Pattern of Lewy Pathology Progression Suggested by Braak Staging System is Supported by Analysis of a Population-based Cohort of Patients
John E. Duda, MD, Joseph V. Noorigian, BS, Helen Petrovitch, MD, Lon R. White, MD, MPH, G. Webster Ross, MD

Background: Braak LB staging has provided an intriguing model of the progression of Lewy pathology accumulation in affected brains and deserves further confirmation in similar cohorts enriched with large numbers of brains with incidental Lewy pathology.

Methods: A total of 126 cases from the brain bank of the Honolulu Asian Aging Study were examined including 23 cases of Parkinson’s disease (PD), seven cases of dementia with Lewy bodies (DLB) and 96 cases with no clinical history of Parkinsonism. This cohort did not exclude patients with concomitant Alzheimer’s disease pathology and was not a random sample in that 35 cases of ILB, which were previously determined by hematoxylin and eosin staining of the pons and midbrain, were included in the sample. Immunohistochemical staining for α-synuclein and semi-quantitative pathology density analyses were performed on available tissue samples collected from fifteen brain regions including the olfactory bulb, medulla, pons, midbrain, hippocampus, amygdala, striatum at the level of the nucleus accumbens, basal forebrain, and seven different neocortical regions. From these regions sixteen specific foci were quantified representing each of the six Braak stages. At least two foci from each stage were quantified, including: olfactory bulb and dorsal motor nucleus of the vagus (Stage 1); pontine raphe nucleus and locus ceruleus (Stage 2); substantia nigra pars compacta, nucleus basalis of Meynert and basolateral nuclear complex of the amygdala (Stage 3); Ammon’s horn and entorhinal cortex (Stage 4); insular, anterior cingulate, dorsolateral prefrontal and supramarginal cortices (Stage 5); and motor, primary sensory and middle temporal cortices (Stage 6).

Objectives: To assess the validity of the Braak Lewy body (LB) staging system in a population-based cohort of patients spanning the spectrum of LB disorders with a large number of incidental LB cases.

Results: Among 126 autopsied cases, 81 cases were found to have some Lewy pathology, including all 30 cases of PD or DLB and 51 cases of ILB. All DLB cases had Braak LB stages of five and six, PD cases were either Braak LB stages three, five or six, and ILBD cases were found representing all stages 1-6. Of these 126 cases, 119 (94.4%) were found to be consistent with the progression of pathological distribution outlined by Braak, defined as cases that had Lewy pathology in at least one foci for each stage affected. Seven cases were found to be clearly inconsistent with the Braak LB staging system with no evidence of pathology in any representative foci for a stage preceding the last stage with pathology. Six of these cases were ILB cases and one was a case of PD. The most common reasons for inconsistency was the absence of pathology in foci representative of Braak LB stages 2 and 4.

Conclusions: The general pattern of progression outlined in the Braak LB staging system is upheld in 94% of cases from this population-based cohort.