{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:01:03Z","timestamp":1790834463908,"version":"4.1.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Insulin resistance\u2013related metabolic burden is associated with cognitive aging, but the relevant white matter microstructural features remain unclear. We examined statistical indirect associations between metabolic indices and cognition through tract-level white matter measures, including associations with subsequent cognitive change.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Cross-sectional and longitudinal analyses used Health and Aging Brain Study\u2013Health Disparities (HABS-HD) data. Exposures were the triglyceride\u2013glucose (TyG) index and its composites with waist-to-height ratio (TyG-WHtR) and visceral adiposity index (TyG-VAI). Candidate mediators were axial and radial diffusivity (RD) in 32 white matter tracts; outcomes covered six cognitive domains. High-dimensional mediation analysis with within-model false discovery rate (FDR) correction selected candidate pathways, supplemented by model-level multiplicity analyses. Selection stability was assessed using 1,000 participant-level bootstrap samples. All candidates underwent longitudinal mixed-effects analysis, with indirect estimates calculated as baseline exposure\u2013white matter coefficients multiplied by white matter-by-time coefficients. Intervals used 2,000 participant-level cluster bootstrap samples. Sensitivity analyses adjusted for white matter hyperintensity (WMH) volume and covariate-by-time interactions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Of 2,606 participants, 788 had two cognitive assessments a median of 2.17 years apart. Fourteen candidate pathways were selected, all involving RD and TyG or TyG-WHtR; 11 had 95% conditional Monte Carlo uncertainty intervals excluding zero. Two of 36 models met the supplementary model-level FDR criterion. Five longitudinal pathways had negative indirect estimates with 95% bootstrap intervals excluding zero: four involved right cingulum RD and processing speed or executive function, and one involved right superior corona radiata RD and processing speed. Four also met the FDR criterion for RD-by-time interactions. The TyG-WHtR\u2013right cingulum RD\u2013executive function indirect estimate was -0.0054 per year (95% bootstrap interval, -0.0110 to -0.0009). Selection frequencies ranged from 6.7% to 42.0%. After WMH and WMH-by-time adjustment, intervals excluded zero for two of these five pathways, decreasing to one with additional core covariate-by-time interactions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Triglyceride\u2013glucose index and TyG-WHtR showed statistical indirect associations with cognition through white matter RD, with some pathways associated with subsequent cognitive change. Limited selection stability and sensitivity to WMH and covariate-by-time adjustment warrant evaluation in independent cohorts.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnins.2026.1967890","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:41:05Z","timestamp":1790833265000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Insulin resistance\u2013related metabolic burden, white matter microstructure, and cognitive change: the HABS-HD study"],"prefix":"10.3389","volume":"20","author":[{"given":"Huaiyi","family":"Li","sequence":"first","affiliation":[{"name":"Department of Radiology, The Second Affiliated Hospital of Xiamen Medical College","place":["Xiamen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiliang","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, The First 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