{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T17:35:47Z","timestamp":1786988147368,"version":"build-2736575974"},"reference-count":47,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T00:00:00Z","timestamp":1772150400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T00:00:00Z","timestamp":1772150400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100006606","name":"Natural Science Foundation of Tianjin Municipality","doi-asserted-by":"publisher","award":["21CYBJC01580"],"award-info":[{"award-number":["21CYBJC01580"]}],"id":[{"id":"10.13039\/501100006606","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006606","name":"Natural Science Foundation of Tianjin Municipality","doi-asserted-by":"publisher","award":["21JCYBJC01060"],"award-info":[{"award-number":["21JCYBJC01060"]}],"id":[{"id":"10.13039\/501100006606","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To explore how cerebral hypoxia and Normal\u2010Appearing White Matter (NAWM) integrity affect MS lesion burden and clinical course.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Seventy\u2010nine MS patients, including 13 clinically isolated syndrome (CIS) patients and 66 relapsing\u2013remitting multiple sclerosis (RRMS) patients, and 44 healthy controls (HCs) were recruited from CLUE, NCT04106830. Quantitative susceptibility mapping (QSM) was employed to evaluate the changes of cerebral venous oxygen saturation (SvO\n                      <jats:sub>2<\/jats:sub>\n                      ) in deep cerebral veins. Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging analyzes (NODDI) were employed to evaluate microstructural alterations in deep brain white matter (WM), including WM lesion and NAWM between MS and HCs. Partial correlations analyzes were conducted to examine associations between imaging biomarkers and clinical indicators. Mediation analysis was used to evaluate the relationship among SvO\n                      <jats:sub>2<\/jats:sub>\n                      , microstructural alterations, lesion volumes, and clinical indicators.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Compared with HCs, patients with MS showed significantly decreased SvO\n                      <jats:sub>2<\/jats:sub>\n                      in the internal cerebral vein (76.56%\u2009\u00b1\u20091.34% vs. 78.80%\u2009\u00b1\u20090.86%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Advanced diffusion metrics revealed extensive microstructural disruption in both WM lesions and NAWM (NAWM mean diffusivity [MD]: 1.03\u2009\u00b1\u20090.12 vs. 0.90\u2009\u00b1\u20090.04 [\u00d710\n                      <jats:sup>\u22123<\/jats:sup>\n                      \u2009mm\n                      <jats:sup>2<\/jats:sup>\n                      \/s],\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Furthermore, microstructural disruption of NAWM (MD and orientation dispersion index [ODI]) significantly correlated with SvO\n                      <jats:sub>2<\/jats:sub>\n                      of the ICV (MD:\n                      <jats:italic>r<\/jats:italic>\n                      \u2009=\u2009\u22120.307,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.036; ODI:\n                      <jats:italic>r<\/jats:italic>\n                      \u2009=\u2009\u22120.279,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.036). Critically, mediation analysis demonstrated that deep brain WM hypoxia (ICV SvO\n                      <jats:sub>2<\/jats:sub>\n                      ) associated with greater lesion burden and clinical disability via NAWM damage as an intermediate pathway.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      In MS patients, lower cerebral SvO\n                      <jats:sub>2<\/jats:sub>\n                      (compared with HCs) is statistically associated with microstructural alterations in the NAWM. Our mediation models are consistent with a pathway whereby lower SvO\n                      <jats:sub>2<\/jats:sub>\n                      is associated with greater lesion burden and worse functional scores via its association with NAWM damage. These findings support the exploratory value of SvO\n                      <jats:sub>2<\/jats:sub>\n                      and NAWM integrity as potential biomarkers for monitoring MS progression, which warrants validation in further longitudinal studies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.70354","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T16:59:05Z","timestamp":1772989145000},"page":"1686-1696","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Normal\u2010Appearing White Matter Injury Mediates Chronic Deep Venous Hypoxia and Disease Progression in Multiple Sclerosis"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1957-1271","authenticated-orcid":false,"given":"Xinli","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Radiology First Central Hospital of Tianjin 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Hospital, Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Lv","sequence":"additional","affiliation":[{"name":"School of Medicine Nankai University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5153-2491","authenticated-orcid":false,"given":"Decai","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Neurology Beijing Tiantan Hospital, Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Chai","sequence":"additional","affiliation":[{"name":"Department of Radiology, Tianjin Institute of Imaging Medicine Tianjin First Central Hospital, School of Medicine, Nankai University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunyun","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Radiology Beijing 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