Pathological α-synuclein distribution in subjects with coincident Alzheimer's and Lewy body pathology

Abstract

We investigated the distribution patterns of Lewy body-related pathology (LRP) and the effect of coincident Alzheimer disease (AD) pathology using a data-driven clustering approach that identified groups with different LRP pathology distributions without any diagnostic or researcher's input in two cohorts including: Parkinson disease patients without (PD, n = 141) and with AD (PD-AD, n = 80), dementia with Lewy bodies subjects without AD (DLB, n = 13) and demented subjects with AD and LRP pathology (Dem-AD-LB, n = 308). The Dem-AD-LB group presented two LRP patterns, olfactory-amygdala and limbic LRP with negligible brainstem pathology, that were absent in the PD groups, which are not currently included in the DLB staging system and lacked extracranial LRP as opposed to the PD group. The Dem-AD-LB individuals showed relative preservation of substantia nigra cells and dopamine active transporter in putamen. PD cases with AD pathology showed increased LRP. The cluster with occipital LRP was associated with non-AD type dementia clinical diagnosis in the Dem-AD-LB group and a faster progression to dementia in the PD groups. We found that (1) LRP pathology in Dem-AD-LB shows a distribution that differs from PD, without significant brainstem or extracranial LRP in initial phases; (2) coincident AD pathology is associated with increased LRP in PD indicating an interaction; (3) LRP and coincident AD pathology independently predict progression to dementia in PD, and (4) evaluation of LRP needs to acknowledge different LRP spreading patterns and evaluate substantia nigra integrity in the neuropathological assessment and consider the implications of neuropathological heterogeneity for clinical and biomarker characterization.

Keywords: Alzheimer disease; Classification; Dementia with Lewy bodies; Diagnosis; Neuropathology; Parkinson disease.

Figure 1. CNDR clusters heatmaps (top) and brain maps showing LRP pathology distribution in the clusters (bottom)

First colored column on the left of the heatmaps represents cluster identify and second column represents clinico-pathological diagnosis with LRP-only groups in green colors (PD and DLB) and groups with coincident LRP and AD in magenta colors (AD-LB and PD-AD). Color scale of the brain maps below represents the mean semi-quantitative scores in each cluster.

Figure 2. BBDP clusters heatmaps (top) and brain maps showing LRP pathology distribution in the clusters (bottom)

First colored column on the left of the heatmaps represents cluster identify and second column represents clinico-pathological diagnosis with LRP-only groups in green colors (PD and DLB) and groups with coincident LRP and AD in magenta colors (AD-LB and PD-AD). Color scale of the brain maps below represents the mean semi-quantitative scores in each cluster.

Figure 3. LRP presence in the esophagus, lumbar spinal cord, submandibular gland and vagus nerve

Barplots represent percentage of cases with LRP based on neuropathological and cluster groups. Measurements were performed in the BBDP cohort.

Figure 4. SN cell density (first row) and percentage of DAT IHC area in the putamen (second row)

Measurements were performed in the CNDR cohort.

Figure 5

Disease duration based on neuropathological diagnosis (top row left) and cluster classification (top row right). Conversion from PD to PDD based on neuropathological diagnosis (bottom row left) and cluster classification (bottom row right).

Figure 6

LRP spreading patterns across the different clinico-pathological groups.