.

Why it moved us toward a cure

It reframed Parkinson's as a spreading disease that begins years before movement symptoms, so it could in principle be intercepted early or blocked in transit.

Lewy pathology in the gut's nerve plexuses had been described in 1988 (landmark 257), which the gut-origin idea drew on.

Outcome

Open. Braak puts the pattern at roughly 80–90% of patients, and a review cited by Alzforum found the brainstem's medullary nuclei spared in 7–8% of manifest cases. The "gut-first versus brain-first" debate continues: one study found gut Lewy pathology in 21 of 29 patients and no controls, another of 92 people found no sign that the disease starts in the gut. In a Danish registry study, full vagus-nerve cutting (truncal vagotomy) was linked to lower risk only after more than 20 years of follow-up (hazard ratio 0.53 against the general population, 95% CI 0.28–0.99; overall 0.85, CI 0.63–1.14).

Sources

• Braak et al., Neurobiol Aging 2003;24:197–211, DOI 10.1016/S0197-4580(02)00065-9, PMID 12498954 (abstract)
• Braak et al., J Neural Transm 2003;110:517–536, DOI 10.1007/s00702-002-0808-2, PMID 12721813
• Braak et al., Mov Disord 2006;21:2042–2051, DOI 10.1002/mds.21065, PMID 17078043 (the 168-case breakdown)
• Alzforum series on the debate (80–90%, 7–8%, 21 of 29, 92 people)
• Svensson et al., Ann Neurol 2015;78:522–529, DOI 10.1002/ana.24448 (PubMed 26031848)
• Not yet verified: the 2003 paper's own case count (the 168 is from Braak's 2006 description of the original study); the full text of the 2003 paper.