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We hypothesized that lesions in LOMS patients show more pronounced axonal damage, less remyelination and an altered inflammatory composition, and performed a detailed histopathological analysis of MS biopsies in patients with early-stage LOMS. The number of T cells, B cells, plasma cells, microglia\/macrophages, different oligodendrocyte populations as well as the axonal density and acute axonal damage were assessed in 31 LOMS and 30 normal-onset MS (NOMS, 20\u201340\u00a0years old) patients. No major differences in the inflammatory infiltrate or axonal damage were found. BCAS1-positive oligodendrocytes indicating early myelinating oligodendrocytes, and mature oligodendrocytes were significantly lower in the normal-appearing white matter of LOMS compared to NOMS patients (<jats:italic>p<\/jats:italic>\u2009=\u20090.05; <jats:italic>p<\/jats:italic>\u2009=\u20090.01), with a negative correlation with age (r\u2009=\u2009\u2212\u00a00.5, <jats:italic>p<\/jats:italic>\u2009=\u20090.01). In active demyelinating lesions, the number of BCAS1-positive oligodendrocytes did not differ between LOMS and NOMS, but NOMS lesions showed a higher proportion of ramified cells indicating active remyelination. In LOMS, BCAS1-positive oligodendrocytes decreased with increasing lesion age, with the lowest numbers found in inactive demyelinated lesions. In contrast, NOMS patients showed high numbers of BCAS1-positive cells with an activated morphology, even in inactive demyelinated lesions. At the last follow-up, LOMS patients had a significantly higher EDSS score (median 3.5) than NOMS patients (median 3.0, <jats:italic>p<\/jats:italic>\u2009=\u20090.05). A higher EDSS score correlated with fewer mature and oligodendrocyte precursor cells in active demyelinating lesions (r\u2009=\u2009\u2212\u00a00.4, <jats:italic>p<\/jats:italic>\u2009=\u20090.01 and r\u2009=\u2009\u2212\u00a00.6, <jats:italic>p<\/jats:italic>\u2009=\u20090.003). These findings suggest a clinically relevant impaired oligodendrocyte differentiation and remyelination in LOMS. Since remyelination is essential for axonal protection, it will be necessary to consider the complex and dynamic tissue environment when researching therapeutics aimed at fostering the differentiation of oligodendrocyte precursor cells into myelinating oligodendrocytes.<\/jats:p>","DOI":"10.1007\/s00401-025-02868-5","type":"journal-article","created":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T20:48:21Z","timestamp":1743713301000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Impaired remyelination in late-onset multiple sclerosis"],"prefix":"10.1007","volume":"149","author":[{"given":"Lidia","family":"Stork","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Schirin","family":"Stephan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriane","family":"Kutllovci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Br\u00fcck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imke","family":"Metz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,1]]},"reference":[{"key":"2868_CR1","doi-asserted-by":"publisher","first-page":"1917","DOI":"10.1016\/j.bbamcr.2014.04.018","volume":"1843","author":"A Barateiro","year":"2014","unstructured":"Barateiro A, Fernandes A (2014) Temporal oligodendrocyte lineage progression: in vitro models of proliferation, differentiation and myelination. 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