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This variability complicates efforts to relate lesion pathology to clinical trajectories. In previous work in the Netherlands Brain Bank MS autopsy cohort (NBB-MS), we showed that relative proportions of different lesion types, lesion load, and microglia\/macrophage activity score, associate with clinical severity, while also revealing marked inter-individual variability. Here, we extend these observations by examining whether selected donor-specific pathological features relate to genetic background, quantitative lesion type distributions, and clinical disease course, and thereby help contextualize this heterogeneity.<\/jats:p>\n                  <jats:p>\n                    Brain tissue from 287 NBB-MS donors was assessed for the presence of the donor-specific pathological features, namely perivascular cuffs, microglial nodules, broad rim lesions (BRLs), and remyelination efficiency. Perivascular cuffs and microglial nodules were more prevalent among carriers of the MS susceptibility allele\n                    <jats:italic>HLA-DRB1*15:01<\/jats:italic>\n                    (rs3135388). BRLs and perivascular cuffs were enriched in carriers of the MS severity-associated SNP in the\n                    <jats:italic>DYSF\u2013ZNF638<\/jats:italic>\n                    locus (rs10191329). Perivascular cuffs associated with increased microglia\/macrophage activation score and decreased age at death. Microglial nodules in the normal appearing white matter associated with a higher proportion of active lesions. BRLs were linked to increased proportions of active and mixed active\/inactive lesions, higher brainstem lesion rate, and a higher age related MS severity score. Poor remyelination efficiency associated with a higher proportion of mixed active\/inactive and inactive lesions, and a shorter disease duration.\n                  <\/jats:p>\n                  <jats:p>Together, these findings show that specific pathological features of donors relate to genetic risk, lesion type distribution, and clinical outcome. Integrating these donor-specific pathological features alongside lesion classification will enable a more biologically refined interpretation of post-mortem MS tissue study results and will improve understanding of inter-individual heterogeneity in MS.<\/jats:p>","DOI":"10.1007\/s00401-026-03040-3","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T17:48:09Z","timestamp":1782409689000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Donor-specific pathological features associate with genetic background, lesion type distribution, and clinical heterogeneity in multiple sclerosis"],"prefix":"10.1007","volume":"151","author":[{"given":"Lukas","family":"L\u00fctje","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Q. 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