Serum metabolomic-lipidomic signatures track long-term neurological performance in multiple sclerosis.

Metabolomics incorporates information from multiple biological systems and is recognized as an emerging tool for identifying novel multiple sclerosis (MS) biomarkers. While prior studies have linked metabolic alterations to the disease severity in people with MS (pwMS), a longitudinal approach enables a significant advantage in studying this relationship over disease progression. Therefore, this study aims to identify metabolomic signatures associated with longitudinal outcomes in pwMS. We performed a multi-site study, profiling the serum metabolome (Biocrates Inc.) from participants for the MS Partners Advancing Technology and Health Solutions (MS PATHS) network. Outcomes, including 25-foot walking speed, manual dexterity, and processing speed, were quantified using the iPad®-based Multiple Sclerosis Performance Test (MSPT). We applied generalized estimating equation regression models (adjusted for potential confounders) to assess the association of 517 metabolites at baseline with longitudinal assessments of MSPT component tests. We performed network, pathway enrichment, and MetaboIndicator analyses to infer biological insights from our findings. This study included 767 pwMS (mean age 44.9 [SD: 11.4]; 72.1% relapsing-remitting MS; 72.9% female; 11.8% non-white), who had an average of 7.0 (SD = 4.57) MSPT measures per person over an average follow-up period of 3.0 (SD = 1.25) years. Certain metabolites were associated with MSPT outcomes over time. For example, a 1 SD decrease in Phosphatidyl-choline aa C36:6 (PC aa 36:6) level was associated with a 9.3% decline in walking speed performance (95% CI: 6.7-11.9; FDR-adjusted p = 8.9E-09) and a 5.4% reduction in manual dexterity performance (95% CI: 3.3-7.4; FDR-adjusted p = 9.6E-05). Metabolite set enrichment and MetaboIndicator analyses pointed to pathways involved in polyunsaturated fatty acid (PUFA) metabolism and suggested altered enzymatic activities, such as increased phospholipase A2 (PLA2) activity. Leveraging a large longitudinal cohort, our findings suggest a potential role of altered lipid metabolism in the progression of MS. Supplementary Information: The online version contains supplementary material available at 10.1186/s44477-025-00008-7.