Metabolomic Signatures of Brain Atrophy and Ibudilast Response in Progressive Multiple Sclerosis

Progressive multiple sclerosis (MS) is characterized by ongoing neurodegeneration and limited therapeutic options. Circulating metabolites provide insight into disease biology, yet biomarkers that predict disability progression and reflect treatment response are lacking. We aimed to identify metabolomic signatures associated with longitudinal MRI measures of brain atrophy and to evaluate whether ibudilast treatment was associated with metabolite trajectories over time.

We repeatedly profiled 1,726 plasma metabolites using untargeted UPLC-MS/MS in 244 participants (mean age 55.6 years; 53.3% female; 3.3% non-White) from the 96-week SPRINT-MS randomized trial of oral ibudilast (≤100 mg daily; n=123) versus placebo (n=121). Weighted gene co-expression network analysis was used to derive groups of related metabolites. Associations between baseline metabolites groups and longitudinal MRI outcomes were evaluated using linear mixed-effects models adjusted for demographic, clinical, and treatment covariates. The primary outcome was the rate of whole-brain atrophy measured by brain parenchymal fraction (BPF), defined as the proportion of intracranial volume occupied by brain tissue. Secondary outcomes included white matter fraction (WMF), gray matter fraction (GMF), and cortical thickness (CTH). Metabolite groups nominally associated with MRI outcomes (p<0.05) were followed by individual metabolite analyses to identify potential drivers. Significant metabolites were tested for replication in a comparable real-world observational HEAL-MS cohort with longitudinal MRI data (n=249; mean age 56.3 years; 71.1% female; 19.4% non-White). Lastly, we tested whether ibudilast treatment was associated with metabolite trajectories and performed metabolite set enrichment analysis.

Higher baseline levels of glycerophospholipids were associated with slower decline in both BPF and WMF, and sphingomyelins were similarly associated with slower BPF decline. For example, higher 1-palmityl-2-stearoyl-GPC (O-16:0/18:0) levels were associated with slower BPF decline in SPRINT-MS (β=0.016 [0.008, 0.024]; p=4.35×10⁻ ⁵ ) and replicated in HEAL-MS (β=0.108 [0.006, 0.211], p=3.90×10⁻ ² ). Metabolites associated with GMF preservation were enriched in androgenic steroids and steroid sulfates, with consistent positive associations observed in the replication cohort, whereas metabolites inversely associated with CTH were predominantly xenobiotic-related. Ibudilast treatment was associated with increased sphingomyelin species (e.g., palmitoyl sphingomyelin (d18:1/16:0); β = 0.185 [0.085, 0.286], FDR = 1.79×10 ^-2 ) and decreased levels of amino acid-related metabolites (e.g., anthranilate; β = -0.270 [-0.403, -0.137]; FDR = 3.87×10 ^-2 ). Pathway-based analyses corroborated these findings, highlighting glycerophospholipid and sphingolipid metabolism as key pathways implicated in brain atrophy in MS.

Distinct lipid subsets were associated with slower brain atrophy in people with MS, and ibudilast treatment was associated with metabolite alterations in potentially neuroprotective directions. Metabolomics may provide prognostic and pharmacodynamic biomarkers for progressive MS.

The study was supported by the National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS133005 and the National Institute of Nursing Research (NINR) grants R01NR018851.

Evidence before this study: Circulating metabolites are altered in people with multiple sclerosis (MS). Before conducting this work, we systematically searched PubMed from database inception to March 23, 2026, for articles published in English using the search terms ("metabolomics" OR "plasma metabolites") AND ("multiple sclerosis" OR "MS") AND ("MRI" OR "brain atrophy" OR "brain parenchymal fraction" OR "gray matter" OR "white matter") AND ("longitudinal" OR "progression" OR "brain atrophy"). We also reviewed reference lists of relevant publications. Prior studies have linked selected metabolites to clinical disability and brain atrophy in MS. However, most studies have been cross-sectional, limited by small sample sizes, or focused on case-control comparisons. Importantly, few studies have evaluated longitudinal associations between circulating metabolites and MRI-derived measures of brain atrophy, and studies integrating clinical trial data, external replication, and treatment-related metabolic changes remain scarce.Added value of this study: In a multicenter randomized clinical trial with longitudinal metabolomic profiling and MRI outcomes, we identified lipid-related metabolic signatures associated with brain atrophy, with consistent directionality observed in an independent cohort. We further demonstrated that ibudilast treatment was associated with longitudinal changes in specific metabolites, linking metabolic pathways to both disease progression and therapeutic response.Implications of all the available evidence: These findings support circulating metabolomic signatures as potential markers of brain atrophy in MS. Metabolomics may provide a scalable approach to identify individuals at risk of progressive brain tissue loss and to inform future mechanistic and therapeutic investigations targeting metabolic pathways involved in disability progression.