{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T16:22:16Z","timestamp":1789662136605,"version":"4.0.1"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T00:00:00Z","timestamp":1641859200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004844","name":"National Cheng Kung University Hospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004844","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>\n                      Diabetes-related cerebral microangiopathy can manifest as cerebral small vessel disease (CSVD) and exhibit cognitive decline. To find the early change of function in advance, this study examined the spatiotemporal dynamics of cerebral vascular permeability (\n                      <jats:italic>Ktrans<\/jats:italic>\n                      ) in the progression of type 2 diabetes mellitus (T2DM).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Ktrans<\/jats:italic>\n                      was cross-sectionally measured in T2DM and non-diabetes groups with or without CSVD using dynamic contrast-enhanced MRI (DCE-MRI).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In all patients with T2DM, the\n                      <jats:italic>Ktrans<\/jats:italic>\n                      of white matter (WM) was increased, whereas the\n                      <jats:italic>Ktrans<\/jats:italic>\n                      of gray matter (GM) was increased only in T2DM with CSVD. The involvement of WM was earlier than GM and was before the CSVD features could be visualized on MRI. Among the commonly available four CSVD items of MRI, microbleeds were the most sensitive, indicating the increased permeability in all patients. Increased\n                      <jats:italic>Ktrans<\/jats:italic>\n                      in T2DM was more associated with moderate WM hyperintensity but less with the presence of lacunae or multiple perivascular spaces, in contrast to patients without diabetes. The differential correlation suggested distinct mechanisms underlying diabetes-related CSVD and other CSVDs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study highlights the early development of cerebral microangiopathy with increased BBB leakage in T2DM, before the CSVD features can be visualized on MRI. The results may increase the proactivity of clinicians in recognizing the subsequent neurological comorbidities.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2021.805637","type":"journal-article","created":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T23:26:53Z","timestamp":1641857213000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Spatiotemporal Dynamics of Cerebral Vascular Permeability in Type 2 Diabetes-Related Cerebral Microangiopathy"],"prefix":"10.3389","volume":"12","author":[{"given":"Ying-Chen","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing-Ze","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Chen","family":"Shu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Ting","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.115.009627","article-title":"Emerging Evidence for Pathogenesis of Sporadic Cerebral Small Vessel Disease","volume":"47","author":"Ihara","year":"2016","journal-title":"Stroke"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.55.04.06.db05-1323","article-title":"Brain Magnetic Resonance Imaging Correlates of Impaired Cognition in Patients With Type 2 Diabetes","volume":"55","author":"Manschot","year":"2006","journal-title":"Diabetes"},{"key":"B3","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/s13643-017-0410-1","article-title":"What is the Relationship Between Type 2 Diabetes Mellitus Status and the Neuroradiological Correlates of Cerebral Small Vessel Disease in Adults? Protocol for a Systematic Review","volume":"6","author":"Funnell","year":"2017","journal-title":"Syst Rev"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.12545","article-title":"Pathogenesis and Neuroimaging of Cerebral Large and Small Vessel Disease in Type 2 Diabetes: A Possible Link Between Cerebral and Retinal Microvascular Abnormalities","volume":"8","author":"Umemura","year":"2017","journal-title":"J Diabetes Investig"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjms.2016.01.011","article-title":"Diabetes and Stroke: Epidemiology, Pathophysiology, Pharmaceuticals and Outcomes","volume":"351","author":"Chen","year":"2016","journal-title":"Am J Med Sci"},{"key":"B6","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1038\/s41574-018-0048-7","article-title":"Cognitive Decline and Dementia in Diabetes Mellitus: Mechanisms and Clinical Implications","volume":"14","author":"Biessels","year":"2018","journal-title":"Nat Rev Endocrinol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2013.11.002","article-title":"Global Estimates of Diabetes Prevalence for 2013 and Projections for 2035","volume":"103","author":"Guariguata","year":"2014","journal-title":"Diabetes Res Clin Pract"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2017.10.034","article-title":"MRI Measurements of Blood-Brain Barrier Function in Dementia: A Review of Recent Studies","volume":"134","author":"Raja","year":"2018","journal-title":"Neuropharmacology"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.2337\/dc15-2671","article-title":"Increased Burden of Cerebral Small Vessel Disease in Patients With Type 2 Diabetes and Retinopathy","volume":"39","author":"Sanahuja","year":"2016","journal-title":"Diabetes Care"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.74.1.70","article-title":"Increased Blood-Brain Barrier Permeability in Type II Diabetes Demonstrated by Gadolinium Magnetic Resonance Imaging","volume":"74","author":"Starr","year":"2003","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmp.2014.04.005","article-title":"A Review of Technical Aspects of T1-Weighted Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) in Human Brain Tumors","volume":"30","author":"Bergamino","year":"2014","journal-title":"Phys Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.2337\/dc20-S002","article-title":"Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2020","volume":"43","year":"2020","journal-title":"Diabetes Care"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.2337\/dc19-S002","article-title":"Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2019","volume":"42","year":"2019","journal-title":"Diabetes Care"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.2337\/dc18-S002","article-title":"Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2018","volume":"41","year":"2018","journal-title":"Diabetes Care"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-139-2-200307150-00013","article-title":"National Kidney Foundation Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification","volume":"139","author":"Levey","year":"2003","journal-title":"Ann Internal Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.7326\/M21-0834","article-title":"Management of Blood Pressure in Patients With Chronic Kidney Disease Not Receiving Dialysis: Synopsis of the 2021 KDIGO Clinical Practice Guideline","volume":"174","author":"Tomson","year":"2021","journal-title":"Ann Internal Med"},{"key":"B17","doi-asserted-by":"publisher","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":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2015.10.018","article-title":"Tracer Kinetic Modelling for DCE-MRI Quantification of Subtle Blood-Brain Barrier Permeability","volume":"125","author":"Heye","year":"2016","journal-title":"Neuroimage"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1148\/radiol.2016152244","article-title":"Blood-Brain Barrier Leakage in Patients With Early Alzheimer Disease","volume":"281","author":"van de Haar","year":"2016","journal-title":"Radiology"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000004042","article-title":"Total Small Vessel Disease Score and Risk of Recurrent Stroke: Validation in 2 Large Cohorts","volume":"88","author":"Lau","year":"2017","journal-title":"Neurology"},{"key":"B21","doi-asserted-by":"publisher","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":"B22","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000010116","article-title":"Early Postmortem Brain MRI Findings in COVID-19 Non-Survivors","volume":"95","author":"Coolen","year":"2020","journal-title":"Neurology"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/ane.12398","article-title":"Is Type 2 Diabetes Related to Leukoaraiosis? An Updated Review","volume":"132","author":"Del Bene","year":"2015","journal-title":"Acta Neurol Scand"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000003556","article-title":"Blood-Brain Barrier Leakage Is More Widespread in Patients With Cerebral Small Vessel Disease","volume":"88","author":"Zhang","year":"2017","journal-title":"Neurology"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1210\/en.2004-0984","article-title":"17beta-Estradiol Differentially Regulates Blood-Brain Barrier Permeability in Young and Aging Female Rats","volume":"145","author":"Bake","year":"2004","journal-title":"Endocrinology"},{"key":"B26","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1016\/j.neuron.2014.12.032","article-title":"Blood-Brain Barrier Breakdown in the Aging Human Hippocampus","volume":"85","author":"Montagne","year":"2015","journal-title":"Neuron"},{"key":"B27","doi-asserted-by":"publisher","first-page":"105971","DOI":"10.1016\/j.biocel.2021.105971","article-title":"Microvascular Cells: A Special Focus on Heterogeneity of Pericytes in Diabetes Associated Complications","volume":"134","author":"Rajendran","year":"2021","journal-title":"Int J Biochem Cell Biol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1479164121990641","DOI":"10.1177\/1479164121990641","article-title":"Hyperglycemia Compromises the Ischemia-Provoked Dedifferentiation of Cerebral Pericytes Through P21-SOX2 Signaling in High-Fat Diet-Induced Murine Model","volume":"18","author":"Wang","year":"2021","journal-title":"Diabetes Vasc Dis Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2020.10.025","article-title":"The Retina as a Window to the Basal Ganglia: Systematic Review of the Potential Link Between Retinopathy and Hyperkinetic Disorders in Diabetes","volume":"80","author":"Lizarraga","year":"2020","journal-title":"Parkinsonism Relat Disord"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.12602","article-title":"Retinopathy: A Sign of Cerebral Small Vessel Disease in Diabetes","volume":"8","author":"Umemura","year":"2017","journal-title":"J Diabetes Investig"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1177\/0300060518789299","article-title":"Positive Correlation Between Cognitive Impairment and Renal Microangiopathy in Patients With Type 2 Diabetic Nephropathy: A Multicenter Retrospective Study","volume":"46","author":"Li","year":"2018","journal-title":"J Int Med Res"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.17-21510","article-title":"The Distribution of Leakage on Fluorescein Angiography in Diabetic Macular Edema: A New Approach to Its Etiology","volume":"58","author":"Haj Najeeb","year":"2017","journal-title":"Invest Ophthalmol Visual Sci"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-008-0961-8","article-title":"What is the Mechanism of Microalbuminuria in Diabetes: A Role for the Glomerular Endothelium","volume":"51","author":"Satchell","year":"2008","journal-title":"Diabetologia"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1111\/aos.13210","article-title":"Viewing the Choroid: Where We Stand, Challenges and Contradictions in Diabetic Retinopathy and Diabetic Macular Oedema","volume":"95","author":"Campos","year":"2017","journal-title":"Acta Ophthalmol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2017.188","article-title":"Blood-Brain Barrier Breakdown in Alzheimer Disease and Other Neurodegenerative Disorders","volume":"14","author":"Sweeney","year":"2018","journal-title":"Nat Rev Neurol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/S1474-4422(05)70284-2","article-title":"Risk of Dementia in Diabetes Mellitus: A Systematic Review","volume":"5","author":"Biessels","year":"2006","journal-title":"Lancet Neurol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1113\/JP272450","article-title":"Parasympathetic Innervation of Vertebrobasilar Arteries: Is This a Potential Clinical Target","volume":"594","author":"Roloff","year":"2016","journal-title":"J Physiol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1113\/JP275973","article-title":"Differences in Autonomic Innervation to the Vertebrobasilar Arteries in Spontaneously Hypertensive and Wistar Rats","volume":"596","author":"Roloff","year":"2018","journal-title":"J Physiol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c170019","article-title":"Impact of Metabolic Diseases on Cerebral Circulation: Structural and Functional Consequences","volume":"8","author":"Coucha","year":"2018","journal-title":"Compr Physiol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.805637\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T23:26:56Z","timestamp":1641857216000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.805637\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,11]]},"references-count":39,"alternative-id":["10.3389\/fendo.2021.805637"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2021.805637","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-970765\/v1","asserted-by":"object"}]},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,11]]},"article-number":"805637"}}