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The glymphatic system, active during slow-wave sleep, clears brain waste through perivascular astrocytic aquaporin-4 (AQP4) channels. The presence of antigens induces a transient, physiological lowering of glymphatic flux as a first step of an inflammatory response. A possible hypothesis linking infection with the Epstein\u2013Barr virus, a well identified causal step in MS, and the development of the disease is that mechanisms such as poor sleep or less functional AQP4 polymorphisms may sustain glymphatic flow reduction. Such chronic glymphatic reduction would trigger a vicious circle in which the persistence of antigens and an inflammatory response maintains glymphatic dysfunction. In addition, viral proteins that persist in demyelinated plaques can depolarize AQP4, further restricting waste elimination and sustaining local inflammation. This review examines the epidemiological evidence connecting sleep and MS risk, and the mechanistic findings showing how poor sleep and other glymphatic modulators heighten inflammatory signaling implicated in MS pathogenesis. Deepening knowledge of glymphatic functioning in MS could open new avenues for personalized prevention and therapy.<\/jats:p>","DOI":"10.3390\/brainsci15070766","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T10:35:31Z","timestamp":1753094131000},"page":"766","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Sleep and Risk of Multiple Sclerosis: Bridging the Gap Between Inflammation and Neurodegeneration via Glymphatic Failure"],"prefix":"10.3390","volume":"15","author":[{"given":"Mariateresa","family":"Buongiorno","sequence":"first","affiliation":[{"name":"Neurology Department, Vall d\u2019Hebron University Hospital, 08035 Barcelona, Spain"},{"name":"Vall d\u2019Hebron Research Institute, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Tur","sequence":"additional","affiliation":[{"name":"Vall d\u2019Hebron Research Institute, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8821-7662","authenticated-orcid":false,"given":"Darly Milena","family":"Giraldo","sequence":"additional","affiliation":[{"name":"Neurology Department, Vall d\u2019Hebron University Hospital, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5118-1014","authenticated-orcid":false,"given":"Natalia","family":"Cullell","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3 per a Doc\u00e8ncia i Recerca, M\u00fatua Terrassa, 08221 Terrassa, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerzy","family":"Krupinski","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3 per a Doc\u00e8ncia i Recerca, M\u00fatua Terrassa, 08221 Terrassa, Spain"},{"name":"Department of Neurology, Fundaci\u00f3 Assistencial M\u00fatua Terrassa, 08221 Terrassa, Spain"},{"name":"Faculty of Science and Engineering, Department of Life Sciences, Manchester Metropolitan University, Manchester M15 6BX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6388-8180","authenticated-orcid":false,"given":"Roberta","family":"Lanzillo","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis Clinical Care and Research Centre, Federico II University Hospital of Naples, 80131 Naples, Italy"},{"name":"Department of Neurosciences, Reproductive Sciences and Odontostomatology, Federico II University, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonzalo","family":"S\u00e1nchez-Benavides","sequence":"additional","affiliation":[{"name":"Barcelona\u03b2eta Brain Research Center (BBRC), Pasqual Maragall Foundation, 08005 Barcelona, Spain"},{"name":"Hospital del Mar Research Institute, 08003 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1038\/ng.3395","article-title":"Class II HLA Interactions Modulate Genetic Risk for Multiple Sclerosis","volume":"47","author":"Moutsianas","year":"2015","journal-title":"Nat. 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