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Peripheral innate immune and bacterial signals relate to clinical heterogeneity in Parkinson's disease.

Accepted version
Peer-reviewed

Type

Article

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Authors

Wijeyekoon, Ruwani S 
Kronenberg-Versteeg, Deborah 
Scott, Kirsten M 
Hayat, Shaista 
Kuan, Wei-Li 

Abstract

The innate immune system is implicated in Parkinson's disease (PD), but peripheral in-vivo clinical evidence of the components and driving mechanisms involved and their relationship with clinical heterogeneity and progression to dementia remain poorly explored. We examined changes in peripheral innate immune-related markers in PD cases (n = 41) stratified according to risk of developing early dementia. 'Higher Risk'(HR) (n = 23) and 'Lower Risk' (LR) (n = 18) groups were defined according to neuropsychological predictors and MAPT H1/H2 genotype, and compared to age, gender and genotype-matched controls. Monocyte subsets and expression of key surface markers were measured using flow cytometry. Serum markers including alpha-synuclein, inflammasome-related caspase-1 and bacterial translocation-related endotoxin were measured using quantitative immuno-based assays. Specific markers were further investigated using monocyte assays and validated in plasma samples from a larger incident PD cohort (n = 95). We found that classical monocyte frequency was elevated in PD cases compared to controls, driven predominantly by the HR group, in whom Toll-Like Receptor (TLR)4+ monocytes and monocyte Triggering Receptor Expressed on Myeloid cells-2 (TREM2) expression were also increased. Monocyte Human Leukocyte Antigen (HLA)-DR expression correlated with clinical variables, with lower levels associated with worse cognitive/motor performance. Notably, monocyte changes were accompanied by elevated serum bacterial endotoxin, again predominantly in the HR group. Serum alpha-synuclein and inflammasome-related caspase-1 were decreased in PD cases compared to controls regardless of group, with decreased monocyte alpha-synuclein secretion in HR cases. Further, alpha-synuclein and caspase-1 correlated positively in serum and monocyte lysates, and in plasma from the larger cohort, though no associations were seen with baseline or 36-month longitudinal clinical data. Principal Components Analysis of all monocyte and significant serum markers indicated 3 major components. Component 1 (alpha-synuclein, caspase-1, TLR2+ monocytes) differentiated PD cases and controls in both groups, while Component 2 (endotoxin, monocyte TREM2, alpha-synuclein) did so predominantly in the HR group. Component 3 (classical monocytes, alpha-synuclein) also differentiated cases and controls overall in both groups. These findings demonstrate that systemic innate immune changes are present in PD and are greatest in those at higher risk of rapid progression to dementia. Markers associated with PD per-se (alpha-synuclein, caspase-1), differ from those related to cognitive progression and clinical heterogeneity (endotoxin, TREM2, TLR4, classical monocytes, HLA-DR), with mechanistic and therapeutic implications. Alpha-synuclein and caspase-1 are associated, suggesting inflammasome involvement common to all PD, while bacterial translocation associated changes may contribute towards progression to Parkinson's dementia. Additionally, HLA-DR-associated variations in antigen presentation/clearance may modulate existing clinical disease.

Description

Keywords

Alpha-synuclein, Caspase-1, Endotoxin, Heterogeneity, Innate immune system, Monocyte, Parkinson’s disease, Biomarkers, Humans, Immunity, Innate, Membrane Glycoproteins, Monocytes, Parkinson Disease, Receptors, Immunologic, alpha-Synuclein

Journal Title

Brain Behav Immun

Conference Name

Journal ISSN

0889-1591
1090-2139

Volume Title

87

Publisher

Elsevier BV
Sponsorship
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC)
Addenbrooke's Charitable Trust (ACT) (PF15/CWG)
Rosetrees Trust (A1389)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Medical Research Council (MR/R007446/1)
Wellcome Trust (105924/Z/14/Z)
Wellcome Trust (105924/Z/14/A)
Wellcome Trust (105924/Z/14/Z)
Wellcome Trust (105924/Z/14/A)
Medical Research Council (MR/S005528/1)
Medical Research Council (MC_PC_12009)
Medical Research Council (MR/R015724/1)
Medical Research Council (MC_PC_17230)