{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 19,
  "authors": [
    {
      "name": "L. Jank"
    },
    {
      "name": "M. K. S. Kumar"
    },
    {
      "name": "D. Joshi"
    },
    {
      "name": "V. Minney"
    },
    {
      "name": "R. Eskinder"
    },
    {
      "name": "R. Thapa"
    },
    {
      "name": "J. G. Heller"
    },
    {
      "name": "A. G. Filippatou"
    },
    {
      "name": "F. Siavoshi"
    },
    {
      "name": "M. D. Smith"
    },
    {
      "name": "C. Harp"
    },
    {
      "name": "I. Abioye"
    },
    {
      "name": "E. S. Sotirchos"
    },
    {
      "name": "B. E. Dewey"
    },
    {
      "name": "S. Saidha"
    },
    {
      "name": "K. C. Fitzgerald"
    },
    {
      "name": "P. A. Calabresi"
    },
    {
      "name": "E. M. Mowry"
    },
    {
      "affs": [
        0
      ],
      "name": "P. Bhargava"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/43hgadtqrn2cj.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.07.26364982",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.10.07.26364982v1.full",
  "id": "43hgadtqrn2cj",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.10.07.26364982v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "neurology"
    ],
    [
      "openalex",
      "2734|Multiple Sclerosis Research Studies"
    ]
  ],
  "openalex": "W7221144492",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.10.07.26364982v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-07",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/43hgadtqrn2cj.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:32Z",
      "native_id": "10.64898/2026.10.07.26364982",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.10.07.26364982v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:neurology",
      "subfield": "neurology"
    }
  ],
  "title": "A Blood-Based Synaptic Biomarker in Neuronally-Enriched Extracellular Vesicles Predicts Disability Progression in Progressive Multiple Sclerosis",
  "title_text": "A Blood-Based Synaptic Biomarker in Neuronally-Enriched Extracellular Vesicles Predicts Disability Progression in Progressive Multiple Sclerosis",
  "type": "preprint",
  "updated_at": "2026-10-30T12:20:32Z",
  "url": "https://research.draconitic.com/paper/43hgadtqrn2cj",
  "venue": "medRxiv",
  "versions": []
}