{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T01:10:45Z","timestamp":1790730645142,"version":"4.1.0"},"reference-count":61,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2015,11,9]],"date-time":"2015-11-09T00:00:00Z","timestamp":1447027200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002283","name":"Alzheimer\u2019s Research UK","doi-asserted-by":"publisher","award":["ART\u2010PG2011\u20101"],"award-info":[{"award-number":["ART\u2010PG2011\u20101"]}],"id":[{"id":"10.13039\/501100002283","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/K015397\/1"],"award-info":[{"award-number":["MR\/K015397\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Pathology"],"published-print":{"date-parts":[[2016,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The earliest decline in cerebral perfusion in Alzheimer's disease (AD) is in the medial parietal cortex (precuneus). We have analyzed precuneus in post\u2010mortem tissue from 70 AD and 37 control brains to explore the pathophysiology of the hypoperfusion: the contribution of arteriolosclerotic small vessel disease (SVD) and cerebral amyloid angiopathy (CAA), and of the vasoconstrictors endothelin\u20101 (EDN1) and angiotensin II (Ang II), and the association with A\u03b2. The myelin\u2010associated glycoprotein:proteolipid protein\u20101 ratio (MAG:PLP1) was used as an indicator of oxygenation of the precuneus prior to death. MAG:PLP1 was reduced \u223c50% in early AD (Braak stage III\u2013IV). Although MAG:PLP1 remained low in advanced AD (stage V\u2013VI), the reduction was less pronounced, possibly reflecting falling oxygen demand. Reduction in cortical MAG:PLP1 correlated with elevation in vascular endothelial growth factor (VEGF), another marker of hypoperfusion. Cortical MAG:PLP1 declined nonsignificantly with increasing SVD and CAA, but significantly with the concentration of EDN1, which was elevated approximately 75% in AD. In contrast, with reduction in cortical MAG:PLP1, Ang II level and angiotensin\u2010converting enzyme (ACE) activity declined, showing a normal physiological response to hypoperfusion. MAG:PLP1 was reduced in the parietal white matter (WM) in AD but here the decline correlated positively (ie, physiologically) with WM EDN1. However, the decline of MAG:PLP1 in the WM was associated with increasing cortical EDN1 and perhaps reflected vasoconstriction of perforating arterioles, which traverse the cortex to perfuse the WM. EDN1 in the cortex correlated highly significantly with both soluble and insoluble A\u03b242, shown previously to upregulate neuronal endothelin\u2010converting enzyme\u20102 (ECE2), but not with A\u03b240. Our findings demonstrate reduced oxygenation of the precuneus in early AD and suggest that elevated EDN1, resulting from A\u03b242\u2010mediated upregulation of ECE2, is a contributor.<\/jats:p>","DOI":"10.1111\/bpa.12331","type":"journal-article","created":{"date-parts":[[2015,10,10]],"date-time":"2015-10-10T01:49:49Z","timestamp":1444441789000},"page":"533-541","source":"Crossref","is-referenced-by-count":111,"title":["Pathophysiology of Hypoperfusion of the Precuneus in Early <scp>A<\/scp>lzheimer's Disease"],"prefix":"10.1111","volume":"26","author":[{"given":"J. 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