{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:57:08Z","timestamp":1792652228555,"version":"4.5.0"},"reference-count":56,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T00:00:00Z","timestamp":1614729600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21 AG051103"],"award-info":[{"award-number":["R21 AG051103"]}],"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":["VA I21 RX002223"],"award-info":[{"award-number":["VA I21 RX002223"]}],"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":["VA I21 BX003023"],"award-info":[{"award-number":["VA I21 BX003023"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We compared the efficacy of neurovascular coupling and substrate supply in cerebral cortex during severe metabolic challenges in transgenic Alzheimer's [CVN\u2010AD] and control [C57Bl\/6] mice, to evaluate the hypothesis that metabolic insufficiency is a critical component of degeneration leading to dementia. We analyzed cerebral blood flow and metabolic responses to spreading depression (induced by K<jats:sup>+<\/jats:sup> applied to the cortex) and anoxia across aging in CVN\u2010AD + C57Bl\/6 genotypes. In the CVN\u2010AD genotype progression to histological and cognitive hallmarks of dementia is a stereotyped function of age. We correlated physiology and imaging of the cortex with the blood flow responses measured with laser doppler probes. The results show that spreading depression resulted in a hyperemic blood flow response that was dramatically reduced (24% in amplitude, 70% in area) in both middle\u2010aged and aged CVN\u2010AD mice compared to C57Bl\/6 age\u2010matched controls. However, spreading depression amplitude and conduction velocity (\u22486\u00a0mm\/min) did not differ among groups. Anoxia (100% N<jats:sub>2<\/jats:sub>) showed significantly decreased (by 62%) reactive blood flow and autoregulation in aged AD\u2010CVN mice compared to aged control animals. Significantly reduced neurovascular coupling occurred prematurely with aging in CVN\u2010AD mice. Abbreviated physiological hyperemia and decreased resilience to anoxia may enhance early\u2010onset metabolic deficiency through decreased substrate supply to the brain. Metabolic deficiency may contribute significantly to the degeneration associated with dementia as a function of aging and regions of the brain involved.<\/jats:p>","DOI":"10.1002\/alz.12289","type":"journal-article","created":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T06:45:38Z","timestamp":1614753938000},"page":"1109-1120","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["CVN\u2010AD Alzheimer's mice show premature reduction in neurovascular coupling in response to spreading depression and anoxia compared to aged controls"],"prefix":"10.1002","volume":"17","author":[{"given":"Dennis A.","family":"Turner","sequence":"first","affiliation":[{"name":"Neurosurgery  Box 3807, Duke University Medical Center Durham North Carolina 27710 USA"},{"name":"Neurobiology  Box 3209, Duke University Medical Center Durham North Carolina 27710 USA"},{"name":"Biomedical Engineering  Box 90281, Duke University Durham North Carolina 27708 USA"},{"name":"Research and Surgery Services Durham VA Medical Center  508 Fulton Street Durham North Carolina 27705 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Degan","sequence":"additional","affiliation":[{"name":"Neurosurgery  Box 3807, Duke University Medical Center Durham North Carolina 27710 USA"},{"name":"Research and Surgery Services Durham VA Medical Center  508 Fulton Street Durham North Carolina 27705 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Anesthesiology  Box 3094, Duke University Medical Center Durham North Carolina 27710 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Galeffi","sequence":"additional","affiliation":[{"name":"Neurosurgery  Box 3807, Duke University Medical Center Durham North Carolina 27710 USA"},{"name":"Research and Surgery Services Durham VA Medical Center  508 Fulton Street Durham North Carolina 27705 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol A.","family":"Colton","sequence":"additional","affiliation":[{"name":"Neurology  Box 2900, Duke University Medical Center Durham North Carolina 27710 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,3,3]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2019.06.001"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nicl.2018.01.019"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2017.07.004"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2016.09.006"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2018.07.222"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3966"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2017.48"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2017.09.004"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2017.09.011"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-170549"},{"key":"e_1_2_6_12_1","doi-asserted-by":"crossref","first-page":"4762404","DOI":"10.1155\/2019\/4762404","article-title":"Evaluation of Task\u2010Related Brain Activity: is There a Role for (18)F FDG\u2010PET Imaging?","volume":"2019","author":"Chiaravalloti A","year":"2019","journal-title":"Biomed Res Int"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2016.12.006"},{"issue":"11","key":"e_1_2_6_14_1","doi-asserted-by":"crossref","first-page":"2877","DOI":"10.1093\/brain\/awu263","article-title":"Neurovascular regulation is critical for metabolic recovery from spreading depression","volume":"137","author":"Turner DA","year":"2014","journal-title":"Brain"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00027.2014"},{"issue":"4","key":"e_1_2_6_16_1","doi-asserted-by":"crossref","first-page":"857","DOI":"10.3233\/JAD-121900","article-title":"Augmentation of sensory\u2010evoked hemodynamic response in an early Alzheimer's disease mouse model","volume":"37","author":"Kim J","year":"2013","journal-title":"Journal of Alzheimer's Disease : JAD"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awm156"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X16654495"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0000000000000094"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2015.08.014"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5066-07.2008"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17718-y"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2016.06.012"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2018.11.011"},{"key":"e_1_2_6_25_1","doi-asserted-by":"crossref","DOI":"10.3389\/fphys.2018.00913","article-title":"Age\u2010Dependent Impairment of Neurovascular and Neurometabolic Coupling in the Hippocampus","volume":"9","author":"Lourenco CF","year":"2018","journal-title":"Front Physiol"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1177\/1073858417703033"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12028"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12127"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-020-00164-6"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4668-14.2015"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-160305"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000010133"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25289"},{"key":"e_1_2_6_34_1","doi-asserted-by":"crossref","DOI":"10.3389\/fpsyt.2018.00201","article-title":"Brain Stimulation in Alzheimer's Disease","volume":"9","author":"Chang CH","year":"2018","journal-title":"Front Psychiatry"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-160017"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000009946"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2010.136"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00222.2017"},{"key":"e_1_2_6_39_1","article-title":"Brain Aging and Electrophysiological Signaling: revisiting the Spreading Depression Model","volume":"11","author":"Guedes RCA","year":"2019","journal-title":"Front Aging Neurosci"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1998.80.3.1514"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1117\/1.2203654"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2018.09.001"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00231.2001"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2005.01.040"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2011.148"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.WCB.0000122745.72175.D5"},{"issue":"6","key":"e_1_2_6_47_1","doi-asserted-by":"crossref","first-page":"2562","DOI":"10.1523\/JNEUROSCI.2308-12.2013","article-title":"Increased 20\u2010HETE synthesis explains reduced cerebral blood flow but not impaired neurovascular coupling after cortical spreading depression in rat cerebral cortex","volume":"33","author":"Fordsmann JC","year":"2013","journal-title":"J Neurosci"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2009.73"},{"issue":"10","key":"e_1_2_6_49_1","first-page":"S135","article-title":"Enhanced capillary amyloid angiopathy\u2010associated pathology in Tg\u2010SwDI mice with deleted nitric oxide synthase 2","volume":"41","author":"Van Nostrand WE","year":"2010","journal-title":"Stroke"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2009.01.023"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2008.03.026"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2012.10.018"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.114.005179"},{"key":"e_1_2_6_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep38977"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00221-010-2447-4"},{"issue":"2","key":"e_1_2_6_56_1","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.neulet.2005.11.025","article-title":"Time\u2010varying spreading depression waves in rat cortex revealed by optical intrinsic signal imaging","volume":"396","author":"Chen S","year":"2006","journal-title":"Neurosci Lett"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jcbfm.9600252"}],"container-title":["Alzheimer's &amp; Dementia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/alz.12289","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/alz.12289","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/alz.12289","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T21:51:46Z","timestamp":1759873906000},"score":1,"resource":{"primary":{"URL":"https:\/\/alz-journals.onlinelibrary.wiley.com\/doi\/10.1002\/alz.12289"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,3]]},"references-count":56,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2021,7]]}},"alternative-id":["10.1002\/alz.12289"],"URL":"https:\/\/doi.org\/10.1002\/alz.12289","archive":["Portico"],"relation":{},"ISSN":["1552-5260","1552-5279"],"issn-type":[{"value":"1552-5260","type":"print"},{"value":"1552-5279","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,3]]},"assertion":[{"value":"2020-03-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-12-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-03-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}