{
  "abstract": "BackgroundQuantitative susceptibility mapping (QSM) exhibits phase cancellation between paramagnetic (e.g. iron) and diamagnetic (e.g. myelin/protein) sources, obscuring microstructural lesion heterogeneity in multiple sclerosis (MS). We evaluated whether biophysical{chi} -separation identifies clinically meaningful lesion phenotypes and whether reduced echo sampling preserves microstructural sensitivity.\n\nMethodsIn this cross-sectional study of 183 people with multiple sclerosis (PwMS), we analyzed 3327 quality-controlled white matter lesions using 3T MRI with a five-echo gradient-recalled echo sequence (GRE5) and a subsampled two-echo dataset (GRE2). A hybrid framework combining unsupervised clustering on whole-lesion paramagnetic ({chi}para) and diamagnetic ({chi}dia) features with rule-based compartmental edge-core gradient assignment resolved MS lesion phenotypes. Intralesional microstructural properties were evaluated using linear mixed-effects models. Multivariable linear regressions assessed associations with physical disability (Expanded Disability Status Scale, EDSS; n = 158), cognitive processing speed (Symbol Digit Modalities Test, SDMT; n = 79), and disease duration (DD; n = 161), with sensitivity models adjusting for total lesion volume, count, or DD.\n\nResultsThe framework identified four reproducible lesion phenotypes (Adjusted Rand Index = 0.924): Type 1 (22.7%; preserved{chi} dia), Type 2 (32.9%; high{chi} para without positive edge-core gradient), Type 3 (35.8%; attenuated{chi} dia), and Type 4 (8.6%; high{chi} para with a positive edge-core paramagnetic gradient). Higher EDSS was selectively associated with more negative signed{chi} dia within Type 4 lesions (whole: {beta} = -0.37, q = 0.020; core: {beta} = -0.37, q = 0.006; edge: {beta} = -0.34, q = 0.030) and Type 2 edge ({beta} = -0.33, q = 0.044). Type 4 core associations remained robust across sensitivity models adjusting for total lesion volume ({beta} = -0.35, q = 0.004), total lesion count ({beta} = -0.37, q = 0.008), and DD ({beta} = -0.32, q = 0.033). Abbreviated GRE2 attenuated Type 4 compartmental associations to non-significance (all q greater than 0.05; core: {beta} = -0.20, q = 0.215).\n\nConclusionsQuantitative{chi} -separation identified four internally stable susceptibility-defined MS lesion phenotypes, revealing disability-associated tissue heterogeneity beyond total lesion burden. Higher EDSS was associated with more negative diamagnetic measures within Type 4 cores after adjustment for lesion burden, pointing toward complex intralesional non-myelin tissue remodeling or reactive astrogliosis. Two-echo subsampling may influence compartment-specific clinical associations. By uncoupling susceptibility sources,{chi} -separation provides a quantitative framework for characterizing disability-associated lesion heterogeneity.",
  "abstract_shown": true,
  "affiliations": [
    "Neuroradiology Section, Vall d'Hebron University Hospital (VHIR)"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "E. Martinez-Heras"
    },
    {
      "name": "M. Alberich"
    },
    {
      "name": "H.-G. Shin"
    },
    {
      "name": "F. Sampedro"
    },
    {
      "name": "E. G. GUZMAN"
    },
    {
      "name": "E. del Agua"
    },
    {
      "name": "N. M. Ochoa"
    },
    {
      "name": "J. S. Garriga"
    },
    {
      "name": "A. Rovira"
    },
    {
      "name": "D. Pareto"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cm9mth8zbezz7.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.15.26365462",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.10.15.26365462v1.full",
  "id": "cm9mth8zbezz7",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.10.15.26365462v1",
  "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",
      "2741|Advanced MRI Techniques and Applications"
    ]
  ],
  "openalex": "W7222551224",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.10.15.26365462v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-15",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/cm9mth8zbezz7.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:21:01Z",
      "native_id": "10.64898/2026.10.15.26365462",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.10.15.26365462v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:neurology",
      "subfield": "neurology"
    }
  ],
  "title": "Microstructural phenotyping and clinical relevance of multiple sclerosis lesions using quantitative susceptibility source separation",
  "title_text": "Microstructural phenotyping and clinical relevance of multiple sclerosis lesions using quantitative susceptibility source separation",
  "type": "preprint",
  "updated_at": "2026-10-30T12:21:01Z",
  "url": "https://research.draconitic.com/paper/cm9mth8zbezz7",
  "venue": "medRxiv",
  "versions": []
}