{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T03:23:14Z","timestamp":1792466594574,"version":"4.5.0"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Blood-brain barrier damage has traditionally been considered to determine the occurrence and development of poststroke brain edema, a devastating and life-threatening complication. However, no treatment strategy targeting blood-brain barrier damage has been proven clinically effective in ameliorating brain edema.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>In mice with stroke models induced by transient middle cerebral artery occlusion (MCAO), the changes in glymphatic system (GS) function impairment were detected by ex vivo fluorescence imaging, 2-photon in vivo imaging, and magnetic resonance imaging within 1 week after MCAO, and the effects of GS impairment and recovery on the formation and resolution of brain edema were evaluated. In addition, in patients with ischemic stroke within 1 week after onset, changes in GS function and brain edema were also observed by magnetic resonance imaging.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>We found that the extravasation of protein-rich fluids into the brain was not temporally correlated with edema formation after MCAO in mice, as brain edema reabsorption preceded blood-brain barrier closure. Strikingly, the time course of edema progression matched well with the GS dysfunction after MCAO. Pharmacological enhancement of the GS function significantly alleviated brain edema developed on day 2 after MCAO, accompanied by less deposition of A\u03b2 (amyloid-\u03b2) and better cognitive function. Conversely, functional suppression of the GS delayed the absorption of brain edema on day 7 after MCAO. Moreover, patients with ischemic stroke revealed a consistent trend of GS dysfunction after reperfusion as MCAO mice, which was correlated with the severity of brain edema and functional outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>GS is a key contributor to the formation of brain edema after ischemic stroke, and targeting the GS may be a promising strategy for treating brain edema in ischemic stroke.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>REGISTRATION:<\/jats:title>\n                    <jats:p>URL: https:\/\/www.chictr.org.cn\/showproj.html?proj=162857; Unique identifier: NFEC-2019-189.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/strokeaha.123.045941","type":"journal-article","created":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T11:34:36Z","timestamp":1722339276000},"page":"1393-1404","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":92,"title":["Glymphatic System Impairment Contributes to the Formation of Brain Edema After Ischemic Stroke"],"prefix":"10.1161","volume":"55","clinical-trial-number":[{"clinical-trial-number":"chictr2200057845","registry":"10.18810\/chictr"}],"author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0269-7773","authenticated-orcid":false,"given":"Juan","family":"Zhu","sequence":"first","affiliation":[{"name":"Departments of Neurology (J.Z., K.L., Q.C., Z.L., Y.H., Y.C., C.L., M.Y., K.H., S.P.), Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0992-2623","authenticated-orcid":false,"given":"Jiaying","family":"Mo","sequence":"additional","affiliation":[{"name":"Medical Imaging Center (J.M., Y.X., X.T.), Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0131-4737","authenticated-orcid":false,"given":"Kewei","family":"Liu","sequence":"additional","affiliation":[{"name":"Departments of Neurology (J.Z., K.L., Q.C., Z.L., Y.H., Y.C., C.L., M.Y., K.H., S.P.), Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9026-9596","authenticated-orcid":false,"given":"Quanfeng","family":"Chen","sequence":"additional","affiliation":[{"name":"Departments of Neurology (J.Z., K.L., Q.C., Z.L., Y.H., Y.C., C.L., M.Y., K.H., S.P.), Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6229-0275","authenticated-orcid":false,"given":"Zheqi","family":"Li","sequence":"additional","affiliation":[{"name":"Departments of Neurology (J.Z., K.L., Q.C., Z.L., Y.H., Y.C., C.L., M.Y., K.H., S.P.), Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihua","family":"He","sequence":"additional","affiliation":[{"name":"Departments of Neurology (J.Z., K.L., Q.C., Z.L., Y.H., Y.C., C.L., M.Y., K.H., S.P.), Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Chang","sequence":"additional","affiliation":[{"name":"Departments of Neurology (J.Z., K.L., Q.C., Z.L., Y.H., Y.C., C.L., M.Y., K.H., S.P.), Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuman","family":"Lin","sequence":"additional","affiliation":[{"name":"Departments of Neurology (J.Z., K.L., Q.C., Z.L., Y.H., Y.C., C.L., M.Y., K.H., S.P.), Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjia","family":"Yu","sequence":"additional","affiliation":[{"name":"Departments of Neurology (J.Z., K.L., Q.C., Z.L., Y.H., Y.C., C.L., M.Y., K.H., S.P.), Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yikai","family":"Xu","sequence":"additional","affiliation":[{"name":"Medical Imaging Center (J.M., Y.X., X.T.), Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2497-215X","authenticated-orcid":false,"given":"Xiangliang","family":"Tan","sequence":"additional","affiliation":[{"name":"Medical Imaging Center (J.M., Y.X., X.T.), Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3360-7031","authenticated-orcid":false,"given":"Kaibin","family":"Huang","sequence":"additional","affiliation":[{"name":"Departments of Neurology (J.Z., K.L., Q.C., Z.L., Y.H., Y.C., C.L., M.Y., K.H., S.P.), Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suyue","family":"Pan","sequence":"additional","affiliation":[{"name":"Departments of Neurology (J.Z., K.L., Q.C., Z.L., Y.H., Y.C., C.L., M.Y., K.H., S.P.), Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2024,3,27]]},"reference":[{"key":"R1-20250410","doi-asserted-by":"crossref","first-page":"e56","DOI":"10.1161\/CIR.0000000000000659","article-title":"Heart Disease and Stroke Statistics-2019 update: a report from the American Heart Association.","volume":"139","author":"Benjamin","year":"2019","journal-title":"Circulation"},{"key":"R2-20250410","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1177\/0271678X15617172","article-title":"Molecular pathophysiology of cerebral edema.","volume":"36","author":"Stokum","year":"2016","journal-title":"J Cereb Blood Flow Metab"},{"key":"R3-20250410","doi-asserted-by":"crossref","first-page":"3084","DOI":"10.1161\/STROKEAHA.107.490193","article-title":"Antiedema therapy in ischemic stroke.","volume":"38","author":"Bardutzky","year":"2007","journal-title":"Stroke"},{"key":"R4-20250410","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1159\/000342030","article-title":"Measurement of brain edema by noninvasive cerebral electrical impedance in patients with massive hemispheric cerebral infarction.","volume":"68","author":"Lou","year":"2012","journal-title":"Eur Neurol"},{"key":"R5-20250410","doi-asserted-by":"crossref","first-page":"120377","DOI":"10.1016\/j.jns.2022.120377","article-title":"Timing stroke: a review on stroke pathophysiology and its influence over time on diffusion measures.","volume":"441","author":"Osa Garc\u00eda","year":"2022","journal-title":"J Neurol Sci"},{"key":"R6-20250410","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1177\/17474930231166306","article-title":"The evolution of blood-brain barrier permeability changes after stroke and its implications on clinical outcome: a systematic review and meta-analysis.","volume":"18","author":"Bernardo-Castro","year":"2023","journal-title":"Int J Stroke"},{"key":"R7-20250410","doi-asserted-by":"crossref","first-page":"e0171558","DOI":"10.1371\/journal.pone.0171558","article-title":"Evolution of blood-brain-barrier permeability after acute ischemic stroke.","volume":"12","author":"Merali","year":"2017","journal-title":"PLoS One"},{"key":"R8-20250410","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1038\/jcbfm.2008.42","article-title":"Dynamic changes in vascular permeability, cerebral blood volume, vascular density, and size after transient focal cerebral ischemia in rats: evaluation with contrast-enhanced magnetic resonance imaging.","volume":"28","author":"Lin","year":"2008","journal-title":"J Cereb Blood Flow Metab"},{"key":"R9-20250410","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.neuroscience.2008.02.012","article-title":"The blood-brain barrier is continuously open for several weeks following transient focal cerebral ischemia.","volume":"153","author":"Strbian","year":"2008","journal-title":"Neuroscience"},{"key":"R10-20250410","doi-asserted-by":"crossref","first-page":"e13006","DOI":"10.1111\/bpa.13006","article-title":"Glycocalyx is critical for blood-brain barrier integrity by suppressing caveolin1-dependent endothelial transcytosis following ischemic stroke.","volume":"32","author":"Zhu","year":"2022","journal-title":"Brain Pathol"},{"key":"R11-20250410","doi-asserted-by":"crossref","first-page":"2985","DOI":"10.1161\/01.STR.0000037675.97888.9D","article-title":"Dynamic changes in cerebral blood flow and angiogenesis after transient focal cerebral ischemia in rats. Evaluation with serial magnetic resonance imaging.","volume":"33","author":"Lin","year":"2002","journal-title":"Stroke"},{"key":"R12-20250410","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1161\/01.STR.31.8.1965","article-title":"Serial MRI after transient focal cerebral ischemia in rats: dynamics of tissue injury, blood-brain barrier damage, and edema formation.","volume":"31","author":"Neumann-Haefelin","year":"2000","journal-title":"Stroke"},{"key":"R13-20250410","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/j.tins.2014.08.010","article-title":"Drowning stars: reassessing the role of astrocytes in brain edema.","volume":"37","author":"Thrane","year":"2014","journal-title":"Trends Neurosci"},{"key":"R14-20250410","doi-asserted-by":"crossref","first-page":"147ra111","DOI":"10.1126\/scitranslmed.3003748","article-title":"A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta.","volume":"4","author":"Iliff","year":"2012","journal-title":"Sci Transl Med"},{"key":"R15-20250410","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s11011-022-00901-0","article-title":"Molecular mechanisms of cognitive impairment associated with stroke.","volume":"37","author":"Kaur","year":"2022","journal-title":"Metab Brain Dis"},{"key":"R16-20250410","doi-asserted-by":"crossref","first-page":"eaax7171","DOI":"10.1126\/science.aax7171","article-title":"Cerebrospinal fluid influx drives acute ischemic tissue swelling.","volume":"367","author":"Mestre","year":"2020","journal-title":"Science"},{"key":"R17-20250410","doi-asserted-by":"crossref","first-page":"e3000410","DOI":"10.1371\/journal.pbio.3000410","article-title":"The ARRIVE guidelines 2.0: updated guidelines for reporting animal research.","volume":"18","author":"Percie du Sert","year":"2020","journal-title":"PLoS Biol"},{"key":"R18-20250410","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1126\/science.1241224","article-title":"Sleep drives metabolite clearance from the adult brain.","volume":"342","author":"Xie","year":"2013","journal-title":"Science"},{"key":"R19-20250410","doi-asserted-by":"crossref","first-page":"e151835","DOI":"10.1172\/jci.insight.151835","article-title":"Attenuation of cerebral edema facilitates recovery of glymphatic system function after status epilepticus.","volume":"6","author":"Liu","year":"2021","journal-title":"JCI Insight"},{"key":"R20-20250410","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1007\/s11604-017-0617-z","article-title":"Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer\u2019s disease cases.","volume":"35","author":"Taoka","year":"2017","journal-title":"Jpn J Radiol"},{"key":"R21-20250410","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1172\/JCI67677","article-title":"Brain-wide pathway for waste clearance captured by contrast-enhanced MRI.","volume":"123","author":"Iliff","year":"2013","journal-title":"J Clin Invest"},{"key":"R22-20250410","doi-asserted-by":"crossref","first-page":"e40070","DOI":"10.7554\/eLife.40070","article-title":"Aquaporin-4-dependent glymphatic solute transport in the rodent brain.","volume":"7","author":"Mestre","year":"2018","journal-title":"Elife"},{"key":"R23-20250410","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1007\/BF02001473","article-title":"Relationship between blood flow and blood-brain barrier permeability of sodium and albumin in focal ischaemia of rats: a triple tracer autoradiographic study.","volume":"120","author":"Ishimaru","year":"1993","journal-title":"Acta Neurochir (Wien)"},{"key":"R24-20250410","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1016\/S1474-4422(18)30318-1","article-title":"The glymphatic pathway in neurological disorders.","volume":"17","author":"Rasmussen","year":"2018","journal-title":"Lancet Neurol"},{"key":"R25-20250410","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/S0377-1237(03)80147-8","article-title":"Cerebral edema and its management.","volume":"59","author":"Jha","year":"2003","journal-title":"Med J Armed Forces India"},{"key":"R26-20250410","doi-asserted-by":"crossref","first-page":"2697","DOI":"10.1161\/STROKEAHA.110.594168","article-title":"Cerebral autoregulation in stroke: a review of transcranial Doppler studies.","volume":"41","author":"Aries","year":"2010","journal-title":"Stroke"},{"key":"R27-20250410","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1038\/s41593-023-01327-2","article-title":"Glymphatic influx and clearance are accelerated by neurovascular coupling.","volume":"26","author":"Holstein-Ronsbo","year":"2023","journal-title":"Nat Neurosci"},{"key":"R28-20250410","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1177\/0271678X15623290","article-title":"Improved long-term outcome after transient cerebral ischemia in aquaporin-4 knockout mice.","volume":"37","author":"Hirt","year":"2017","journal-title":"J Cereb Blood Flow Metab"},{"key":"R29-20250410","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/72256","article-title":"Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke.","volume":"6","author":"Manley","year":"2000","journal-title":"Nat Med"},{"key":"R30-20250410","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1002\/ana.24271","article-title":"Impairment of paravascular clearance pathways in the aging brain.","volume":"76","author":"Kress","year":"2014","journal-title":"Ann Neurol"},{"key":"R31-20250410","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.ejphar.2013.11.032","article-title":"Pseudoephedrine\/ephedrine shows potent anti-inflammatory activity against TNF-\u03b1-mediated acute liver failure induced by lipopolysaccharide\/D-galactosamine.","volume":"724","author":"Wu","year":"2014","journal-title":"Eur J Pharmacol"},{"key":"R32-20250410","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1002\/ana.24271","article-title":"Impairment of paravascular clearance pathways in the aging brain.","volume":"76","author":"Kress","year":"2014","journal-title":"Ann Neurol"},{"key":"R33-20250410","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1161\/STROKEAHA.114.008322","article-title":"How sustained is 24-hour diffusion-weighted imaging lesion reversal? Serial magnetic resonance imaging in a patient cohort thrombolyzed within 4.5 hours of stroke onset.","volume":"46","author":"Soize","year":"2015","journal-title":"Stroke"},{"key":"R34-20250410","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1148\/radiol.2021203651","article-title":"Venous outflow profiles are linked to cerebral edema formation at noncontrast head CT after treatment in acute ischemic stroke regardless of collateral vessel status at CT angiography.","volume":"299","author":"Faizy","year":"2021","journal-title":"Radiology"}],"container-title":["Stroke"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.lww.com\/10.1161\/STROKEAHA.123.045941","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T12:01:55Z","timestamp":1744286515000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1161\/STROKEAHA.123.045941"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,27]]},"references-count":34,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2024]]}},"URL":"https:\/\/doi.org\/10.1161\/strokeaha.123.045941","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.05.20.23290281","asserted-by":"object"}]},"ISSN":["0039-2499"],"issn-type":[{"value":"0039-2499","type":"print"}],"subject":[],"published":{"date-parts":[[2024,3,27]]},"assertion":[{"value":"2023-05-20","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-02-29","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}