{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T12:39:27Z","timestamp":1793363967938,"version":"4.5.0"},"reference-count":65,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2021,6,5]],"date-time":"2021-06-05T00:00:00Z","timestamp":1622851200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["19PRE34380371"],"award-info":[{"award-number":["19PRE34380371"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P41 EB015909"],"award-info":[{"award-number":["P41 EB015909"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AG064792"],"award-info":[{"award-number":["R01 AG064792"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AG071515"],"award-info":[{"award-number":["R01 AG071515"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS106702"],"award-info":[{"award-number":["R01 NS106702"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS106711"],"award-info":[{"award-number":["R01 NS106711"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["S10 OD021648"],"award-info":[{"award-number":["S10 OD021648"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Blood\u2013brain barrier (BBB) breakdown has been suggested to be an early biomarker in human cognitive impairment. However, the relationship between BBB breakdown and brain pathology, most commonly Alzheimer disease (AD) and vascular disease, is still poorly understood. The present study measured human BBB function in mild cognitive impairment (MCI) patients on 2 molecular scales, specifically BBB's permeability to water and albumin molecules.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Fifty\u2010five elderly participants were enrolled, including 33 MCI patients and 22 controls. BBB permeability to water was measured with a new magnetic resonance imaging technique, water extraction with phase contrast arterial spin tagging. BBB permeability to albumin was determined using cerebrospinal fluid (CSF)\/serum albumin ratio. Cognitive performance was assessed by domain\u2010specific composite scores. AD pathology (including CSF A\u03b2 and ptau) and vascular risk factors were examined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared to cognitively normal subjects, BBB in MCI patients manifested an increased permeability to small molecules such as water but was no more permeable to large molecules such as albumin. BBB permeability to water was found to be related to AD markers of CSF A\u03b2 and ptau. On the other hand, BBB permeability to albumin was found to be related to vascular risk factors, especially hypercholesterolemia, but was not related to AD pathology. BBB permeability to small molecules, but not to large molecules, was found to be predictive of cognitive function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>These findings provide early evidence that BBB breakdown is related to both AD and vascular risks, but their effects can be differentiated by spatial scales. BBB permeability to small molecules has a greater impact on cognitive performance. ANN NEUROL 2021;90:227\u2013238<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.26134","type":"journal-article","created":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T06:56:11Z","timestamp":1622098571000},"page":"227-238","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":147,"title":["Blood\u2013Brain Barrier Breakdown in Relationship to Alzheimer and Vascular Disease"],"prefix":"10.1002","volume":"90","author":[{"given":"Zixuan","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Johns Hopkins University School of Medicine  Baltimore MD"},{"name":"Russell H. Morgan Department of Radiology and Radiological Science Johns Hopkins University School of Medicine  Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeepa","family":"Sur","sequence":"additional","affiliation":[{"name":"Russell H. Morgan Department of Radiology and Radiological Science Johns Hopkins University School of Medicine  Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiying","family":"Liu","sequence":"additional","affiliation":[{"name":"Russell H. Morgan Department of Radiology and Radiological Science Johns Hopkins University School of Medicine  Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Russell H. Morgan Department of Radiology and Radiological Science Johns Hopkins University School of Medicine  Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dengrong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Russell H. Morgan Department of Radiology and Radiological Science Johns Hopkins University School of Medicine  Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xirui","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Johns Hopkins University School of Medicine  Baltimore MD"},{"name":"Russell H. Morgan Department of Radiology and Radiological Science Johns Hopkins University School of Medicine  Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Darrow","sequence":"additional","affiliation":[{"name":"Department of Neurology Johns Hopkins University School of Medicine  Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay J.","family":"Pillai","sequence":"additional","affiliation":[{"name":"Russell H. Morgan Department of Radiology and Radiological Science Johns Hopkins University School of Medicine  Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sevil","family":"Yasar","sequence":"additional","affiliation":[{"name":"Department of Medicine Johns Hopkins University School of Medicine  Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Rosenberg","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences Johns Hopkins University  Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilyn","family":"Albert","sequence":"additional","affiliation":[{"name":"Department of Neurology Johns Hopkins University School of Medicine  Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhay","family":"Moghekar","sequence":"additional","affiliation":[{"name":"Department of Neurology Johns Hopkins University School of Medicine  Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3871-1564","authenticated-orcid":false,"given":"Hanzhang","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Johns Hopkins University School of Medicine  Baltimore MD"},{"name":"Russell H. Morgan Department of Radiology and Radiological Science Johns Hopkins University School of Medicine  Baltimore MD"},{"name":"F. M. Kirby Research Center for Functional Brain Imaging Kennedy Krieger Research Institute  Baltimore MD"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,6,5]]},"reference":[{"key":"e_1_2_8_2_1","unstructured":"https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/dementia. Dementia; Last acessed June 3 2021."},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2013.135"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2007.07.015"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2005.02.001"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0297-y"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.12.032"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaw8954"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.27632"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1148\/radiol.2016152244"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2019.01.035"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2018.09.030"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.28496"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2247-3"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1824"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.14-04-02225.1994"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1982.tb26848.x"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-510X(83)90157-0"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-510X(85)90189-3"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1097\/00002093-199706000-00004"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.50.4.966"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaf1059"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.2174\/1573406411666151030111820"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.55.11.1407"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2013.1342"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.01.003"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18091965"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2018.00926"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.74.1.70"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1159\/000008242"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1136\/bcr-2016-218794"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21549"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.27141"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.28687"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2011.03.008"},{"key":"e_1_2_8_36_1","volume-title":"WMS\u2010R: Wechsler memory scale\u2013revised","author":"Wechsler D","year":"1987"},{"key":"e_1_2_8_37_1","volume-title":"Hopkins verbal learning test\u2013revised, professional manual","author":"Brandt J","year":"2001"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1037\/h0044509"},{"key":"e_1_2_8_39_1","volume-title":"WAIS\u2010R manual: Wechsler adult intelligence scale\u2013revised manual","author":"Wechsler D","year":"1981"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1037\/h0054651"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1355617712001282"},{"key":"e_1_2_8_42_1","volume-title":"Multilingual aphasia examination manual","author":"Benton A","year":"1976"},{"key":"e_1_2_8_43_1","first-page":"44","article-title":"Counting of tubercle bacilli","volume":"22","author":"Crone PB","year":"1963","journal-title":"Mon Bull Minist Health Public Health Lab Serv"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmri.24866"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.25197"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.20178"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.24260"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000150668.58689.f2"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.3090"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000010133"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmri.27264"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000010946"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2009.01.027"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2017.06.028"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0404.1990.tb01563.x"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2016.11.017"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2018.12.026"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2016.4370"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e3181fd252c"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-804279-3.00002-2"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16002-4"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.180372"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1111\/cns.12503"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13122"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1159\/000285518"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20071632"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.26134","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ana.26134","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.26134","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T04:08:58Z","timestamp":1692245338000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.26134"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,5]]},"references-count":65,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,8]]}},"alternative-id":["10.1002\/ana.26134"],"URL":"https:\/\/doi.org\/10.1002\/ana.26134","archive":["Portico"],"relation":{},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,5]]},"assertion":[{"value":"2021-01-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-05-15","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-06-05","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}