{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T09:49:50Z","timestamp":1774000190758,"version":"3.50.1"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"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":"\n Purpose<\/jats:title>\n To investigate the associations between retinal parameters and cognitive impairment and identify retinal biomarkers for detecting cognitive dysfunction in patients with cerebral small vessel disease (CSVD).<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n This cross-sectional study enrolled 125 patients with CSVD-related white matter hyperintensities. Participants were independent in daily activities and free of significant ophthalmic diseases. Cognition was assessed using the Mini-Mental State Examination (MMSE). Multimodal retinal imaging was employed to evaluate retinal structural and vascular features, including peripapillary retinal nerve fibre layer (pRNFL) and ganglion cell complex thicknesses and vessel densities (VDs) of the radial peripapillary capillary (RPC) network, macular superficial retinal capillary plexus (SRCP), and deep RCP (DRCP). The central retina vascular diameter, mean angle, angle tortuosity, arc length tortuosity, and fractal dimension of the retinal arteries and veins were quantified using a fully automated vessel segmentation and parameter calculation method. Linear and logistic regression models were applied to assess the associations between retinal parameters with general cognitive domains (general cognition, memory, visuospatial space, attention and numeracy, language, and orientation). Receiver operating characteristic (ROC) curves and areas under the ROC curve (AUCs) were used to evaluate the predictive performance of the retinal biomarkers.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A smaller central retinal arteriolar equivalent\/central retinal venular equivalent ratio [odds ratio (OR)\u202f=\u202f0.013,\n p<\/jats:italic>\n \u202f=\u202f0.035] and lower VDs in whole macular SRCP (OR\u202f=\u202f0.864,\n p<\/jats:italic>\n \u202f=\u202f0.029), perifoveal SRCP (OR\u202f=\u202f0.862,\n p<\/jats:italic>\n \u202f=\u202f0.027), perifoveal superior SRCP (OR\u202f=\u202f0.855,\n p<\/jats:italic>\n \u202f=\u202f0.014), perifoveal nasal SRCP (OR\u202f=\u202f0.833,\n p<\/jats:italic>\n \u202f=\u202f0.008), and inside-disc capillary RPC network (OR\u202f=\u202f0.901,\n p<\/jats:italic>\n \u202f=\u202f0.028) were significantly associated with lower MMSE scores. Attention and orientation scores were significantly correlated with the VDs of the SRCP (\n \u03b2<\/jats:italic>\n \u202f=\u202f0.734,\n p<\/jats:italic>\n \u202f=\u202f0.027 and \u03b2\u202f=\u202f\u22129.460,\n p<\/jats:italic>\n \u202f=\u202f0.037, respectively) and DRCP (\n \u03b2<\/jats:italic>\n \u202f=\u202f\u22120.553,\n p<\/jats:italic>\n \u202f=\u202f0.004 and\n p<\/jats:italic>\n \u202f=\u202f0.044, respectively), whereas visuospatial and language function scores were associated with the VD of the inside-disc RPC network (\n \u03b2<\/jats:italic>\n \u202f=\u202f0.018,\n p<\/jats:italic>\n \u202f=\u202f0.026 and \u03b2\u202f=\u202f0.068,\n p<\/jats:italic>\n \u202f=\u202f0.012, respectively). The VDs of the whole macular, perifoveal, perifoveal superior, and nasal SRCPs achieved AUCs of 0.71\u20130.74 for screening cognitive impairment.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n Specific retina parameters are associated with cognitive decline in patients with CSVD. These findings suggest that multimodal retinal evaluation might provide an objective, imaging-based adjunct to conventional subjective cognitive tests for screening cognitive impairment in patients with CSVD.<\/jats:p>\n <\/jats:sec>\n \n Clinical trial registration<\/jats:title>\n \n https:\/\/www.chictr.org.cn\/<\/jats:ext-link>\n , identifier ChiCTR 2100043346.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fnins.2026.1773266","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T06:39:13Z","timestamp":1773988753000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Associations between multimodal retinal measurements and cognitive functions in patients with cerebral small vessel disease"],"prefix":"10.3389","volume":"20","author":[{"given":"Meizi","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lan","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Neurology, Liangxiang Hospital","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengxi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qianqian","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuetong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongyi","family":"Yan","sequence":"additional","affiliation":[{"name":"China National Clinical Research Center for Neurological Diseases","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuan","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Xuanwu Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ning","family":"He","sequence":"additional","affiliation":[{"name":"Engineering Research Center of Molecular and Neuro-Imaging, Ministry of Education, School of Life Science and Technology, Xidian University","place":["Xi\u2019an, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuxiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Xuanwu Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"Advanced Research Institute of Multidisciplinary Sciences, Beijing Institute of Technology","place":["Beijing, China"]},{"name":"Department of Medicine, The University of British Columbia","place":["Vancouver, BC, Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tingting","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1002\/alz.13469","article-title":"Retinal perfusion is linked to cognition and brain MRI biomarkers in Black Americans","volume":"20","author":"Abdolahi","year":"2024","journal-title":"Alzheimers Dement."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"e14433","DOI":"10.1002\/alz.14433","article-title":"Retinal dysfunction in APOE4 knock-in mouse model of Alzheimer's disease","volume":"21","author":"Abhyankar","year":"2025","journal-title":"Alzheimers Dement."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"e12071","DOI":"10.1002\/dad2.12071","article-title":"Lower retinal capillary density in minimal cognitive impairment among older Latinx adults","volume":"12","author":"Ashimatey","year":"2020","journal-title":"Alzheimers Dement (Amst)."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1097\/wno.0000000000002230","article-title":"Optical coherence tomography angiography retinal imaging associations with burden of small vessel disease and amyloid positivity in the brain","volume":"45","author":"Bermudez","year":"2025","journal-title":"J. Neuroophthalmol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1146","DOI":"10.1212\/wnl.0000000000007654","article-title":"CNS small vessel disease: a clinical review","volume":"92","author":"Cannistraro","year":"2019","journal-title":"Neurology"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"e70342","DOI":"10.1002\/brb3.70342","article-title":"Lower retinal arteriolar density is associated with higher cerebral small vessel disease burden: an optical coherence tomography angiography study","volume":"15","author":"Cao","year":"2025","journal-title":"Brain Behav."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1987","DOI":"10.1093\/brain\/awq127","article-title":"Retinal microvascular abnormalities and subclinical magnetic resonance imaging brain infarct: a prospective study","volume":"133","author":"Cheung","year":"2010","journal-title":"Brain"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"993621","DOI":"10.3389\/fnagi.2022.993621","article-title":"A two-year longitudinal study of retinal vascular impairment in patients with amnestic mild cognitive impairment","volume":"14","author":"Chiara","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1186\/s13195-020-00724-0","article-title":"Retinal microvasculature dysfunction is associated with Alzheimer's disease and mild cognitive impairment","volume":"12","author":"Chua","year":"2020","journal-title":"Alzheimer's Res. Ther."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1016\/j.ophtha.2007.06.036","article-title":"Arteriolar oxygen saturation, cerebral blood flow, and retinal vessel diameters. The Rotterdam study","volume":"115","author":"de Jong","year":"2008","journal-title":"Ophthalmology"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"843198","DOI":"10.3389\/fneur.2022.843198","article-title":"Fundus changes evaluated by OCTA in patients with cerebral small vessel disease and their correlations: a cross-sectional study","volume":"13","author":"Fu","year":"2022","journal-title":"Front. Neurol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/s13195-024-01408-9","article-title":"Macular vessel density in the superficial plexus is not a proxy of cerebrovascular damage in non-demented individuals: data from the NORFACE cohort","volume":"16","author":"Garc\u00eda-S\u00e1nchez","year":"2024","journal-title":"Alzheimer's Res. Ther."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.1111\/dom.15492","article-title":"Retinal vascular density as a potential biomarker of diabetic cerebral small vessel disease","volume":"26","author":"Huang","year":"2024","journal-title":"Diabetes Obes. Metab."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1093\/brain\/awh688","article-title":"Retinal vessel diameters and cerebral small vessel disease: the Rotterdam scan study","volume":"129","author":"Ikram","year":"2006","journal-title":"Brain"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.ajo.2019.04.011","article-title":"Changes in retinal microcirculation precede the clinical onset of diabetic retinopathy in children with type 1 diabetes mellitus","volume":"207","author":"Inanc","year":"2019","journal-title":"Am. J. Ophthalmol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.ophtha.2019.05.021","article-title":"Quantitative assessment of the retina using OCT and associations with cognitive function","volume":"127","author":"Ito","year":"2020","journal-title":"Ophthalmology"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s13195-025-01676-z","article-title":"Retinal optical coherence tomography intensity spatial correlation features as new biomarkers for confirmed Alzheimer's disease","volume":"17","author":"Jin","year":"2025","journal-title":"Alzheimer's Res. Ther."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1186\/s13195-020-00638-x","article-title":"Optical coherence tomography angiography as a potential screening tool for cerebral small vessel diseases","volume":"12","author":"Lee","year":"2020","journal-title":"Alzheimer's Res. Ther."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"932","DOI":"10.21037\/qims-23-927","article-title":"The association of global vessel width with cognitive decline and cerebral small vessel disease burden in the KaiLuan study","volume":"14","author":"Li","year":"2024","journal-title":"Quant. Imaging Med. Surg."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1711","DOI":"10.1177\/0963689718795148","article-title":"Cerebral small vessel disease","volume":"27","author":"Li","year":"2018","journal-title":"Cell Transplant."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1111\/j.1747-4949.2012.00865.x","article-title":"Differing associations of white matter lesions and lacunar infarction with retinal microvascular signs","volume":"9","author":"Liew","year":"2014","journal-title":"Int. J. Stroke"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/nrneurol.2012.227","article-title":"The retina as a window to the brain-from eye research to CNS disorders","volume":"9","author":"London","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1007\/s43657-022-00082-x","article-title":"A genome-wide association study for susceptibility to axial length in highly myopic eyes","volume":"3","author":"Lu","year":"2023","journal-title":"Phenomics"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.dadm.2016.11.001","article-title":"The application of retinal fundus camera imaging in dementia: a systematic review","volume":"6","author":"McGrory","year":"2017","journal-title":"Alzheimers Dement (Amst)."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"e70672","DOI":"10.1002\/alz.70672","article-title":"Retinal biomarkers in cognitive impairment and dementia: structural, functional, and molecular insights","volume":"21","author":"Min","year":"2025","journal-title":"Alzheimers Dement."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"2321","DOI":"10.1007\/s00417-022-05561-5","article-title":"Radial peripapillary vessel density as early biomarker in preperimetric glaucoma and amnestic mild cognitive impairment","volume":"260","author":"Montorio","year":"2022","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1111\/j.1469-7580.2005.00395.x","article-title":"Retinal vascular image analysis as a potential screening tool for cerebrovascular disease: a rationale based on homology between cerebral and retinal microvasculatures","volume":"206","author":"Patton","year":"2005","journal-title":"J. Anat."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1001\/archneur.56.3.303","article-title":"Mild cognitive impairment: clinical characterization and outcome","volume":"56","author":"Petersen","year":"1999","journal-title":"Arch. Neurol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.ajo.2016.08.030","article-title":"Regional comparisons of optical coherence tomography angiography vessel density in primary open-angle Glaucoma","volume":"171","author":"Rao","year":"2016","journal-title":"Am. J. Ophthalmol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1016\/j.acn.2006.08.001","article-title":"The relation of education and gender on the attention items of the Mini-mental state examination in Spanish speaking Hispanic elders","volume":"21","author":"Rosselli","year":"2006","journal-title":"Arch. Clin. Neuropsychol."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"8221","DOI":"10.3390\/ijms25158221","article-title":"Age-related retinal layer thickness changes measured by OCT in APP(NL-F\/NL-F) mice: implications for Alzheimer's disease","volume":"25","author":"S\u00e1nchez-Puebla","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1007\/s00417-024-06623-6","article-title":"Vascular density normative data of radial peripapillary capillary plexus in healthy Caucasian subjects","volume":"263","author":"Serra","year":"2025","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1228","DOI":"10.1212\/wnl.0000000000000837","article-title":"Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden","volume":"83","author":"Staals","year":"2014","journal-title":"Neurology"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"945964","DOI":"10.3389\/fnagi.2022.945964","article-title":"Retinal microvasculature and imaging markers of brain frailty in normal aging adults","volume":"14","author":"Tao","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1016\/j.omtn.2023.05.001","article-title":"Improved gene therapy for MFRP deficiency-mediated retinal degeneration by knocking down endogenous bicistronic Mfrp and Ctrp5 transcript","volume":"32","author":"Tian","year":"2023","journal-title":"Mol Ther Nucleic Acids."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1288380","DOI":"10.3389\/fnins.2024.1288380","article-title":"Retinal structure and vessel density changes in cerebral small vessel disease","volume":"18","author":"Wang","year":"2024","journal-title":"Front. Neurosci."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"3615","DOI":"10.1007\/s10072-021-05038-z","article-title":"The vessel density of the superficial retinal capillary plexus as a new biomarker in cerebral small vessel disease: an optical coherence tomography angiography study","volume":"42","author":"Wang","year":"2021","journal-title":"Neurol. Sci."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1016\/s1474-4422(13)70124-8","article-title":"Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration","volume":"12","author":"Wardlaw","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1016\/s1474-4422(19)30079-1","article-title":"Small vessel disease: mechanisms and clinical implications","volume":"18","author":"Wardlaw","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1177\/0271678x221135658","article-title":"Retinal capillary microvessel morphology changes are associated with vascular damage and dysfunction in cerebral small vessel disease","volume":"43","author":"Wiseman","year":"2023","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"1089188","DOI":"10.3389\/fnagi.2023.1089188","article-title":"The correlation of retinal neurodegeneration and brain degeneration in patients with Alzheimer's disease using optical coherence tomography angiography and MRI","volume":"15","author":"Zhao","year":"2023","journal-title":"Front. Aging Neurosci."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2026.1773266\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T06:39:14Z","timestamp":1773988754000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2026.1773266\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,20]]},"references-count":41,"alternative-id":["10.3389\/fnins.2026.1773266"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2026.1773266","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,20]]},"article-number":"1773266"}}