Objective: To understand how Lewy body (LB) pathology progresses in the cerebrum and how Alzheimer’s disease (AD) pathology influences LB distribution in LB disease (LBD).

Background: LBD shows variation in regional LB burden across cases, and LB progression patterns within the cerebrum are not fully understood. Additionally, most LBD cases have concomitant AD pathology; however, how senile plaques (SP) and neurofibrillary tangles (NFT) influence LB progression remains unclear. Understanding these aspects is essential for elucidating LBD heterogeneity.

Method: We examined 2,308 autopsy cases (age at death 77.6±8.7 years; 867 women) from the Mayo Clinic brain bank containing LB in any brain region, with complete LB counts in six regions (amygdala, parahippocampal cortex, cingulate cortex, frontal, temporal, and parietal cortices) and SP/NFT counts in three cortices (frontal, temporal, parietal). We assessed LB using α-synuclein immunohistochemistry (20× field) and SP/NFT using thioflavin S fluorescent microscopy (10× and 40× field, respectively). Analytical approaches included kernel density estimation, SuStaIn analysis (an unsupervised machine learning algorithm for disease progression modeling), Spearman correlations, partial correlations with age/sex adjustment, and multiple linear regression.

Results: Median Braak NFT stage and Thal amyloid phase were IV [IQR: III, VI] and 4 [IQR: 2, 5]. Kernel density plots and SuStaIn analysis demonstrated that 99% of cases had unidirectional LB progression from amygdala through limbic cortices to neocortices. Early neocortical involvement with relative amygdala sparing occurred in only 1%. Following age/sex adjustment, neocortical LB burden had positive correlation with neocortical SP (ρ=0.240, p<0.0001) and negative correlation with NFT (ρ=-0.194, p<0.0001). Multiple regression analysis identified independent opposite effects: SP facilitated (standardized β=0.533, p<0.0001) whereas NFT suppressed (β=-0.463, p<0.0001) neocortical LB accumulation (R²=27.1%).

Conclusion: While LB progression largely follows a stereotyped anatomical sequence, concomitant AD pathology modulates LB spread. Elevated SP/NFT ratios facilitate diffuse neocortical LB distribution, whereas reduced ratios restrict LB to limbic regions. These pathological findings provide insights into LBD heterogeneity.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/senile-plaques-and-neurofibrillary-tangles-modulate-lewy-body-distribution-autopsy-study-of-2308-cases/