Mutations in GBA and LRRK2 Are Not Associated with Increased Inflammatory Markers

Abstract

Background: Inflammation is an integral part of neurodegeneration including in Parkinson’s disease (PD). Ashkenazi Jews have high rates of genetic PD with divergent phenotypes among GBA-PD and LRRK2-PD. The role of inflammation in the prodromal phase of PD and the association with disease phenotype has yet to be elucidated. Objective: To assess central and peripheral cytokines among PD patients with mutations in the LRRK2 and GBA genes and among non-manifesting carriers (NMC) of these mutations in order to determine the role of inflammation in genetic PD. Methods: The following cytokines were assessed from peripheral blood and cerebrospinal fluid (CSF): TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10 and INF- γ. A comprehensive intake including general medical conditions, use of anti-inflammatory treatments, motor and cognitive assessments and additional laboratory measures were recorded, enabling the construction of the MDS probable prodromal score. Results: Data from 362 participants was collected: 31 idiopathic PD (iPD), 30 LRRK2-PD, 77 GBA-PD, 3 homozygote GBA-PD, 3 GBA-LRRK2-PD, 67 LRRK2-NMC, 105 GBA-NMC, 14 LRRK2-GBA-NMC, and 32 healthy controls. No between-group differences in peripheral or CSF cytokines were detected. No correlation between disease characteristics or risk for prodromal PD could be associated with any inflammatory measure. Conclusion: In this study, we could not detect any evidence on dysregulated immune response among GBA and LRRK2 PD patients and non-manifesting mutation carriers.

Blood and Cerebrospinal Fluid Biomarkers of Inflammation in Parkinson’s Disease

“…In a subgroup with CSF available, higher levels of S190 M. Zimmermann and K. Brockmann / Blood and Cerebrospinal Fluid Biomarkers of Inflammation in Parkinson's Disease VEGF and IL-8 were detected in PD patients with LRRK2 mutations compared to those with LRRK2wildtype status [66]. A recent study from Israel confirmed the findings of relatively similar inflammatory profiles between PD patients with vs. without LRRK2 mutations as the colleagues also did not find any differences in blood or CSF levels of cytokines [67].…”

“…While 1 of the 3 studies reports higher serum levels of IL-1␤ [66], the other 2 studies did not find differences in inflammatory profiles in blood and/or CSF between non-manifesting LRRK2 mutation carriers and healthy controls, even when clinically stratified for prodromal markers [38,67]. A recent study in Norwegian individuals revealed higher CSF levels of TNF-␣ in LRRK2 mutation carriers when compared to controls [68].…”

Neuroinflammation and Immune Changes in Prodromal Parkinson’s Disease and Other Synucleinopathies

“…And numerous studies suggest a role for LRRK2 in the immune function and microglial activation [87]. However, most of the studies addressing non-manifesting LRRK2 have found none or few changes in immune biomarkers in blood [70,88]. Brockmann et al showed no differences between non-manifesting LRRK2 and controls, although in manifested LRRK2-PD and iPD certain inflammatory markers differed suggesting a differential immune response in these two PD types [88].…”

Immunogenetic Determinants of Parkinson’s Disease Etiology

“…Hence, investigating the mechanisms and mediators through which GBA mutations initiate and propagate neuroinflammation is now a hot area of research [ 66 ]. Despite the mentioned association of GBA mutations with central and peripheral inflammatory responses, initial investigations of central and peripheral inflammatory cytokines as early markers of PD have returned with negative outcomes [ 67 ].…”