Cortical α-synuclein load is associated with amyloid-β plaque burden in a subset of Parkinson’s disease patients

Abstract

Amyloid-beta (Abeta) peptide pathology in Alzheimer's disease (AD) comprises extracellular plaques and cerebral amyloid angiopathy (CAA). In Parkinson's disease (PD), alpha-synuclein forms intraneuronal Lewy bodies (LBs), and cortical LBs are thought to play a major role in cognitive decline designated as PD with dementia. As there is increasing evidence that Abeta may also promote alpha-synuclein fibrillization, we assessed the relationship between LB pathology and Abeta deposition in 40 cases of PD and 20 age-matched controls. In five cortical areas, we established the severity of Abeta plaque load using an approach similar to that recommended by CERAD in AD. LB densities were determined using a morphometric approach. CAA was graded using previously described scales. The APOE genotype was established in 38 PD and 19 control cases. We have found that the overall Abeta plaque burden and, in particular, the diffuse plaque load shows a statistically significant 'large' correlation with the overall cortical LB burden. The strength of this correlation further increases in PD cases (about 50% of the cases) with moderate to high Abeta plaque load. The APOE epsilon4 allele is over-represented in this subgroup. Our data indicate a strong association between pathologically identifiable Abeta plaque burden and alpha-synuclein load in cerebral cortex and provide indirect evidence that Abeta pathology is likely to be an important factor contributing to cognitive decline in a subgroup of PD patients.

In vivo amyloid imaging in autopsy-confirmed Parkinson disease with dementia

“…Diffuse A␤ plaques are typically abundant in cases with cortical Lewy bodies 37,38 and Lewy body counts are highly correlated with amyloid plaque counts in PD and PDD. 33,39 However, the timing of deposition of amyloid, Lewy bodies, and neurofibrillary tangles relative to clinical manifestations of dementia can only be inferred from postmortem studies. Serial imaging to measure the rate of amyloid deposition 40 in individuals with and without Lewy body disorders (subsequently confirmed by autopsy) can directly test whether ␣-synucleinopathy exacerbates amyloidosis and accelerates cognitive decline.…”

Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

“…The right hemisphere was fixed and left hemisphere frozen as per standard protocol, and the right hemisphere cut into 5mm thick coronal slices. Paraffin-embedded tissue sections from a large number of brain regions underwent routine post-mortem analysis, including examination for tau, transactive response DNA binding protein 43 (TDP-43), alpha-synuclein and amyloid beta (Aβ) deposition, neuronal, myelin and axonal loss and astrogliosis (Lashley et al, 2008; Ryan et al, 2015). The circle of Willis was examined for presence of atheroma, and other relevant cortical, subcortical and hippocampal regions (including leptomeningeal vessels) were examined for vascular pathology.…”

Characterizing mild cognitive impairment in incident Parkinson disease

“…27 Although the precise pathophysiologic substrates underlying cognitive impairment in PD remain unclear and may vary among subjects, there is increasing evidence for a synergistic role between asyn and Ab accumulation. 28 Tau may also contribute, because it has been shown that polymorphisms in the MAPT gene increase the risk of PDD. 4 Furthermore, cholinergic dysfunction is likely to influence cognitive decline, with evidence from autopsy studies of a greater cholinergic deficit in subjects with dementia with Lewy bodies (DLB) than in AD.…”