{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T06:57:31Z","timestamp":1781161051561,"version":"3.54.1"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"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. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>MicroRNAs (miRNAs) are promising biomarkers for the diagnosis and prognosis of neurodegenerative diseases. Over the past few years, miR-34a-5p and miR-126-3p have become some of the most characterized miRNA, the former being associated with cellular senescence and apoptosis and the latter with the maintenance of vascular endothelial function. The present study aimed to evaluate diagnostic performance of miR-34a-5p and miR-126-3p for cognitive dysfunction in CSVD patients. In addition, we investigated whether these miR-34a-5p and miR-126-3p have mediating effect of impaired glucose regulation (IGR) status on cognitive dysfunction. The final objective was to the identification of better diagnostic biomarkers and further investigation on their value of practical application in Chinese population.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The study included 300 patients with cerebral small vessel disease (CSVD), who were further stratified by oral glucose tolerance test into those with impaired glucose regulation (IGR,\n                      <jats:italic>n<\/jats:italic>\n                      =\u202f151) and those with normal glucose metabolism (NGM,\n                      <jats:italic>n<\/jats:italic>\n                      =\u202f149), with the NGM group serving as the internal control. Concurrently, all patients were stratified according to Montreal Cognitive Assessment scores into cognitive function subgroups (normal\/mild\/moderate\/severe impairment). Plasma levels of miR-34a-5p and miR-126-3p were measured in all participants using reverse transcription-polymerase chain reaction (RT-PCR). Mediation analysis was employed to assess the mediating role of the relevant miRNAs in the pathway from IGR to cognitive dysfunction in CSVD patients. The diagnostic performance of these miRNAs for cognitive function and long-term prognosis in CSVD patients with IGR was compared in terms of specificity, sensitivity, and accuracy. Moreover, the miR-34a-5p target genes were screened, and functional and pathway enrichment analyses were performed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The results show that, in the analysis based on cognitive stratification, plasma miR-126-3p expression levels were negatively correlated with the severity of cognitive impairment in CSVD patients, whereas miR-34a-5p levels showed a positive correlation. miR-126-3p exhibited a stepwise decrease with increasing cognitive severity, while miR-34a-5p significantly distinguished between normal and impaired cognitive status. Mediation analysis revealed that only miR-34a-5p demonstrated a significant mediating effect in the pathway from IGR to cognitive dysfunction (indirect effect\u202f=\u202f0.4519, 95% BootCI: 0.0277\u20130.8879), and it exhibited superior diagnostic performance for cognitive impairment within the CSVD cohort. Following evaluation using the Youden index, miR-34a-5p at the 2-year follow-up demonstrated a balanced diagnostic performance with an area under the curve (AUC) of 0.803, a sensitivity of 65.3%, and a specificity of 84.0% at the optimal cut-off of 2.49, indicating its potential utility for risk stratification. Compared with its performance at baseline (AUC: 0.679, sensitivity: 58.3%, specificity: 75.0%), the diagnostic performance of miR-34a-5p at the 2-year follow-up showed improvements across all metrics, particularly in specificity. In contrast, miR-126-3p (an inverse indicator) showed a moderate sensitivity (64.6\u201370.5%) and specificity (60.7\u201363.2%), which may limit its standalone diagnostic application. Enrichment analysis indicated that miR-34a-5p could be involved in the pathological aspects of cognitive impairment by regulating pathways related to apoptosis, oxidative stress, and synaptic function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>The IGR stage may represent a potential early pathological window of cognitive impairment in CSVD patients. Plasma miR-34a-5p is more valuable as diagnostic and long-term prognostic marker in IGR patients than miR-126-3p and may mediate association between IGR and cognitive decline via apoptosis, oxidative stress and synaptic pathway.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2026.1807882","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T06:11:05Z","timestamp":1781158265000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Plasma miR-34a-5p outperforms miR-126-3p in predicting cognitive decline in cerebral small vessel disease patients with impaired glucose regulation"],"prefix":"10.3389","volume":"18","author":[{"given":"Yanan","family":"Wang","sequence":"first","affiliation":[{"name":"Tianjin Medical University General Hospital","place":["Tianjin, China"]},{"name":"Department of Neurology, Affiliated Hospital of North China University of Science and Technology","place":["Tangshan, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoying","family":"Sun","sequence":"additional","affiliation":[{"name":"Fengnan District Hospital","place":["Tangshan, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, Affiliated Hospital of North China University of Science and Technology","place":["Tangshan, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Neurology, Affiliated Hospital of North China University of Science and Technology","place":["Tangshan, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Affiliated Hospital of North China University of Science and Technology","place":["Tangshan, Hebei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijun","family":"Song","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Tianjin, China"]},{"name":"Tianjin Institutes of Health Science","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"806","DOI":"10.1002\/jcp.29908","article-title":"MicroRNA alterations in neuropathologic cognitive disorders with an emphasis on dementia: lessons from animal models","volume":"236","author":"Bahlakeh","year":"2021","journal-title":"J. Cell. Physiol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1177\/1073858418780971","article-title":"Aging in the brain: new roles of epigenetics in cognitive decline","volume":"24","author":"Barter","year":"2018","journal-title":"Neuroscientist"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1373\/clinchem.2008.112797","article-title":"The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments","volume":"55","author":"Bustin","year":"2009","journal-title":"Clin. Chem."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"8516","DOI":"10.1002\/alz.14288","article-title":"Artificial intelligence-assisted oculo-gait measurements for cognitive impairment in cerebral small vessel disease","volume":"20","author":"Chen","year":"2024","journal-title":"Alzheimers Dement."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1398009","DOI":"10.3389\/fneur.2024.1398009","article-title":"Amygdala and cognitive impairment in cerebral small vessel disease: structural, functional, and metabolic changes","volume":"15","author":"Cheng","year":"2024","journal-title":"Front. Neurol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"91","DOI":"10.3233\/JAD-215223","article-title":"Cerebrovascular microRNA expression profile during early development of Alzheimer's disease in a mouse model","volume":"85","author":"Chum","year":"2022","journal-title":"J. Alzheimer's Dis"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/S1474-4422(23)00131-X","article-title":"Neuroimaging standards for research into small vessel disease\u2014advances since 2013","volume":"22","author":"Duering","year":"2023","journal-title":"Lancet Neurol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1186\/s13195-020-00669-4","article-title":"White matter hyperintensities across the adult lifespan: relation to age, a\u03b2 load, and cognition","volume":"12","author":"Garnier-Crussard","year":"2020","journal-title":"Alzheimer's Res. Ther."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"533","DOI":"10.3892\/ijmm.2020.4806","article-title":"MicroRNA-34a-5p expression in the plasma and in its extracellular vesicle fractions in subjects with Parkinson's disease: an exploratory study","volume":"47","author":"Grossi","year":"2021","journal-title":"Int. J. Mol. Med."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"2220","DOI":"10.1161\/01.STR.0000237236.88823.47","article-title":"National Institute of Neurological Disorders and Stroke\u2013Canadian stroke network vascular cognitive impairment harmonization standards","volume":"37","author":"Hachinski","year":"2006","journal-title":"Stroke"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1598","DOI":"10.1253\/circj.CJ-17-0950","article-title":"Nonfasting glucose and incident stroke and its types - the circulatory risk in communities study (CIRCS)","volume":"82","author":"Imano","year":"2018","journal-title":"Circ. J."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"e661","DOI":"10.1016\/S2468-2667(20)30185-7","article-title":"Prevalence, risk factors, and management of dementia and mild cognitive impairment in adults aged 60 years or older in China: a cross-sectional study","volume":"5","author":"Jia","year":"","journal-title":"Lancet Public Health"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/S1474-4422(19)30290-X","article-title":"Dementia in China: epidemiology, clinical management, and research advances","volume":"19","author":"Jia","year":"","journal-title":"Lancet Neurol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1007\/s11682-024-00889-4","article-title":"Structural network disruption of corticothalamic pathways in cerebral small vessel disease","volume":"18","author":"Jia","year":"2024","journal-title":"Brain Imaging and Behavior"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"095004","DOI":"10.1088\/1361-6579\/ae0675","article-title":"Chronic hyperglycemia is associated with vascular impairment in microangiopathic lacunar stroke","volume":"46","author":"Lakatos","year":"2025","journal-title":"Physiol. Meas."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1210\/clinem\/dgad562","article-title":"SIRT1 and miR-34a-5p Expression in PBMCs as Potential Biomarkers for Patients With Type 2 Diabetes With Cognitive Impairments","volume":"109","author":"Liu","year":"2024","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1309","DOI":"10.4103\/NRR.NRR-D-23-01566","article-title":"The complex effects of miR-146a in the pathogenesis of Alzheimer\u2019s disease","volume":"20","author":"Long","year":"2025","journal-title":"Neural Regen. Res."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1152\/physrev.00028.2024","article-title":"The pathogenesis of cerebral small vessel disease and vascular cognitive impairment","volume":"105","author":"Markus","year":"2025","journal-title":"Physiol. Rev."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"103156","DOI":"10.1016\/j.dsx.2024.103156","article-title":"MicroRNA-34a and promoter methylation contribute to peroxisome proliferator-activated receptor gamma gene expression in patients with type 2 diabetes","volume":"18","author":"Moghadasi","year":"2024","journal-title":"Diab. Metab. Syndr."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"e964","DOI":"10.1212\/WNL.0000000000011375","article-title":"Prospective analysis of leisure-time physical activity in midlife and beyond and brain damage on MRI in older adults","volume":"96","author":"Palta","year":"2021","journal-title":"Neurology"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"e214113","DOI":"10.1212\/WNL.0000000000214113","article-title":"Multimarker cerebral small vessel disease score and risk of incident dementia in the Framingham heart study","volume":"105","author":"Pinheiro","year":"2025","journal-title":"Neurology"},{"key":"ref23","doi-asserted-by":"publisher","DOI":"10.1101\/2025.06.23.25330130","article-title":"Neurocognition in youth with versus without prediabetes","author":"Quillian","year":"2025","journal-title":"medRxiv"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1286","DOI":"10.1001\/jama.2019.2000","article-title":"Association of amyloid positron emission tomography with subsequent change in clinical management among Medicare beneficiaries with mild cognitive impairment or dementia","volume":"321","author":"Rabinovici","year":"2019","journal-title":"JAMA"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"843953","DOI":"10.3389\/fneur.2022.843953","article-title":"Cerebral small vessel disease: neuroimaging features, biochemical markers, influencing factors, pathological mechanism and treatment","volume":"13","author":"Ren","year":"2022","journal-title":"Review Front Neurol"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1228","DOI":"10.1212\/WNL.000000000000000837","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":"ref27","doi-asserted-by":"publisher","first-page":"773797","DOI":"10.3389\/fnagi.2021.773797","article-title":"Long-term use of metformin is associated with reduced risk of cognitive impairment with alleviation of cerebral small vessel disease burden in patients with type 2 diabetes","volume":"13","author":"Teng","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1038\/s41572-025-00635-0","article-title":"Prediabetes","volume":"11","author":"Unnikrishnan","year":"2025","journal-title":"Nat Rev Dis Primers"},{"key":"ref29","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":"ref30","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":"ref31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.bcp.2015.11.021","article-title":"Micro-RNAs in cognition and cognitive disorders: potential for novel biomarkers and therapeutics","volume":"104","author":"Woldemichael","year":"2016","journal-title":"Biochem. Pharmacol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.neulet.2018.01.045","article-title":"miR-34a deficiency in APP\/PS1 mice promotes cognitive function by increasing synaptic plasticity via AMPA and NMDA receptors","volume":"670","author":"Xu","year":"2018","journal-title":"Neurosci. Lett."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"962","DOI":"10.2174\/138161208784139729","article-title":"Role of advanced glycation end products (AGEs) and oxidative stress in diabetic retinopathy","volume":"14","author":"Yamagishi","year":"2008","journal-title":"Rev Curr Pharm Des."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"2497","DOI":"10.1177\/0271678X18800593","article-title":"Role of microRNA-126 in vascular cognitive impairment in mice","volume":"39","author":"Yu","year":"2019","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1186\/s12877-022-02833-x","article-title":"Psychometric properties and modification of the 15-item geriatric depression scale among Chinese oldest-old and centenarians: a mixed-methods study","volume":"22","author":"Zhang","year":"2022","journal-title":"BMC Geriatr."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2026.1807882\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T06:11:07Z","timestamp":1781158267000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2026.1807882\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,11]]},"references-count":34,"alternative-id":["10.3389\/fnagi.2026.1807882"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2026.1807882","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,11]]},"article-number":"1807882"}}