{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T22:17:11Z","timestamp":1792016231663,"version":"4.4.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T00:00:00Z","timestamp":1626825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>\n                    There is increasing evidence that impairments of cerebrovascular function and\/or abnormalities of the cerebral vasculature might contribute to early neuronal cell loss in Huntington\u2019s disease (HD). Studies in both healthy individuals as well as in patients with other neurodegenerative disorders have used an exogenous carbon dioxide (CO\n                    <jats:sub>2<\/jats:sub>\n                    ) challenge in conjunction with functional magnetic resonance imaging (fMRI) to assess regional cerebrovascular reactivity (CVR). In this study, we explored potential impairments of CVR in HD. Twelve gene expanded HD individuals, including both pre-symptomatic and early symptomatic HD and eleven healthy controls were administered a gas mixture targeting a 4\u20138 mmHg increase in CO\n                    <jats:sub>2<\/jats:sub>\n                    relative to the end-tidal partial pressure of CO\n                    <jats:sub>2<\/jats:sub>\n                    (P\n                    <jats:sub>\n                      <jats:italic>ET<\/jats:italic>\n                    <\/jats:sub>\n                    CO\n                    <jats:sub>2<\/jats:sub>\n                    ) at rest. A Hilbert Transform analysis was used to compute the cross-correlation between the time series of regional BOLD signal changes (\u0394BOLD) and increased P\n                    <jats:sub>\n                      <jats:italic>ET<\/jats:italic>\n                    <\/jats:sub>\n                    CO\n                    <jats:sub>2<\/jats:sub>\n                    , and to estimate the response delay of \u0394BOLD relative to P\n                    <jats:sub>\n                      <jats:italic>ET<\/jats:italic>\n                    <\/jats:sub>\n                    CO\n                    <jats:sub>2<\/jats:sub>\n                    . After correcting for age, we found that the cross-correlation between the time series for regional \u0394BOLD and for P\n                    <jats:sub>\n                      <jats:italic>ET<\/jats:italic>\n                    <\/jats:sub>\n                    CO\n                    <jats:sub>2<\/jats:sub>\n                    was weaker in HD subjects than in controls in several subcortical white matter regions, including the corpus callosum, subcortical white matter adjacent to rostral and caudal anterior cingulate, rostral and caudal middle frontal, insular, middle temporal, and posterior cingulate areas. In addition, greater volume of dilated perivascular space (PVS) was observed to overlap, primarily along the periphery, with the areas that showed greater \u0394BOLD response delay. Our preliminary findings support that alterations in cerebrovascular function occur in HD and may be an important, not as yet considered, contributor to early neuropathology in HD.\n                  <\/jats:p>","DOI":"10.3389\/fphys.2021.663898","type":"journal-article","created":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T05:50:12Z","timestamp":1626846612000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Impaired Cerebrovascular Reactivity in Huntington\u2019s Disease"],"prefix":"10.3389","volume":"12","author":[{"given":"Suk Tak","family":"Chan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel D.","family":"Mercaldo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth K.","family":"Kwong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Hersch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herminia D.","family":"Rosas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1597","DOI":"10.1152\/jappl.2000.88.5.1597","article-title":"Simple contrivance \u201cclamps\u201d end-tidal PCO(2) and PO(2) despite rapid changes in ventilation.","volume":"88","author":"Banzett","year":"2000","journal-title":"J. Appl. Physiol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practival and powerful approach to multiple testing.","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Statist. Soc."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1462","DOI":"10.1093\/cvr\/cvy113","article-title":"Understanding the role of the perivascular space in cerebral small vessel disease.","volume":"114","author":"Brown","year":"2018","journal-title":"Cardiovasc. Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"e0238946","DOI":"10.1371\/journal.pone.0238946","article-title":"Dynamic brain-body coupling of breath-by-breath O2-CO2 exchange ratio with resting state cerebral hemodynamic fluctuations.","volume":"15","author":"Chan","year":"","journal-title":"PLoS One"},{"key":"B5","doi-asserted-by":"publisher","first-page":"11121","DOI":"10.1212\/WNL.0000000000011121","article-title":"Association of dilated perivascular spaces and disease severity in patients with Huntington\u2019s disease.","volume":"2020","author":"Chan","year":"","journal-title":"Neurology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1016\/j.neuroimage.2011.08.112","article-title":"Complex relationships between cerebral blood flow and brain atrophy in early Huntington\u2019s disease.","volume":"59","author":"Chen","year":"2012","journal-title":"Neuroimage"},{"key":"B7","first-page":"506","article-title":"Huntington disease: genetics and epidemiology.","volume":"36","author":"Conneally","year":"1984","journal-title":"Am. J. Hum. Genet."},{"key":"B8","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1006\/cbmr.1996.0014","article-title":"software for analysis and visualization of functional magnetic resonance neuroimages.","volume":"29","author":"Cox","year":"1996","journal-title":"Comput. Biomed. Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1006\/nimg.1998.0395","article-title":"Cortical surface-based analysis. I. Segmentation and surface reconstruction.","volume":"9","author":"Dale","year":"1999","journal-title":"Neuroimage"},{"key":"B10","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/s0006-8993(00)02506-3","article-title":"Vasomotor hyporeactivity in the anterior cerebral artery during motor activation in Huntington\u2019s disease patients.","volume":"872","author":"Deckel","year":"2000","journal-title":"Brain Res."},{"key":"B11","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1002\/ana.24406","article-title":"Cerebrovascular and blood-brain barrier impairments in Huntington\u2019s disease: Potential implications for its pathophysiology.","volume":"78","author":"Drouin-Ouellet","year":"2015","journal-title":"Ann. Neurol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"5809","DOI":"10.1113\/jphysiol.2013.259150","article-title":"Measuring cerebrovascular reactivity: what stimulus to use?","volume":"591","author":"Fierstra","year":"2013","journal-title":"J. Physiol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1006\/nimg.1998.0396","article-title":"Cortical surface-based analysis. II: Inflation, flattening, and a surface-based coordinate system.","volume":"9","author":"Fischl","year":"1999","journal-title":"Neuroimage"},{"key":"B14","first-page":"1","article-title":"On the \u2018probable error\u2019 of a coefficient of correlation deduced from a small sample.","volume":"1","author":"Fisher","year":"1921","journal-title":"Metron"},{"key":"B15","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1016\/j.nbd.2011.09.003","article-title":"Age-dependent neurovascular abnormalities and altered microglial morphology in the YAC128 mouse model of Huntington disease.","volume":"45","author":"Franciosi","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"B16","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/(sici)1097-0193(1998)6:2<73::aid-hbm1>3.0.co;2-h","article-title":"Functional MRI statistical software packages: a comparative analysis.","volume":"6","author":"Gold","year":"1998","journal-title":"Hum. Brain Mapp."},{"key":"B17","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1016\/j.nurt.2008.01.003","article-title":"Neuroprotection for Huntington\u2019s disease: ready, set, slow.","volume":"5","author":"Hersch","year":"2008","journal-title":"Neurotherapeutics"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.3174\/ajnr.A2018","article-title":"Onset and progression of pathologic atrophy in Huntington disease: a longitudinal MR imaging study.","volume":"31","author":"Hobbs","year":"2010","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1684","DOI":"10.1002\/mds.23747","article-title":"The structural involvement of the cingulate cortex in premanifest and early Huntington\u2019s disease.","volume":"26","author":"Hobbs","year":"2011","journal-title":"Mov. Disord."},{"key":"B20","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1002\/ana.24428","article-title":"Aberrant astrocytes impair vascular reactivity in Huntington disease.","volume":"78","author":"Hsiao","year":"2015","journal-title":"Ann. Neurol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1002\/mds.25591","article-title":"Elevated arteriolar cerebral blood volume in prodromal Huntington\u2019s disease.","volume":"29","author":"Hua","year":"2014","journal-title":"Mov. Disord."},{"key":"B22","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1002\/glia.23050","article-title":"Frequency of nuclear mutant huntingtin inclusion formation in neurons and glia is cell-type-specific.","volume":"65","author":"Jansen","year":"2017","journal-title":"Glia"},{"key":"B23","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1038\/nrn.2017.48","article-title":"Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease.","volume":"18","author":"Kisler","year":"2017","journal-title":"Nat. Rev. Neurosci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1365","DOI":"10.1016\/j.celrep.2017.04.021","article-title":"Huntington\u2019s Disease iPSC-Derived Brain Microvascular Endothelial Cells Reveal WNT-Mediated Angiogenic and Blood-Brain Barrier Deficits.","volume":"19","author":"Lim","year":"2017","journal-title":"Cell Rep."},{"key":"B25","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.expneurol.2013.08.019","article-title":"Neurovascular abnormalities in humans and mice with Huntington\u2019s disease.","volume":"250","author":"Lin","year":"2013","journal-title":"Exp. Neurol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.neuroimage.2018.03.047","article-title":"Cerebrovascular reactivity (CVR) MRI with CO2 challenge: A technical review.","volume":"187","author":"Liu","year":"2019","journal-title":"Neuroimage"},{"key":"B27","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1111\/biom.12812","article-title":"Covariate-adjusted Spearman\u2019s rank correlation with probability-scale residuals.","volume":"74","author":"Liu","year":"2018","journal-title":"Biometrics"},{"key":"B28","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1161\/01.str.0000012808.81667.4b","article-title":"Cerebral perfusion and cerebrovascular reactivity are reduced in white matter hyperintensities.","volume":"33","author":"Marstrand","year":"2002","journal-title":"Stroke"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1170","DOI":"10.1152\/japplphysiol.00641.2002","article-title":"Neural correlates of voluntary breathing in humans.","volume":"95","author":"McKay","year":"2003","journal-title":"J. Appl. Physiol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/s41591-018-0297-y","article-title":"Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction.","volume":"25","author":"Nation","year":"2019","journal-title":"Nat. Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1016\/0092-8674(93)90585-e","article-title":"A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington\u2019s disease chromosomes. The Huntington\u2019s Disease Collaborative Research Group.","volume":"72","author":"MacDonald","year":"1993","journal-title":"Cell"},{"key":"B32","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.expneurol.2018.03.015","article-title":"Brain pericyte activation occurs early in Huntington\u2019s disease.","volume":"305","author":"Padel","year":"2018","journal-title":"Exp. Neurol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1212\/wnl.58.5.695","article-title":"Regional and progressive thinning of the cortical ribbon in Huntington\u2019s disease.","volume":"58","author":"Rosas","year":"2002","journal-title":"Neurology"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1093\/brain\/awn025","article-title":"Cerebral cortex and the clinical expression of Huntington\u2019s disease: complexity and heterogeneity.","volume":"131","author":"Rosas","year":"2008","journal-title":"Brain"},{"key":"B35","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1016\/j.nicl.2018.01.029","article-title":"Complex spatial and temporally defined myelin and axonal degeneration in Huntington disease.","volume":"20","author":"Rosas","year":"2018","journal-title":"Neuroimage Clin."},{"key":"B36","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/S1053-8119(02)00024-1","article-title":"Estimation of FMRI response delays.","volume":"18","author":"Saad","year":"2003","journal-title":"Neuroimage"},{"key":"B37","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1002\/ana.24712","article-title":"Development of White Matter Hyperintensity Is Preceded by Reduced Cerebrovascular Reactivity.","volume":"80","author":"Sam","year":"2016","journal-title":"Ann. Neurol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1104","DOI":"10.1002\/jmri.24273","article-title":"Optimized simultaneous ASL and BOLD functional imaging of the whole brain.","volume":"39","author":"Schmithorst","year":"2014","journal-title":"J. Magnetic Resonance Imaging JMRI"},{"key":"B39","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1159\/000362276","article-title":"Pericyte dynamics during angiogenesis: new insights from new identities.","volume":"51","author":"Stapor","year":"2014","journal-title":"J. Vasc. Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/nrneurol.2017.188","article-title":"Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders.","volume":"14","author":"Sweeney","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"B41","author":"Talairach","year":"1988","journal-title":"Co-Planar Stereotaxic Atlas of the Human Brain."},{"key":"B42","author":"Ward","year":"1997","journal-title":"Simultaneous inference for fMRI data."},{"key":"B43","author":"West","year":"1992","journal-title":"Pulmonary Pathophysiology."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.663898\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T05:50:22Z","timestamp":1626846622000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.663898\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,21]]},"references-count":43,"alternative-id":["10.3389\/fphys.2021.663898"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2021.663898","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,21]]},"article-number":"663898"}}