Longitudinal untargeted metabolomics of cognitive impairment in Parkinson's disease

INTRODUCTION: Cognitive impairment is a common non-motor symptom of Parkinson's disease (PD), yet the mechanism remains unclear. METHODS: Longitudinal serum samples from PD patients in a community-based case-control study were profiled, with cognition assessed by the Mini-Mental State Examination at baseline and follow-up. We performed three metabolome-wide association studies: a baseline cross-sectional analysis (n = 632), a time-to-event analysis (n = 412), and a repeated measures analysis (n = 265), followed by "Mummichog" pathway analysis. RESULTS: Of the 4762 metabolomic features, four reached statistical significance in the baseline analysis, 22 in the time-to-event analysis, and none in the repeated measures analysis. Dysregulated pathways included purine metabolism, the pentose phosphate pathway, fatty acid pathways, and C21-steroid hormone biosynthesis and metabolism. DISCUSSION: Disruptions in core metabolic pathways may contribute to PD-related cognitive impairments. Disturbances in pentose and purine pathways may occur before clinical cognitive decline is observed, suggesting early metabolic markers.