Metabolomic Profiling of Plasma Samples from PPMI Identifies Molecular Signatures of Parkinson’s Disease and Genetic Parkinson’s Disease Susceptibility (P3-11.011)

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. Disclosure: Dr. Huntwork-Rodriguez has received personal compensation for serving as an employee of Denali Therapeutics. Dr. Huntwork-Rodriguez has stock in Denali Therapeutics. Dr. Huntwork-Rodriguez has received intellectual property interests from a discovery or technology relating to health care. Dr. Suh has received personal compensation for serving as an employee of Denali Therapeutics . The institution of Dr. Crotty has received research support from Parkinson’s Foundation. Mr. Maciuca has received personal compensation for serving as an employee of Denali Therapeutics. Mr. Maciuca has received stock or an ownership interest from Denali Therapeutics. The institution of Dr. Macklin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AI Therapeutics. Dr. Macklin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cortexyze. Dr. Macklin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Chase Therapeutics. Dr. Macklin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bial Biotech. Dr. Macklin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Macklin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Stoparkinson Healthcare LLC. Dr. Macklin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Macklin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Macklin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. The institution of Dr. Macklin has received research support from Biohaven. The institution of Dr. Macklin has received research support from Clene Nanomedicine. The institution of Dr. Macklin has received research support from Mitsubishi Tanabe Pharmaceuticals America. The institution of Dr. Macklin has received research support from Prilenia. The institution of Dr. Macklin has received research support from UCB Ra Pharma. The institution of Dr. Macklin has received research support from Revalesio. The institution of Dr. Macklin has received research support from Seelos. The institution of Dr. Macklin has received research support from Calico. The institution of Dr. Macklin has received research support from Denali. The institution of Dr. Macklin has received research support from NeuroDex. The institution of Dr. Macklin has received research support from Alector. Dr. Davis has received personal compensation for serving as an employee of Denali Therapeutics. Mr. Alkabsh has received personal compensation for serving as an employee of Denali Therepeutics. An immediate family member of Rachit Bakshi has received personal compensation for serving as an employee of Partner Therapeutics. The institution of Rachit Bakshi has received research support from MJFF. Dr. Chen has nothing to disclose. Dr. Molsberry has nothing to disclose. The institution of Dr. Ascherio has received research support from NIH and US Department of Defense . The institution of Dr. Schwarzschild has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bial Biotech (indirectly, as a service of the Parkinson Study Group service). The institution of Dr. Schwarzschild has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen (indirectly, as a service of the Parkinson Study Group service). The institution of Dr. Schwarzschild has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for UCB (indirectly, as a service of the Parkinson Study Group service). Dr. Schwarzschild has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eli Lilly. The institution of Dr. Schwarzschild has received research support from NIH. The institution of Dr. Schwarzschild has received research support from Parkinson’s Foundation. The institution of Dr. Schwarzschild has received research support from Michael J Fox Foundation. The institution of Dr. Schwarzschild has received research support from Farmer Family Foundation. Dr. Schwarzschild has a non-compensated relationship as a Chair, Executive Committee with the Parkinson Study Group that is relevant to AAN interests or activities.