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Neuroinflammation and protein pathology in Parkinson's disease dementia.

Accepted version
Peer-reviewed

Type

Article

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Authors

Camacho, Marta 
Allinson, Kieren 
Williams-Gray, Caroline H 

Abstract

Parkinson's disease dementia is neuropathologically characterized by aggregates of α-synuclein (Lewy bodies) in limbic and neocortical areas of the brain with additional involvement of Alzheimer's disease-type pathology. Whilst immune activation is well-described in Parkinson's disease (PD), how it links to protein aggregation and its role in PD dementia has not been explored. We hypothesized that neuroinflammatory processes are a critical contributor to the pathology of PDD. To address this hypothesis, we examined 7 brain regions at postmortem from 17 PD patients with no dementia (PDND), 11 patients with PD dementia (PDD), and 14 age and sex-matched neurologically healthy controls. Digital quantification after immunohistochemical staining showed a significant increase in the severity of α-synuclein pathology in the hippocampus, entorhinal and occipitotemporal cortex of PDD compared to PDND cases. In contrast, there was no difference in either tau or amyloid-β pathology between the groups in any of the examined regions. Importantly, we found an increase in activated microglia in the amygdala of demented PD brains compared to controls which correlated significantly with the extent of α-synuclein pathology in this region. Significant infiltration of CD4+ T lymphocytes into the brain parenchyma was commonly observed in PDND and PDD cases compared to controls, in both the substantia nigra and the amygdala. Amongst PDND/PDD cases, CD4+ T cell counts in the amygdala correlated with activated microglia, α-synuclein and tau pathology. Upregulation of the pro-inflammatory cytokine interleukin 1β was also evident in the substantia nigra as well as the frontal cortex in PDND/PDD versus controls with a concomitant upregulation in Toll-like receptor 4 (TLR4) in these regions, as well as the amygdala. The evidence presented in this study show an increased immune response in limbic and cortical brain regions, including increased microglial activation, infiltration of T lymphocytes, upregulation of pro-inflammatory cytokines and TLR gene expression, which has not been previously reported in the postmortem PDD brain.

Description

Keywords

Infiltrating lymphocytes, Microglia, Neuroinflammation, Neuropathology, Parkinson’s disease dementia, Pro-inflammatory cytokines, Toll-like receptors, Aged, Aged, 80 and over, Amygdala, Amyloid beta-Peptides, Astrocytes, Brain, Cytokines, Dementia, Female, Frontal Lobe, Gliosis, Hippocampus, Humans, Inflammation, Male, Microglia, Parkinson Disease, Substantia Nigra, Synucleinopathies, T-Lymphocytes, Toll-Like Receptor 2, Toll-Like Receptor 4, alpha-Synuclein, tau Proteins

Journal Title

Acta Neuropathol Commun

Conference Name

Journal ISSN

2051-5960
2051-5960

Volume Title

8

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Medical Research Council (MR/R007446/1)
Academy of Medical Sciences (unknown)
Rosetrees Trust (A1389)