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Brain biological age can be estimated by machine learning algorithms that use large brain MRI data sets to integrate and compute neuroimaging-derived age-related features. Predicted and chronological ages difference (brain-age gap) reflects advanced or delayed brain aging in an individual. The present study firstly reports the brain aging status of cerebral small vessel disease. In addition, we investigated whether global or certain regional brain age could mediate the cognitive functions in cerebral small vessel disease. Global and regional (400 cortical, 14 subcortical and 28 cerebellum regions of interest) brain-age prediction models were constructed using grey matter features from MRI of 1482 healthy individuals (age: 18\u201392 years). Predicted and chronological ages differences were obtained and then applied to non-stroke, non-demented individuals, aged \u226550 years, from another community-dwelling population (I-Lan Longitudinal Aging Study cohort). Among the 734 participants from the I-Lan Longitudinal Aging Study cohort, 124 were classified into the cerebral small vessel disease group. The cerebral small vessel disease group demonstrated significantly poorer performances in global cognitive, verbal memory and executive functions than that of non-cerebral small vessel disease group. Global brain-age gap was significantly higher in the cerebral small vessel disease (3.71\u2009\u00b1\u20097.60 years) than that in non-cerebral small vessel disease (\u22120.43\u2009\u00b1\u20099.47 years) group (P\u2009=\u20090.003, \u03b72\u2009=\u20090.012). There were 82 cerebral cortical, 3 subcortical and 4 cerebellar regions showing significantly different brain-age gap between the cerebral small vessel disease and non-cerebral small vessel disease groups. Global brain-age gap failed to mediate the relationship between cerebral small vessel disease and any of the cognitive domains. In 89 regions with increased brain-age gap in the cerebral small vessel disease group, seven regional brain-age gaps were able to show significant mediation effects in cerebral small vessel disease-related cognitive impairment (we set the statistical significance P\u2009&amp;lt;\u20090.05 uncorrected in 89 mediation models). Of these, the left thalamus and left hippocampus brain-age gap explained poorer global cognitive performance in cerebral small vessel disease. We demonstrated the interconnections between cerebral small vessel disease and brain age. Strategic brain aging, i.e. advanced brain aging in critical regions, may be involved in the pathophysiology of cerebral small vessel disease-related cognitive impairment. Regional rather than global brain-age gap could potentially serve as a biomarker for predicting heterogeneous cognitive outcomes in patients with cerebral small vessel disease.<\/jats:p>","DOI":"10.1093\/braincomms\/fcac233","type":"journal-article","created":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T14:26:10Z","timestamp":1663165570000},"source":"Crossref","is-referenced-by-count":32,"title":["Regional rather than global brain age mediates cognitive function in cerebral small vessel disease"],"prefix":"10.1093","volume":"4","author":[{"given":"Pei-Lin","family":"Lee","sequence":"first","affiliation":[{"name":"Institute of Neuroscience, National Yang Ming Chiao Tung University , Taipei , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Yuan","family":"Kuo","sequence":"additional","affiliation":[{"name":"Aging and Health Research Center, National Yang Ming Chiao Tung University , Taipei , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Ning","family":"Wang","sequence":"additional","affiliation":[{"name":"Aging and Health Research Center, National Yang Ming Chiao Tung University , Taipei , Taiwan"},{"name":"Department of Neurology, Neurological Institute, Taipei Veterans General Hospital , Taipei , Taiwan"},{"name":"Brain Research Center, National Yang Ming Chiao Tung University , Taipei , Taiwan"},{"name":"Center for Geriatric and Gerontology, Taipei Veterans General Hospital , Taipei , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang-Kung","family":"Chen","sequence":"additional","affiliation":[{"name":"Aging and Health Research Center, National Yang Ming Chiao Tung University , Taipei , Taiwan"},{"name":"Center for Geriatric and Gerontology, Taipei Veterans General Hospital , Taipei , Taiwan"},{"name":"Taipei Municipal Gan-Dau Hospital (managed by Taipei Veterans General Hospital) , Taipei , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6848-8776","authenticated-orcid":false,"given":"Ching-Po","family":"Lin","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience, National Yang Ming Chiao Tung University , Taipei , Taiwan"},{"name":"Brain Research Center, National Yang Ming Chiao Tung University , Taipei , Taiwan"},{"name":"Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University , Taipei , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun-Hsien","family":"Chou","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience, National Yang Ming Chiao Tung University , Taipei , Taiwan"},{"name":"Brain Research Center, National Yang Ming Chiao Tung University , Taipei , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9419-9070","authenticated-orcid":false,"given":"Chih-Ping","family":"Chung","sequence":"additional","affiliation":[{"name":"Aging and Health Research Center, National Yang Ming Chiao Tung University , Taipei , Taiwan"},{"name":"Department of Neurology, Neurological Institute, Taipei Veterans General Hospital , Taipei , Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,9,14]]},"reference":[{"key":"2022093018510524200_fcac233-B1","volume-title":"Decade of healthy ageing: Baseline report. 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