{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T16:03:02Z","timestamp":1792598582301,"version":"4.5.0"},"reference-count":76,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Obesity is a risk factor for white matter hyperintensities (WMH) and cognitive decline, but underlying mechanisms regarding sex differences, obesity metrics, and the glymphatic system remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>Using data from the UK Biobank, we performed sex-stratified analyses. Our approach integrated obesity trajectory modeling (over a mean 9-year period), genome-wide association studies, and 2-sample Mendelian randomization. We examined associations of body mass index, waist-hip ratio, and body fat percentage with glymphatic system function assessed via the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, WMH volume, and cognitive performance. Models were adjusted for age, education, socioeconomic status, vascular risk factors, and intracranial volume, and a sensitivity check was conducted.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      In 37\u2009684 middle-aged and aging participants (mean age 63.9\u00b17.6 years), significant sex-by-obesity interactions were observed (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      <jats:sub>inter<\/jats:sub>\n                      &lt;0.05). Men showed consistently greater effects for obesity-related declines in total DTI-ALPS index, total WMH burden, and symbol digit substitution test compared with women (all\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt;0.001). Trajectory analysis identified waist-hip ratio as the primary driver for men, specifically for deep WMH, middle DTI-ALPS index (all\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt;0.001), whereas body mass index\/body fat percentage predominated in women. Sex-stratified genome-wide association studies confirmed divergent genetic architectures supporting these phenotypes. MR validated stronger causal effects of waist-hip ratio on deep WMH in men than in women (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt;0.001). Crucially, mediation analyses demonstrated a significant role of the DTI-ALPS index in women. The effect of body fat percentage on periventricular WMH was primarily explained by an indirect pathway via total DTI-ALPS index (indirect effect, \u03b2=0.037 [95% CI, 0.032\u20130.042];\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt;0.001), with a nonsignificant direct effect (\u03b2=\u22120.002 [95% CI, \u22120.016 to 0.011];\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.806), indicating full mediation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Obesity impacts WMH burden or cognition via sex-divergent pathways, with central adiposity (waist-hip ratio) more detrimental in men and general adiposity (body mass index\/body fat percentage) acting through DTI-ALPS index in women. These findings advocate for sex-tailored interventions to control weight, thereby protecting the glymphatic system and reducing the risk of brain injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/strokeaha.125.053462","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T09:01:10Z","timestamp":1781773270000},"page":"2437-2451","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Obesity, White Matter Hyperintensities, and Cognitive Decline: Sex-Specific DTI-ALPS Index Mediation"],"prefix":"10.1161","volume":"57","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6965-1424","authenticated-orcid":true,"given":"Lusen","family":"Ran","sequence":"first","affiliation":[{"name":"Department of Neurology (L.R., H.H., Y.H., Y.F., C.C., S.X., X.L., W.W., Z.T., M.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China."},{"name":"Hubei Provincial Clinical Research Center for Stroke, Wuhan, China (L.R., H.H., Y.H., Y.F., C.C., S.X., X.L., W.W., Z.T., M.W.)."},{"name":"Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China (L.R., H.H., Y.H., Y.F., C.C., S.X., X.L., W.W., Z.T., M.W.)."},{"name":"Department of Neurology, Shenzhen Nanshan People\u2019s Hospital, Shenzhen, China (L.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurology (L.R., H.H., Y.H., Y.F., C.C., S.X., X.L., W.W., Z.T., M.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China."},{"name":"Hubei Provincial Clinical Research Center for Stroke, Wuhan, China (L.R., H.H., Y.H., Y.F., C.C., S.X., X.L., W.W., Z.T., M.W.)."},{"name":"Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China (L.R., H.H., Y.H., Y.F., C.C., S.X., X.L., W.W., Z.T., M.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1116-1227","authenticated-orcid":true,"given":"Yuqin","family":"He","sequence":"additional","affiliation":[{"name":"Department of Neurology (L.R., H.H., Y.H., Y.F., C.C., S.X., X.L., W.W., Z.T., M.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China."},{"name":"Hubei Provincial Clinical Research Center for Stroke, Wuhan, China (L.R., H.H., Y.H., Y.F., C.C., S.X., X.L., W.W., Z.T., M.W.)."},{"name":"Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China (L.R., H.H., Y.H., Y.F., C.C., S.X., X.L., W.W., Z.T., 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