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Beyond well-established grey and white matter pathology, alterations in cortical gyrification have recently been observed, yet their clinical relevance and molecular underpinnings remain to be understood. Here, we investigated this premise by examining its microstructural and transcriptional basis in 60 patients with amyotrophic lateral sclerosis (median age = 55, range = 25\u201372 years) and 60 matched controls (median age = 56, range = 27\u201372 years) using structural and diffusion MRI. Patients exhibited a significant reduction in local gyrification index within bilateral precentral and postcentral gyri, left middle frontal gyrus and left superior parietal lobule. This was accompanied by reduced fractional anisotropy in the white matter tracts, primarily involving the corticospinal tract and corpus callosum. Higher local gyrification index and fractional anisotropy values were associated with better motor function as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, and local gyrification index also showed positive associations with global cognitive status. A mediation analysis indicated that fractional anisotropy partially accounted for the relationship between local gyrification index and functional disability, suggesting that disrupted white matter pathways contribute to the clinical impact of gyrification changes. To explore underlying mechanisms, we integrated neuroimaging findings with transcriptomic data from the Allen Human Brain Atlas. Regions of reduced local gyrification index showed spatial convergence with cortical expression of amyotrophic lateral sclerosis-related genes such as TARDBP and C9orf72, enriched for biological processes related to protein aggregation, axon guidance and synaptic signalling. Together, these findings suggest that cortical gyrification abnormalities in amyotrophic lateral sclerosis are closely linked to white matter degeneration, functional impairment and genetic vulnerability, thereby offering an integrative window into the multiscale pathology of amyotrophic lateral sclerosis.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaf491","type":"journal-article","created":{"date-parts":[[2025,12,14]],"date-time":"2025-12-14T12:41:45Z","timestamp":1765716105000},"source":"Crossref","is-referenced-by-count":0,"title":["Microstructure and gene expression influence gyrification in amyotrophic lateral sclerosis"],"prefix":"10.1093","volume":"8","author":[{"given":"Yihan","family":"Jiang","sequence":"first","affiliation":[{"name":"The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, University of Electronic Science and Technology of China , Chengdu 610054 ,","place":["P. R. China"]},{"name":"School of Life Science and Technology, University of Electronic Science and Technology of China , Chengdu 610054 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8300-4573","authenticated-orcid":false,"given":"Yan","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430030 ,","place":["P.R. China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyu","family":"Song","sequence":"additional","affiliation":[{"name":"Xiangya Hospital, Central South University, Jiangxi (National Regional Center for Neurological Diseases) , Nanchang, Jiangxi 330038 ,","place":["P. R. China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xueying","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Radiology, Xiangya Hospital, Central South University , Changsha , Hunan 410008 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianyu","family":"Li","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, University of Electronic Science and Technology of China , Chengdu 610054 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luqi","family":"Cheng","sequence":"additional","affiliation":[{"name":"School of Life and Environmental Sciences, Guilin University of Electronic Technology , Guilin 541004 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yifan","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, University of Electronic Science and Technology of China , Chengdu 610054 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanchao","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, University of Electronic Science and Technology of China , Chengdu 610054 ,","place":["P. R. China"]},{"name":"School of Life Science and Technology, University of Electronic Science and Technology of China , Chengdu 610054 ,","place":["China"]},{"name":"College of Health Solutions, Arizona State University , Phoenix, AZ 85004 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5117-5204","authenticated-orcid":false,"given":"Junling","family":"Wang","sequence":"additional","affiliation":[{"name":"Xiangya Hospital, Central South University, Jiangxi (National Regional Center for Neurological Diseases) , Nanchang, Jiangxi 330038 ,","place":["P. R. China"]},{"name":"Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases , Changsha, Hunan 410008 ,","place":["P. R. China"]},{"name":"National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University , Changsha, Hunan 410008 ,","place":["P. R. China"]},{"name":"Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University , Changsha, Hunan 410008 ,","place":["P. R. China"]},{"name":"Center for Medical Genetics, School of Life Sciences, Central South University , Changsha, Hunan 410008 ,","place":["P. R. China"]},{"name":"Engineering Research Center of Hunan Province in Cognitive Impairment Disorders, Central South University , Changsha, Hunan 410008 ,","place":["P. R. China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoping","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of Radiology, Chongqing University Three Gorges Hospital, Chongqing University , Chongqing 410008 ,","place":["P.R. China"]},{"name":"Clinical Research Center (CRC), Medical Pathology Center (MPC), Cancer Early Detection and Treatment Center (CEDTC) and Translational Medicine Research Center (TMRC), Chongqing University Three Gorges Hospital, Chongqing University , Chongqing 404000 ,","place":["P.R. China"]},{"name":"School of Medicine, Chongqing University , Chongqing 400030 ,","place":["P.R. China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1640-7182","authenticated-orcid":false,"given":"Lena","family":"Palaniyappan","sequence":"additional","affiliation":[{"name":"Douglas Mental Health University Institute, McGill University , Montreal, Quebec ,","place":["Canada, H4H 1R3"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,12,16]]},"reference":[{"issue":"2022; 400(10360","key":"2026010810514269900_fcaf491-B1","first-page":"1363","article-title":"Amyotrophic lateral sclerosis","author":"Feldman","journal-title":"Lancet."},{"issue":"11","key":"2026010810514269900_fcaf491-B2","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/nrneurol.2011.153","article-title":"Clinical diagnosis and management of amyotrophic lateral sclerosis","volume":"7","author":"Hardiman","year":"2011","journal-title":"Nat Rev 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