Causal Association Between Cerebrospinal Fluid Metabolites and Parkinson's Disease: A Two-Sample Bidirectional Mendelian Randomization Study

Objective: Observational studies suggest CSF metabolites may be linked to Parkinson's disease (PD) onset, but causality is uncertain. This study uses a two-sample bidirectional Mendelian randomization approach to investigate the causal relationship between CSF metabolites and PD.

Methods: Data on 338 CSF metabolites and PD-related traits were obtained from genome-wide association studies (GWAS). Causal relationships between CSF metabolites and PD were assessed using inverse variance-weighted (IVW), MR-Egger regression, weighted median method, simple mode, and weighted mode. Sensitivity analyses for heterogeneity and pleiotropy were conducted to explore the robustness of the results.

Results: Our analysis identified an association between nine CSF metabolites and PD. Notably, significant increases in the risk of PD were observed for Ribitol (IVW, OR: 1.45; 95% CI: 1.09-1.91; P=9.04×E-03), Lysine (IVW, OR: 1.54; 95% CI: 1.09-2.17; P=1.24×E-02), and O-sulfo-l-tyrosine (IVW, OR: 1.38; 95% CI: 1.06-1.79; P=1.60×E-02). Additionally, we found that elevated levels of oxidized cysteinyl-glycine and 1,5-anhydroglucitol were associated with a decreased risk of PD. Furthermore, PD was associated with alterations in 12 CSF metabolites, including significant increases in Acetoacetate (IVW, OR: 1.15; 95% CI: 1.02-1.30; P=1.79×E-02), S-methylcysteine (IVW, OR: 1.14; 95% CI: 1.02-1.29; P=2.62×E-02), and N-acetyl-3-methylhistidine (IVW, OR: 1.12; 95% CI: 1.01-1.23; P=2.22×E-02).

Conclusion: The identified CSF metabolites may serve as potential CSF metabolic biomarkers for screening and preventing PD in clinical practice and could also be considered as candidate molecules for future mechanistic exploration and drug target selection.