A Blood-Based Synaptic Biomarker in Neuronally-Enriched Extracellular Vesicles Predicts Disability Progression in Progressive Multiple Sclerosis
- 1Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA
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.
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BibTeX
@misc{jank2026bloodbased,
title = {{A Blood-Based Synaptic Biomarker in Neuronally-Enriched Extracellular Vesicles Predicts Disability Progression in Progressive Multiple Sclerosis}},
author = {L. Jank and M. K. S. Kumar and D. Joshi and V. Minney and R. Eskinder and R. Thapa and J. G. Heller and A. G. Filippatou and F. Siavoshi and M. D. Smith and C. Harp and I. Abioye and E. S. Sotirchos and B. E. Dewey and S. Saidha and K. C. Fitzgerald and P. A. Calabresi and E. M. Mowry and P. Bhargava},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.07.26364982},
url = {https://www.medrxiv.org/content/10.64898/2026.10.07.26364982v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A Blood-Based Synaptic Biomarker in Neuronally-Enriched Extracellular Vesicles Predicts Disability Progression in Progressive Multiple Sclerosis
AU - L. Jank
AU - M. K. S. Kumar
AU - D. Joshi
AU - V. Minney
AU - R. Eskinder
AU - R. Thapa
AU - J. G. Heller
AU - A. G. Filippatou
AU - F. Siavoshi
AU - M. D. Smith
AU - C. Harp
AU - I. Abioye
AU - E. S. Sotirchos
AU - B. E. Dewey
AU - S. Saidha
AU - K. C. Fitzgerald
AU - P. A. Calabresi
AU - E. M. Mowry
AU - P. Bhargava
PY - 2026
DA - 2026/10/07
PB - medRxiv
DO - 10.64898/2026.10.07.26364982
UR - https://www.medrxiv.org/content/10.64898/2026.10.07.26364982v1
AB - 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.
ER -