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Here we test the hypothesis that there is a combination of impaired elimination of interstitial fluid from the white matter together with a degree of hypoxia in WMH. One of the mechanisms for the elimination of amyloid-\u03b2 (A\u03b2) from the brain is along the basement membranes in the walls of capillaries and arteries (Intramural Peri-Arterial Drainage \u2013 IPAD). We compared the dynamics of IPAD in the grey matter of the hippocampus and in the white matter of the corpus callosum in 10\u2009week old C57\/B16 mice by injecting soluble A\u03b2 as a tracer. The dynamics of IPAD in the white matter were significantly slower compared with the grey matter and this was associated with a lower density of capillaries in the white matter. Exposing cultures of smooth muscle cells to hypercapnia as a model of cerebral hypoperfusion resulted in a reduction in fibronectin and an increase in laminin in the extracellular matrix. Similar changes were detected in the white matter in human WMH suggesting that hypercapnia\/hypoxia may play a role in WMH. Employing therapies to enhance both IPAD and blood flow in the white matter may reduce WMH in patients with dementia.<\/jats:p>","DOI":"10.1186\/s40478-020-01009-1","type":"journal-article","created":{"date-parts":[[2020,8,8]],"date-time":"2020-08-08T10:02:48Z","timestamp":1596880968000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Demonstrating a reduced capacity for removal of fluid from cerebral white matter and hypoxia in areas of white matter hyperintensity associated with age and dementia"],"prefix":"10.1186","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6623-5078","authenticated-orcid":false,"given":"Matthew","family":"MacGregor Sharp","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoshi","family":"Saito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abby","family":"Keable","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maureen","family":"Gatherer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roxana","family":"Aldea","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nivedita","family":"Agarwal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie E.","family":"Simpson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen B.","family":"Wharton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roy O.","family":"Weller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roxana O.","family":"Carare","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,8,8]]},"reference":[{"issue":"3","key":"1009_CR1","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s00401-010-0652-7","volume":"119","author":"LT Grinberg","year":"2010","unstructured":"Grinberg LT, Thal DR (2010) Vascular pathology in the aged human brain. 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AnnNYAcadSci. 481:123\u2013134","journal-title":"AnnNYAcadSci."}],"container-title":["Acta Neuropathologica Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-020-01009-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40478-020-01009-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-020-01009-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,7]],"date-time":"2021-08-07T23:26:58Z","timestamp":1628378818000},"score":1,"resource":{"primary":{"URL":"https:\/\/actaneurocomms.biomedcentral.com\/articles\/10.1186\/s40478-020-01009-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,8]]},"references-count":52,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["1009"],"URL":"https:\/\/doi.org\/10.1186\/s40478-020-01009-1","relation":{},"ISSN":["2051-5960"],"issn-type":[{"value":"2051-5960","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,8]]},"assertion":[{"value":"17 June 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 August 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 August 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Human autopsy CNS tissue was obtained from the MRC Cognitive Function and Ageing Study (CFAS, ethical approval 15\/SW\/0246). Control cases were from CFAS and Parkinson\u2019s UK brain bank (REC Reference numbers 15\/SW\/0246 and 08\/MRE09\/31\u2009+\u20095). The Parkinson\u2019s UK Brain Bank is funded by Parkinson\u2019s UK, a charity registered in England and Wales (258197) and in Scotland (SC037554). All procedures involving animals were carried out in accordance with animal care guidelines stipulated by the United Kingdom Animals (Scientific Procedures) Act 1986, Home Office licence P12102B2A.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All human data are post-mortem tissue obtained with consent by the MRC CFAS and Parkinson\u2019s UK Brain Banks.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"131"}}