{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:29:49Z","timestamp":1791473389903,"version":"4.3.4"},"reference-count":44,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T00:00:00Z","timestamp":1717545600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["F31AG072872"],"award-info":[{"award-number":["F31AG072872"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG080043"],"award-info":[{"award-number":["R01AG080043"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Increased blood-brain barrier permeability (BBBp) has been hypothesized as a feature of aging that may lead to the development of Alzheimer\u2019s disease (AD). We sought to identify the brain regions most vulnerable to greater BBBp during aging and examine their regional relationship with neuroimaging biomarkers of AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We studied 31 cognitively normal older adults (OA) and 10 young adults (YA) from the Berkeley Aging Cohort Study (BACS). Both OA and YA received dynamic contrast-enhanced MRI (DCE-MRI) to quantify K\n                      <jats:sub>trans<\/jats:sub>\n                      values, as a measure of BBBp, in 37 brain regions across the cortex. The OA also received Pittsburgh compound B (PiB)-PET to create distribution volume ratios (DVR) images and flortaucipir (FTP)- PET to create partial volume corrected standardized uptake volume ratios (SUVR) images. Repeated measures ANOVA assessed the brain regions where OA showed greater BBBp than YA. In OA, K\n                      <jats:sub>trans<\/jats:sub>\n                      values were compared based on sex, A\u03b2 positivity status, and APO\n                      <jats:italic>E4<\/jats:italic>\n                      carrier status within a composite region across the areas susceptible to aging. We used linear models and sparse canonical correlation analysis (SCCA) to examine the relationship between K\n                      <jats:sub>trans<\/jats:sub>\n                      and AD biomarkers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      OA showed greater BBBp than YA predominately in the temporal lobe, with some involvement of parietal, occipital and frontal lobes. Within an averaged ROI of affected regions, there was no difference in K\n                      <jats:sub>trans<\/jats:sub>\n                      values based on sex or A\u03b2 positivity, but OA who were APO\n                      <jats:italic>E4<\/jats:italic>\n                      carriers had significantly higher K\n                      <jats:sub>trans<\/jats:sub>\n                      values. There was no direct relationship between averaged K\n                      <jats:sub>trans<\/jats:sub>\n                      and global A\u03b2 pathology, but there was a trend for an Ab status by tau interaction on K\n                      <jats:sub>trans<\/jats:sub>\n                      in this region. SCCA showed increased K\n                      <jats:sub>trans<\/jats:sub>\n                      was associated with increased PiB DVR, mainly in temporal and parietal brain regions. There was not a significant relationship between K\n                      <jats:sub>trans<\/jats:sub>\n                      and FTP SUVR.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our findings indicate that the BBB shows regional vulnerability during normal aging that overlaps considerably with the pattern of AD pathology. Greater BBBp in brain regions affected in aging is related to APOE genotype and may also be related to the pathological accumulation of A\u03b2.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0299764","type":"journal-article","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T13:23:45Z","timestamp":1717593825000},"page":"e0299764","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":21,"title":["Associations between regional blood-brain barrier permeability, aging, and Alzheimer\u2019s disease biomarkers in cognitively normal older adults"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3696-3795","authenticated-orcid":true,"given":"Marisa","family":"Denkinger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Baker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Inglis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Juarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Mason","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Jagust","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,6,5]]},"reference":[{"key":"pone.0299764.ref001","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.neurobiolaging.2016.11.017","article-title":"Increased blood-brain barrier permeability is associated with dementia and diabetes but not amyloid pathology or APOE genotype","volume":"51","author":"S Janelidze","year":"2017","journal-title":"Neurobiol Aging"},{"key":"pone.0299764.ref002","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1111\/j.1600-0404.1990.tb01563.x","article-title":"Blood-brain barrier disturbance in patients with Alzheimer\u2019s disease is related to vascular factors","volume":"81","author":"K Blennow","year":"1990","journal-title":"Acta Neurol Scand"},{"key":"pone.0299764.ref003","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1038\/jcbfm.2013.135","article-title":"Blood\u2014Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer\u2019s Disease","volume":"33","author":"MA Erickson","year":"2013","journal-title":"J Cereb Blood Flow Metab"},{"key":"pone.0299764.ref004","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1111\/bpa.12004","article-title":"Deficiency in Mural Vascular Cells Coincides with Blood-Brain Barrier Disruption in Alzheimer\u2019s Disease: Pericytes in Alzheimer\u2019s Disease","volume":"23","author":"JD Sengillo","year":"2013","journal-title":"Brain Pathol"},{"key":"pone.0299764.ref005","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.nicl.2014.09.002","article-title":"Assessment of blood\u2014brain barrier disruption using dynamic contrast-enhanced MRI. A systematic review","volume":"6","author":"AK Heye","year":"2014","journal-title":"NeuroImage Clin"},{"key":"pone.0299764.ref006","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.neuron.2014.12.032","article-title":"Blood-Brain Barrier Breakdown in the Aging Human Hippocampus","volume":"85","author":"A Montagne","year":"2015","journal-title":"Neuron"},{"key":"pone.0299764.ref007","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1177\/0271678X20952012","article-title":"Hippocampal blood\u2014brain barrier permeability is related to the APOE4 mutation status of elderly individuals without dementia","volume":"41","author":"W-J Moon","year":"2021","journal-title":"J Cereb Blood Flow Metab"},{"key":"pone.0299764.ref008","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41591-018-0297-y","article-title":"Blood\u2014brain barrier breakdown is an early biomarker of human cognitive dysfunction","volume":"25","author":"DA Nation","year":"2019","journal-title":"Nat Med"},{"key":"pone.0299764.ref009","article-title":"Blood-brain barrier dysfunction in aging induces hyperactivation of TGFb signaling and chronic yet reversible neural dysfunction","volume":"15","author":"VVS Senatorov","year":"2019","journal-title":"Sci Transl Med"},{"key":"pone.0299764.ref010","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.pscychresns.2008.04.003","article-title":"Blood\u2014brain barrier permeability in Alzheimer\u2019s disease: a case\u2014control MRI study","volume":"171","author":"JM Starr","year":"2009","journal-title":"Psychiatry Res Neuroimaging"},{"key":"pone.0299764.ref011","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1148\/radiol.2016152244","article-title":"Blood-Brain Barrier Leakage in Patients with Early Alzheimer Disease","volume":"281","author":"HJ van de Haar","year":"2016","journal-title":"Radiology"},{"key":"pone.0299764.ref012","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1007\/s11357-020-00211-2","article-title":"(2020) Increase in blood\u2014brain barrier leakage in healthy, older adults","volume":"42","author":"ICM Verheggen","journal-title":"GeroScience"},{"key":"pone.0299764.ref013","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41586-020-2247-3","article-title":"APOE4 leads to blood\u2014brain barrier dysfunction predicting cognitive decline","volume":"581","author":"A Montagne","year":"2020","journal-title":"Nature"},{"key":"pone.0299764.ref014","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nrneurol.2017.188","article-title":"Blood\u2014brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders","volume":"14","author":"MD Sweeney","year":"2018","journal-title":"Nat Rev Neurol"},{"key":"pone.0299764.ref015","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1016\/j.jalz.2019.01.013","article-title":"Quantifying blood-brain barrier leakage in small vessel disease: Review and consensus recommendations","volume":"15","author":"MJ Thrippleton","year":"2019","journal-title":"Alzheimers Dement"},{"key":"pone.0299764.ref016","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/j.neuron.2016.01.028","article-title":"PET Imaging of Tau Deposition in the Aging Human Brain","volume":"89","author":"M Sch\u00f6ll","year":"2016","journal-title":"Neuron"},{"key":"pone.0299764.ref017","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s12880-015-0062-3","article-title":"ROCKETSHIP: a flexible and modular software tool for the planning, processing and analysis of dynamic MRI studies","volume":"15","author":"SR Barnes","year":"2015","journal-title":"BMC Med Imaging"},{"key":"pone.0299764.ref018","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/jcbfm.1983.1","article-title":"Graphical Evaluation of Blood-to-Brain Transfer Constants from Multiple-Time Uptake Data","volume":"3","author":"CS Patlak","year":"1983","journal-title":"J Cereb Blood Flow Metab"},{"key":"pone.0299764.ref019","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1038\/jcbfm.2014.126","article-title":"Accurate Determination of Blood\u2014Brain Barrier Permeability Using Dynamic Contrast-Enhanced T1-Weighted MRI: A Simulation and in vivo Study on Healthy Subjects and Multiple Sclerosis Patients","volume":"34","author":"SP Cramer","year":"2014","journal-title":"J Cereb Blood Flow Metab"},{"key":"pone.0299764.ref020","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.neuroimage.2015.10.018","article-title":"Tracer kinetic modelling for DCE-MRI quantification of subtle blood\u2014brain barrier permeability","volume":"125","author":"AK Heye","year":"2016","journal-title":"NeuroImage"},{"key":"pone.0299764.ref021","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/j.dib.2017.10.024","article-title":"Considerations and code for partial volume correcting [18F]-AV-1451 tau PET data","volume":"15","author":"SL Baker","year":"2017","journal-title":"Data Brief"},{"key":"pone.0299764.ref022","first-page":"904","article-title":"Correction for Partial Volume Effects in PET: Principle and Validation","volume":"39","author":"OG Rousset","year":"1997","journal-title":"J Nucl Med"},{"key":"pone.0299764.ref023","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1097\/00004647-199609000-00008","article-title":"Distribution Volume Ratios without Blood Sampling from Graphical Analysis of PET Data","volume":"16","author":"J Logan","year":"1996","journal-title":"J Cereb Blood Flow Metab"},{"key":"pone.0299764.ref024","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1016\/j.neuroimage.2011.07.098","article-title":"Not quite PIB-positive, not quite PIB-negative: Slight PIB elevations in elderly normal control subjects are biologically relevant","volume":"59","author":"EC Mormino","year":"2012","journal-title":"NeuroImage"},{"key":"pone.0299764.ref025","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1093\/brain\/awv112","article-title":"Existing Pittsburgh Compound-B positron emission tomography thresholds are too high: statistical and pathological evaluation","volume":"138","author":"S Villeneuve","year":"2015","journal-title":"Brain"},{"key":"pone.0299764.ref026","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.jalz.2016.08.005","article-title":"Defining imaging biomarker cut points for brain aging and Alzheimer\u2019s disease","volume":"13","author":"CR Jack","year":"2017","journal-title":"Alzheimers Dement"},{"key":"pone.0299764.ref027","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-662-45171-7","author":"WK H\u00e4rdle","year":"2015","journal-title":"Applied Multivariate Statistical Analysis"},{"key":"pone.0299764.ref028","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1093\/biomet\/28.3-4.321","article-title":"Relations Between Two Sets of Variates","volume":"28","author":"Harold Hotelling","year":"1936","journal-title":"Biometrika"},{"key":"pone.0299764.ref029","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1093\/biostatistics\/kxp008","article-title":"A penalized matrix decomposition, with applications to sparse principal components and canonical correlation analysis","volume":"10","author":"DM Witten","year":"2009","journal-title":"Biostatistics"},{"key":"pone.0299764.ref030","doi-asserted-by":"crossref","first-page":"eabc0655","DOI":"10.1126\/scitranslmed.abc0655","article-title":"The cortical origin and initial spread of medial temporal tauopathy in Alzheimer\u2019s disease assessed with positron emission tomography","volume":"13","author":"JS Sanchez","year":"2021","journal-title":"Sci Transl Med"},{"key":"pone.0299764.ref031","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neurobiolaging.2022.03.005","article-title":"Rates of \u03b2-amyloid deposition indicate widespread simultaneous accumulation throughout the brain","volume":"115","author":"MR LaPoint","year":"2022","journal-title":"Neurobiol Aging"},{"key":"pone.0299764.ref032","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological stageing of Alzheimer-related changes","volume":"82","author":"H Braak","year":"1991","journal-title":"Acta Neuropathol (Berl)"},{"key":"pone.0299764.ref033","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1002\/alz.12357","article-title":"Water exchange rate across the blood-brain barrier is associated with CSF amyloid-\u03b2 42 in healthy older adults","volume":"17","author":"BT Gold","year":"2021","journal-title":"Alzheimers Dement"},{"key":"pone.0299764.ref034","doi-asserted-by":"crossref","first-page":"1088140","DOI":"10.3389\/fnagi.2023.1088140","article-title":"Alzheimer\u2019s disease pathology: pathways between chronic vascular risk factors and blood-brain barrier dysfunction in a cohort of patients with different types of dementia","volume":"15","author":"J Gan","year":"2023","journal-title":"Front Aging Neurosci"},{"key":"pone.0299764.ref035","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1002\/ana.26134","article-title":"Blood\u2014Brain Barrier Breakdown in Relationship to Alzheimer and Vascular Disease","volume":"90","author":"Z Lin","year":"2021","journal-title":"Ann Neurol"},{"key":"pone.0299764.ref036","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1038\/nrneurol.2018.12","article-title":"BACE1 inhibitors block new A\u03b2 plaque formation","volume":"14","author":"C Ridler","year":"2018","journal-title":"Nat Rev Neurol"},{"key":"pone.0299764.ref037","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.neuropharm.2017.12.026","article-title":"Targeted inhibition of RAGE reduces amyloid-\u03b2 influx across the blood-brain barrier and improves cognitive deficits in db\/db mice","volume":"131","author":"H Wang","year":"2018","journal-title":"Neuropharmacology"},{"key":"pone.0299764.ref038","first-page":"463","article-title":"Blood-Brain Barrier Permeability Precedes Senile Plaque Formation in an Alzheimer Disease Model","volume":"10","author":"M Ujiie","year":"2003","journal-title":"Microcirculation"},{"key":"pone.0299764.ref039","doi-asserted-by":"crossref","first-page":"2932","DOI":"10.1038\/ncomms3932","article-title":"Pericyte loss influences Alzheimer-like neurodegeneration in mice","volume":"4","author":"AP Sagare","year":"2013","journal-title":"Nat Commun"},{"key":"pone.0299764.ref040","doi-asserted-by":"crossref","first-page":"3151","DOI":"10.1084\/jem.20171406","article-title":"Alzheimer\u2019s disease: A matter of blood\u2014brain barrier dysfunction?","volume":"214","author":"A Montagne","year":"2017","journal-title":"J Exp Med"},{"key":"pone.0299764.ref041","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s40478-015-0186-2","article-title":"Tau depletion prevents progressive blood-brain barrier damage in a mouse model of tauopathy","volume":"3","author":"LJ Blair","year":"2015","journal-title":"Acta Neuropathol Commun"},{"key":"pone.0299764.ref042","doi-asserted-by":"crossref","first-page":"2101462","DOI":"10.1002\/advs.202101462","article-title":"Modeling Sporadic Alzheimer\u2019s Disease in Human Brain Organoids under Serum Exposure","volume":"8","author":"X Chen","year":"2021","journal-title":"Adv Sci"},{"key":"pone.0299764.ref043","article-title":"Amyloid induced hyperexcitability in default mode network drives medial temporal hyperactivity and early tau accumulation","author":"J Giorgio","year":"2023","journal-title":"Neuron"},{"key":"pone.0299764.ref044","doi-asserted-by":"crossref","first-page":"6553","DOI":"10.1523\/JNEUROSCI.0023-23.2023","article-title":"Effect of Alzheimer\u2019s Pathology on Task-Related Brain Network Reconfiguration in Aging","volume":"43","author":"KE Cassady","year":"2023","journal-title":"J Neurosci"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0299764","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T13:24:12Z","timestamp":1717593852000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0299764"}},"subtitle":[],"editor":[{"given":"Tamlyn Julie","family":"Watermeyer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,6,5]]},"references-count":44,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,6,5]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0299764","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.02.16.580788","asserted-by":"object"}]},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,5]]}}}