{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:42:19Z","timestamp":1791931339913,"version":"4.3.4"},"reference-count":88,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background\/Objectives: Cerebral small vessel disease (CSVD) is a leading cause of cognitive decline and dementia. The comparative prognostic value of MRI-based neuroimaging markers and genetic risk factors such as the APOE \u03b54 allele for cognitive outcomes remains uncertain. The objectives of this study were to estimate the pooled prevalence of cognitive impairment in CSVD, evaluate the associations of key neuroimaging markers (white matter hyperintensities [WMHs], cerebral microbleeds [CMBs], lacunes) and APOE \u03b54 with cognitive outcomes, and assess their diagnostic performance. Methods: This study included a systematic review and meta-analysis in accordance with PRISMA and MOOSE guidelines, searching five databases (2005\u20132025). Eligible studies included adults with CSVD and MRI-visible markers reporting cognitive outcomes (mild cognitive impairment [MCI], global cognitive impairment [GCI], all-cause dementia [ACD], vascular dementia [VaD], and Alzheimer\u2019s disease [AD]). Thirty-nine studies comprising 18,425 participants were included. Pooled prevalence and associations were estimated using random-effects models, and diagnostic accuracy was evaluated. Certainty of evidence was assessed using the GRADE framework. Results: The pooled prevalence of GCI in CSVD was 57% (95% CI: 51\u201362%), while MCI prevalence was 46% (95% CI: 42\u201351%). WMHs were strongly associated with VaD (OR 10.35, 95% CI: 7.32\u201314.64), lacunes with ACD (OR 3.18, 95% CI: 1.24\u20138.20), and CMBs with AD (OR 1.52, 95% CI: 1.04\u20132.24). APOE \u03b54 carriage increased the risk of GCI (OR 1.80, 95% CI: 1.41\u20132.29). Across markers, diagnostic sensitivity was low, specificity was moderate-to-high, and AUROC values were modest. GRADE certainty ranged from low to moderate, with the highest confidence for WMHs and VaD. Conclusions: CSVD-related MRI markers and APOE \u03b54 are significantly associated with both early and late cognitive outcomes, supporting the integrated vascular\u2013neurodegenerative continuum. The limited diagnostic sensitivity and variable certainty of evidence highlight the need for harmonized definitions, lesion quantification, and multimodal imaging\u2013genetic approaches to improve early detection and risk stratification of CSVD-related cognitive impairment.<\/jats:p>","DOI":"10.3390\/diagnostics15202585","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T05:48:21Z","timestamp":1760420901000},"page":"2585","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Neuroimaging and Genetic Markers of Cerebral Small Vessel Disease and Cognitive Outcomes: A Systematic Review and Meta-Analysis (NEUROGEN-SVD Study)"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4150-6671","authenticated-orcid":false,"given":"Chelsea","family":"Jin","sequence":"first","affiliation":[{"name":"Global Health Neurology Lab, Sydney, NSW 2150, Australia"},{"name":"South West Sydney Clinical Campuses, UNSW Medicine and Health, University of New South Wales (UNSW), Sydney, NSW 2170, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5884-0606","authenticated-orcid":false,"given":"Roy G.","family":"Beran","sequence":"additional","affiliation":[{"name":"Global Health Neurology Lab, Sydney, NSW 2150, Australia"},{"name":"South West Sydney Clinical Campuses, UNSW Medicine and Health, University of New South Wales (UNSW), Sydney, NSW 2170, Australia"},{"name":"NSW Brain Clot Bank, NSW Health Pathology, Sydney, NSW 2170, Australia"},{"name":"School of Medicine, Western Sydney University, Sydney, NSW 2000, Australia"},{"name":"Griffith Health, School of Medicine and Dentistry, Griffith University, Southport, QLD 4215, Australia"},{"name":"Clinical Sciences Stream, Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia"},{"name":"Department of Neurology & Neurophysiology, Liverpool Hospital and South West Sydney Local Health District, Liverpool, NSW 2150, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9783-3628","authenticated-orcid":false,"given":"Sonu M. M.","family":"Bhaskar","sequence":"additional","affiliation":[{"name":"Global Health Neurology Lab, Sydney, NSW 2150, Australia"},{"name":"NSW Brain Clot Bank, NSW Health Pathology, Sydney, NSW 2170, Australia"},{"name":"Clinical Sciences Stream, Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia"},{"name":"Department of Neurology & Neurophysiology, Liverpool Hospital and South West Sydney Local Health District, Liverpool, NSW 2150, Australia"},{"name":"Department of Neurology, Division of Cerebrovascular Medicine and Neurology, National Cerebral and Cardiovascular Center (NCVC), Suita 564-8565, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/S1474-4422(10)70104-6","article-title":"Cerebral small vessel disease: From pathogenesis and clinical characteristics to therapeutic challenges","volume":"9","author":"Pantoni","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e70246","DOI":"10.1111\/ejn.70246","article-title":"Unifying Vascular Injury and Neurodegeneration: A Mechanistic Continuum in Cerebral Small Vessel Disease and Dementia","volume":"62","author":"Jin","year":"2025","journal-title":"Eur. 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