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In order toevaluate the influence of the metabolic syndrome (MS) (obesity, hypertension, elevated triglycerides, reduced levels of HDL cholesterol and glucose impairment) on the phenotype of LRRK2 and GBA Parkinson’s disease (PD), and on the prevalence of prodromal features among individuals at risk, we collected, laboratory test results, blood pressure, demographic, cognitive, motor, olfactory and affective information enabling the assessment of each component of MS and the construction of the MDS prodromal probability score. The number of metabolic components and their levels were compared between participants who were separated based on disease state and genetic status. One hundred and four idiopathic PD, 40 LRRK2-PD, 70 GBA-PD, 196 healthy non-carriers, 55 LRRK2-NMC and 97 GBA-NMC participated in this study. PD groups and non manifesting carriers (NMC) did not differ in the number of metabolic components (p = 0.101, p = 0.685, respectively). LRRK2-PD had higher levels of triglycerides (p = 0.015) and higher rates of prediabetes (p = 0.004), while LRRK2-NMC had higher triglyceride levels (p = 0.014). NMC with probability rates for prodromal PD above 50% had higher frequencies of hypertriglyceridemia and prediabetes (p < 0.005, p = 0.023 respectively). While elevated triglycerides and prediabetes were more frequent among LRRK2 carriers, MS does not seem to influence GBA and LRRK2-PD phenotype.

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.

Background: Mutations in the GBA gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are risk factors for Parkinson's disease (PD).Objective: To explore the association between GCase activity, PD phenotype, and probability for prodromal PD among carriers of mutations in the GBA and LRRK2 genes. Methods: Participants were genotyped for the G2019S-LRRK2 and nine GBA mutations common in Ashkenazi Jews. Performance-based measures enabling the calculation of the Movement Disorder Society (MDS) prodromal probability score were collected. Results: One hundred and seventy PD patients (102 GBA-PD, 38 LRRK2-PD, and 30 idiopathic PD) and 221 non-manifesting carriers (NMC) (129 GBA-NMC, 45 LRRK2-NMC, 15 GBA-LRRK2-NMC, and 32 healthy controls) participated in this study. GCase activity was lower among GBA-PD (3.15 AE 0.85 μmol/L/h), GBA-NMC (3.23 AE 0.91 μmol/L/h), and GBA-LRRK2-NMC (3.20 AE 0.93 μmol/L/h) compared to the other groups of participants, with no correlation to clinical phenotype. Conclusions: Low GCase activity does not explain the clinical phenotype or risk for prodromal PD in this cohort.

BackgroundThe phenotype of Parkinson's disease (PD) is milder among patients with LRRK2‐PD and more severe among patients with GBA‐PD; however, whether an additive phenotypical effect occurs among dual‐mutation carriers requires validation.ObjectiveThe objective of this study was to explore the phenotypic expression of patients with PD who carry mutations in both genes compared with a single‐mutation presentation.MethodsPatients with PD were genotyped for the G2019S‐LRRK2 mutation and 9 mutations in the GBA gene. Subjects were classified into 5 groups: idiopathic PD, mild GBA‐PD, severe GBA‐PD, LRRK2‐PD, and LRRK2+GBA‐PD. Clinical symptoms were evaluated using performance‐based measures.ResultsA total of 1090 patients with idiopathic PD, 155 patients with LRRK2‐PD, 155 patients with mild GBA‐PD, 56 patients with severe GBA‐PD, and 27 patients with LRRK2+GBA‐PD participated in this study. The patients with LRRK2‐PD and LRRK2+GBA‐PD exhibited lower scores on total Unified Parkinson's Disease Rating Scale (P < 0.01) and better olfaction (P < 0.01) compared with GBA‐PD.ConclusionsPatients with LRRK2+GBA‐PD were symptomatically similar to patients with LRRK2‐PD, suggesting a dominant effect of LRRK2 over GBA in the phenotypic presentation. © 2020 International Parkinson and Movement Disorder Society