A Blood-Based Synaptic Biomarker in Neuronally-Enriched Extracellular Vesicles Predicts Disability Progression in Progressive Multiple Sclerosis.

Authors

Larissa Jank, Madathiparambil Ks Kumar, Deepika Joshi, Veronica Minney, Rahel Eskinder, Rohit Thapa, John G Heller, Angeliki G Filippatou, Fatemeh Siavoshi, Matthew D Smith, Christopher Harp, Ibraheem Abioye, Elias S Sotirchos, Blake E Dewey, Shiv Saidha, Kathryn C Fitzgerald, Peter A Calabresi, Ellen M Mowry, Pavan Bhargava

Published in

medRxiv : the preprint server for health sciences. Oct 09, 2026. Epub Oct 09, 2026.

Abstract

Progressive multiple sclerosis (PMS) lacks blood-based biomarkers of the neurodegenerative processes driving disability. We measured synaptopodin, a postsynaptic protein, in neuronal-enriched extracellular vesicles (NEVs) across two independent cohorts: the SPRINT-MS trial (n=184) and a real-world validation cohort (n=268). A one SD increase in baseline synaptopodin was associated with ∼32% lower risk of confirmed disability progression in PMS (p=0.011), with the strongest effect in secondary PMS (SPMS) (∼57% lower odds, p=0.019). This SPMS association was replicated in the validation cohort (∼60% lower odds, p=0.009). Higher baseline synaptopodin was associated with future slower whole-brain atrophy and preserved microstructural integrity across MRI metrics (p=0.007-0.013). Longitudinal changes in NEV synaptopodin were associated with disability worsening (p=0.007) and paralleled MRI microstructural changes. NEV synaptopodin, but not NfL, was associated with confirmed disability progression in PMS participants with both biomarkers measured (HR 0.71 vs 1.12, p=0.007 vs 0.22 for NEV synaptopodin and NfL, respectively) and SPMS (HR 0.58 vs 1.10, p=0.003 vs 0.50). Adding synaptopodin, but not NfL, to a base model improved discrimination for disability progression in SPMS in both cohorts (e.g. validation AUC 0.755 to 0.838, p=0.005). These findings identify NEV synaptopodin as a prognostic and longitudinal, blood biomarker of synaptic integrity in PMS, particularly SPMS, complementing NfL.

PMID:
42927044
Bibliographic data and abstract were imported from PubMed on 25 Oct 2026.

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