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Using cross-sectional T1-weighted and diffusion-weighted MRI, we test the hypothesis that cortical microstructural alterations, quantified as cortical mean diffusivity (cMD), are detectable earlier and are more strongly associated with clinical progression than cortical thickness (CTh). The sample comprised\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009710 individuals (47.8\u2009\u00b1\u200913.5 years, 56.6% female, 14.1\u2009\u00b1\u20093.3 years of education), including 118 symptomatic carriers and 305 presymptomatic carriers with mutations in\n                    <jats:italic>C9orf72<\/jats:italic>\n                    ,\n                    <jats:italic>GRN<\/jats:italic>\n                    or\n                    <jats:italic>MAPT<\/jats:italic>\n                    genes, and 287 non-carriers, collected from 24 GENFI sites. A subset of\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009453 individuals (289 carriers, 164 non-carriers) were investigated across Clinical Dementia Rating (CDR)\u2009=\u20090, 0.5 and \u22651 stages. Two subsets had longitudinal clinical outcome measures, including\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009403 individuals (239 carriers, 164 non-carriers) with Cambridge Behavioural Inventory-Revised scores during 2.8\u2009\u00b1\u20091.6 years, and\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009261 individuals (164 carriers, 97 non-carriers) with CDR Sum-of-Boxes scores during 2.0\u2009\u00b1\u20090.8 years. Regional cMD and CTh were entered into linear mixed-effects models incorporating age, sex and education as covariates; site, and individual nested within site were random intercepts. The results demonstrated that cMD is more sensitive than CTh to track early cortical injury, with elevated cMD first observed at CDR\u2009=\u20090 in\n                    <jats:italic>C9orf72<\/jats:italic>\n                    carriers, followed by\n                    <jats:italic>MAPT<\/jats:italic>\n                    carriers (from CDR\u2009=\u20090.5 stage), and by\n                    <jats:italic>GRN<\/jats:italic>\n                    carriers (beginning at CDR\u2009\u2265\u20091). At all stages, cortical microstructural injury had stronger effect size and was more widespread than cortical thinning. In all mutation carrier types, cMD was more strongly associated than CTh with subsequent clinical progression. Cortical microstructure is a promising biomarker to identify at-risk individuals before atrophy and clinical progression, with utility in therapeutic trials.\n                  <\/jats:p>","DOI":"10.1038\/s41380-025-03280-x","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T07:29:24Z","timestamp":1759994964000},"page":"5800-5812","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Cortical microstructure is associated with disease severity and clinical progression in genetic frontotemporal dementia: a GENFI study"],"prefix":"10.1038","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6639-8141","authenticated-orcid":false,"given":"Elena","family":"Rodriguez-Vieitez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa 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