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). This latter group presented two LRP patterns, olfactory-amygdala and limbic LRP with negligible brainstem pathology, that were absent in the PD groups, 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.

CSF biomarkers associated with disease heterogeneity in early Parkinson’s disease: the Parkinson’s Progression Markers Initiative study

“…2). Rather, differences in the interaction between α-syn and tau species or Aβ 1–42 may contribute to the variable progression and/or differential clinical and pathological features of PD [38]. In some autopsy studies of PD, topographical distribution of amyloid pathology and tau pathology were significantly correlated with rapid development of PD dementia [6, 19, 38].…”

“…Rather, differences in the interaction between α-syn and tau species or Aβ 1–42 may contribute to the variable progression and/or differential clinical and pathological features of PD [38]. In some autopsy studies of PD, topographical distribution of amyloid pathology and tau pathology were significantly correlated with rapid development of PD dementia [6, 19, 38]. In fact, when we classified PD patients by quintile levels of CSF biomarkers, PD patients with low Aβ 1–42 and a high t-tau/Aβ 1–42 ratio, but not α-syn levels, showed more severe clinical symptoms compared with patients with high CSF Aβ 1–42 concentrations and low t-tau/Aβ 1–42 ratio values (Table 4).…”

Anti-α-synuclein immunotherapy reduces α-synuclein propagation in the axon and degeneration in a combined viral vector and transgenic model of synucleinopathy

“…Various neuropathological studies suggest that the spatial and temporal patterns of distribution of α-syn pathology in the CNS among the different types of synucleinopathies follow known patterns of synaptic connectivity [6, 14, 65]. This, in combination with recent studies showing that α-syn oligomers can be released by neurons and promote neurodegeneration and inflammation by propagating to other neurons [8, 12, 20, 37, 50] and glial cells [35], has strengthened the concept that cell-to-cell transmission of pathogenic forms of α-syn might play a role in the pathogenesis of synucleinopathies.…”

Assessing cognitive dysfunction in Parkinson's disease: An online tool to detect visuo‐perceptual deficits

“…Converging evidence shows that PD patients with involvement of visual processing are at highest risk of PD dementia 2, 3. However, current measures of visuo‐perceptual function are poorly sensitive (eg, copying intersecting pentagons4 or clock drawing5 or require trained personnel and are time consuming to perform (such as the Vision Object and Space Perception battery6 or Benton's Judgment of Line Orientation7, 8.…”