2023 American Academy of Neurology Abstract Website

Objective:

To validate and explore metabolomics-based plasma biomarkers of Parkinson’s disease (PD) in LRRK2 and GBA carriers as compared to sporadic PD patients among PPMI participants.

Background:

Prior plasma metabolomic analysis in PD(+) and PD(-) subjects including LRRK2 and GBA mutation carriers replicated significant differences in caffeine-related metabolites in PD(+) versus PD(-) and showed reduced GCase activity in GBA carrier plasma versus non-carriers (Crotty MDS Madrid 2022). Here, we report additional exploratory analysis of metabolomic profiles associated with disease and genetic status.

Design/Methods:

Plasma from 629 PPMI participants selected based on PD (+/-) and genetic status (a GBA or LRRK2 mutation or neither) were analyzed by liquid chromatography coupled to mass spectrometry. 298 plasma analytes met reporting criteria. Normalized analyte levels were compared between groups using robust ANCOVA models for log2 analyte level as the dependent variable and age, sex, PD status, genetic status, levodopa use, and their interactions as independent variables.

Results:

Results replicated predicted PD associations with ergothioneine and caffeine metabolites and GBA associations with glucosylsphingosine (GlcSph). LRRK2 status was uniquely associated with increases in circulating levels of docosahexanoic acid (DHA) and other lipid classes containing DHA including lysophosphatidylcholine (LPC) and bis(monoacylglycero)phosphate (BMP). Additionally, modest but highly specific association between decreased 4-trimethylaminobutanal (TMABA; protein lysine-derived catabolite) and GBA status.

Conclusions:

Metabolic profiles show highly distinct associations with PD, LRRK2 and GBA status, potentially delineating differences in underlying biology. While lifestyle/xenobiotic profiles are dominant in PD, unique associations between GlcSph and TMABA and GBA status implicated anticipated alteration in lysosomal function. Broad alterations in DHA containing lipids, including LPC-DHA required for brain DHA, were observed only in LRRK2 (+) subjects, independent of disease and L-DOPA status. Dominant LRRK2-dependent lipid profiles show novel associations between systemic DHA homeostasis and LRRK2 polymorphism. Further studies will be needed to clarify potential causal implications of these findings.