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However, accumulating evidence suggests that multiple sclerosis pathophysiology extends beyond such classical lesions, affecting also \u2018normal\u2019 appearing tissue in both white and gray matter, referred to as \u2018normal-appearing white matter\u2019 and \u2018normal-appearing gray matter\u2019, respectively. Here, we provide a comprehensive overview of the widespread biochemical, cellular, and microstructural alterations occurring in these \u2018normal-appearing\u2019 CNS regions. Additionally, we discuss the evidence derived from human post-mortem studies that support that normal-appearing white and gray matter could be the drivers of smoldering-associated pathological worsening once repair mechanisms are exhausted. Comprehensive understanding of multiple sclerosis pathology beyond classical lesions not only provides a more complete picture of disease progression, but also provides further insights into potential novel therapeutic avenues in order to slow or halt disability accumulation.<\/jats:p>","DOI":"10.1007\/s00401-025-02923-1","type":"journal-article","created":{"date-parts":[[2025,8,10]],"date-time":"2025-08-10T13:00:37Z","timestamp":1754830837000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["A focus on the normal-appearing white and gray matter within the multiple sclerosis brain: a link to smoldering progression"],"prefix":"10.1007","volume":"150","author":[{"given":"Gema","family":"Mu\u00f1oz Gonz\u00e1lez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bert A.","family":"\u00b4t Hart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Bugiani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason R.","family":"Plemel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geert J.","family":"Schenk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gijs","family":"Kooij","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Luchicchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,10]]},"reference":[{"key":"2923_CR1","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1212\/WNL.0000000000003820","volume":"88","author":"M Absinta","year":"2017","unstructured":"Absinta M, Cortese ICM, Vuolo L, Nair G, de Alwis MP, Ohayon J et al (2017) Leptomeningeal gadolinium enhancement across the spectrum of chronic neuroinflammatory diseases. 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