Metabolites in cerebrospinal fluid (CSF) and plasma have been implicated in Parkinson’s disease (PD), but their causal roles remain unclear. This study aims to investigate the causal relationships between specific CSF and plasma metabolites and PD risk, using Mendelian Randomization (MR) analysis. We utilized MR with inverse-variance weighting (IVW) as the primary analytical method, supplemented by four additional MR models to validate robustness. Data included 1,400 plasma metabolites from the Canadian Longitudinal Study on Aging, and 338 CSF metabolites from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention, USA. metabolites from the Canadian Longitudinal Study on Aging. PD outcome data were obtained from a GWAS meta-analysis by the International Parkinson’s Disease Genomics Consortium. MR analysis identified six CSF metabolites with suggestive causal relationships with PD. Dimethylglycine, gluconate, oxalate (ethanedioate), and an unknown metabolite (X-12015) were positively associated with PD risk, while (1-enyl-palmitoyl)-2-arachidonoyl-GPC (P-16:0/20:4) and an unknown compound (X-23587) were negatively associated. In plasma, 49 metabolites demonstrated suggestive causal relationships with PD risk. Key metabolites included hydroxy-3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (hydroxy-CMPF), carnitine C14, and 1-dihomo-linolenylglycerol (20:3) with positive associations, and tryptophan, succinate to acetoacetate ratio, and O-sulfo-L-tyrosine with negative associations. Notably, O-sulfo-L-tyrosine emerged as the most significant protective metabolite in plasma, showing robust associations across four MR models. This study highlights causal relationships between specific CSF and plasma metabolites and PD risk, underscoring O-sulfo-L-tyrosine as a potential biomarker and therapeutic target. These findings provide a foundation for further exploration of metabolic pathways in PD pathogenesis and intervention strategies.
Wang et al. (Mon,) studied this question.