To evaluate the clinical utility of a novel plasma biomarker of demyelination (Sema4A) in people with multiple sclerosis (pwMS).

Blood-based biomarkers are essential for guiding clinical management for pwMS given the limitations of magnetic resonance imaging in some MS subtypes. Current MS biomarkers (eg, neurofilament light chain [NfL], glial fibrillary acid protein [GFAP]) lack specificity for central nervous system (CNS) demyelination and remyelination and are limited in distinguishing MS subtypes or predicting disease progression. Sema4A has demonstrated cytotoxicity towards oligodendrocytes, the key myelin-producing cells in the CNS. Early small pilot studies identified elevated Sema4A levels in pwMS. 

In a clinic-based prospective cohort, we are evaluating ~1400 participants with MS, related conditions and controls. Plasma Sema4A (pSema4A) levels are measured using immunoassay. We collected demographics, clinical characteristics, and longitudinal multi-modal outcomes (including patient-reported, rater-assessed, and neuroimaging metrics) following baseline. Group differences in pSema4A were assessed using the Kruskal-Wallis test. Associations between pSema4A and MS diagnosis, subtypes, and prognosis are evaluated with adjustment for demographic and clinical covariates.

Although immunoassays for all participants are ongoing, initial results are promising: stable relapsing-remitting multiple sclerosis (RRMS, n=13), active relapse (n=6), primary progressive (PPMS, n=6), secondary progressive (SPMS, n=6) and healthy controls (n=10). Participants with active relapse (20.55±11.98 ng/mL), PPMS (25.07±16.20 ng/mL), SPMS (86.56±105.23 ng/mL) showed higher pSema4A levels (mean±SD) compared to healthy controls (12.26±6.66 ng/mL) and stable RRMS (10.63±5.69 ng/mL) (group differences, p=0.019). We will present the full results.

Progressive MS and active relapse groups exhibited elevated pSema4A levels, whereas pwMS in stable remission showed levels comparable to controls. These preliminary results support further investigation into the clinical utility of Sema4A as blood biomarker for acute and chronic demyelination in MS.