{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T01:36:08Z","timestamp":1789263368656,"version":"build-2803163510"},"reference-count":75,"publisher":"Oxford University Press (OUP)","issue":"3","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\/100000049","name":"National institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Washington Alzheimer's Disease Research Centre","award":["P30 AG066509"],"award-info":[{"award-number":["P30 AG066509"]}]},{"name":"Adult Changes in Thought study","award":["U19 AG066567"],"award-info":[{"award-number":["U19 AG066567"]}]},{"name":"Johns Hopkins Alzheimer\u2019s Disease Research Centre","award":["P30 AG066507"],"award-info":[{"award-number":["P30 AG066507"]}]},{"name":"Johns Hopkins Alzheimer\u2019s Disease Research Centre","award":["K08 AG065426"],"award-info":[{"award-number":["K08 AG065426"]}]},{"DOI":"10.13039\/100007512","name":"Nancy and Buster Alvord Endowment","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007512","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Despite the presence of significant Alzheimer's disease pathology, characterized by amyloid \u03b2 (A\u03b2) plaques and phosphorylated tau (pTau) tangles, some cognitively unimpaired elderly individuals do not inevitably develop dementia. Cortical astroglial inflammation, a ubiquitous feature of symptomatic Alzheimer's disease, shows a strong correlation with cognitive impairment severity, highlighting the influence of factors beyond classical pathology. However, non-invasively imaging neuroinflammation, particularly astrogliosis, using MRI remains a significant challenge. Here we sought to address this challenge and to leverage multidimensional (MD) MRI, a powerful approach that combines relaxation with diffusion MR contrasts, to map cortical astrogliosis in the human brain by accessing sub-voxel information. Our goal was to investigate whether MD-MRI can map astroglial pathology in the cerebral cortex, and if so, whether it can distinguish cognitively normal state from dementia in the presence of hallmark Alzheimer's disease neuropathological changes. We adopted a multimodal approach by integrating histological and MRI analyses using human postmortem brain samples from two independent discovery and replication cohorts. Ex vivo cerebral cortical tissue specimens were derived from two groups\u2014non-demented individuals with varying levels of postmortem Alzheimer's disease pathology and individuals with both Alzheimer's disease pathology and dementia\u2014and scanned using 7 T MRI. We acquired and processed MD-MRI, diffusion tensor, and quantitative T1 and T2 MRI data, followed by histopathology on the same tissue. By co-registering MRI and microscopy data, we performed quantitative multimodal analyses, leveraging targeted immunostaining to assess MD-MRI sensitivity and specificity towards A\u03b2, pTau, and glial fibrillary acidic protein (GFAP), a marker for astrogliosis. Our discovery analysis reveals a distinct MD-MRI signature of cortical astrogliosis, enabling the creation of predictive maps for cognitive state amid Alzheimer's disease neuropathological changes. Multiple linear regression analysis linked histological values to MRI changes, revealing that the MD-MRI cortical astrogliosis biomarker was significantly associated with GFAP burden (standardized \u03b2 = 0.658\/0.709, pFDR &amp;lt; 0.0001), but not with A\u03b2 (standardized \u03b2 = 0.009\/0.120, pFDR = 0.913\/0.274) or pTau (standardized \u03b2 = \u22120.196\/0.158, pFDR = 0.051\/0.251), for the discovery\/replication groups, respectively. Conversely, none of the conventional MRI parameters showed significant associations with GFAP burden in the cortex. Finally, we showed that the MD-MRI-derived astrogliosis biomarker is the only MRI measure capable of predicting cognitive state. While the extent to which pathological glial activation contributes to neuronal damage and cognitive impairment in Alzheimer's disease is uncertain, developing a non-invasive imaging method to see its effects holds promise from a mechanistic perspective and as a potential predictor of cognitive outcomes.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaf245","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T12:34:57Z","timestamp":1751027697000},"source":"Crossref","is-referenced-by-count":10,"title":["Multidimensional MRI reveals cortical astrogliosis linked to dementia in Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8135-5590","authenticated-orcid":false,"given":"Stephanie","family":"Barsoum","sequence":"first","affiliation":[{"name":"Multiscale Imaging and Integrative Biophysics Unit, Laboratory of Behavioral Neuroscience, National Institute on Aging, NIH , 251 Bayview Blvd., Baltimore, MD 21224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin S","family":"Latimer","sequence":"additional","affiliation":[{"name":"Division of Neuropathology, Department of Pathology, University of Washington , Seattle, WA 98104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber L","family":"Nolan","sequence":"additional","affiliation":[{"name":"Division of Neuropathology, Department of Pathology, University of Washington , Seattle, WA 98104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Barrett","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, MD 21205 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7873-3640","authenticated-orcid":false,"given":"Koping","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, MD 21205 ,","place":["USA"]},{"name":"Department and Graduate Institute of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine , Taipei 100225 ,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan C","family":"Troncoso","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, MD 21205 ,","place":["USA"]},{"name":"Department of Neurology, Johns Hopkins University School of Medicine , Baltimore, MD 21205 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C Dirk","family":"Keene","sequence":"additional","affiliation":[{"name":"Division of Neuropathology, Department of Pathology, University of Washington , Seattle, WA 98104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Benjamini","sequence":"additional","affiliation":[{"name":"Multiscale Imaging and Integrative Biophysics Unit, Laboratory of Behavioral Neuroscience, National Institute on Aging, NIH , 251 Bayview Blvd., Baltimore, MD 21224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,6,18]]},"reference":[{"issue":"12","key":"2025062708352492700_fcaf245-B1","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1002\/alz.12362","article-title":"Population estimate of people with clinical Alzheimer\u2019s disease and mild cognitive impairment in the United States (2020\u20132060)","volume":"17","author":"Rajan","year":"2021","journal-title":"Alzheimers 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