Elisa de Paula França Resende1, Amber L Nolan1, Cathrine Petersen1, Alexander J Ehrenberg1, Salvatore Spina1, Isabel E Allen1, Howard J Rosen1, Joel Kramer1, Bruce L Miller1, William W Seeley1, Maria Luiza Gorno-Tempini1, Zachary Miller1, Lea T Grinberg2. 1. From the Memory and Aging Center (E.d.P.F.R., A.L.N., C.P., A.J.E., S.S., I.E.A., H.J.R., J.K., B.L.M., W.W.S., M.L.G.-T., Z.M., L.T.G.), Weill Institute for Neurosciences, and Department of Biostatistics and Epidemiology (L.T.G.), University of California, San Francisco; Global Brain Health Institute based at University of California (E.d.P.F.R., L.T.G.), San Francisco; Trinity College (E.d.P.F.R., L.T.G.), Dublin, Ireland; Department of Neurology (E.d.P.F.R.), Federal University of Minas Gerais, Belo Horizonte, Brazil; Department of Integrative Biology (A.J.E.), University of California, Berkeley; and Department of Pathology (L.T.G.), Lim-22, Lim-66, University of Sao Paulo Medical School, Sao Paulo, Brazil. 2. From the Memory and Aging Center (E.d.P.F.R., A.L.N., C.P., A.J.E., S.S., I.E.A., H.J.R., J.K., B.L.M., W.W.S., M.L.G.-T., Z.M., L.T.G.), Weill Institute for Neurosciences, and Department of Biostatistics and Epidemiology (L.T.G.), University of California, San Francisco; Global Brain Health Institute based at University of California (E.d.P.F.R., L.T.G.), San Francisco; Trinity College (E.d.P.F.R., L.T.G.), Dublin, Ireland; Department of Neurology (E.d.P.F.R.), Federal University of Minas Gerais, Belo Horizonte, Brazil; Department of Integrative Biology (A.J.E.), University of California, Berkeley; and Department of Pathology (L.T.G.), Lim-22, Lim-66, University of Sao Paulo Medical School, Sao Paulo, Brazil. lea.grinberg@ucsf.edu.
Abstract
OBJECTIVES: Alzheimer disease (AD) shows a broad array of clinical presentations, but the mechanisms underlying these phenotypic variants remain elusive. Aging-related astrogliopathy (ARTAG) is a relatively recent term encompassing a broad array of tau deposition in astroglia outside the range of traditional tauopathies. White matter thorn-shaped astrocyte (WM-TSA) clusters, a specific ARTAG subtype, has been associated with atypical language presentation of AD in a small study lacking replication. To interrogate the impact of WM-TSA in modifying clinical phenotype in AD, we investigated a clinicopathologic sample of 83 persons with pure cortical AD pathology and heterogeneous clinical presentations. METHODS: We mapped WM-TSA presence and density throughout cortical areas and interrogated whether WM-TSA correlated with atypical AD presentation or worse performance in neuropsychological testing. RESULTS: WM-TSA was present in nearly half of the cases and equally distributed in typical and atypical AD presentations. Worsening language and visuospatial functions were correlated with higher WM-TSA density in language-related and visuospatial-related regions, respectively. These findings were unrelated to regional neurofibrillary tangle burden. Next, unsupervised clustering divided the participants into 2 groups: a high-WM-TSA (n = 9) and low-WM-TSA (n = 74) pathology signature. The high-WM-TSA group scored significantly worse in language but not in other cognitive domains. CONCLUSIONS: The negative impact of WM-TSA pathology to language and possibly visuospatial networks suggests that WM-TSA is not as benign as other ARTAG types and may be explored as a framework to understand the mechanisms and impact of astrocytic tau deposition in AD in humans.
OBJECTIVES:Alzheimer disease (AD) shows a broad array of clinical presentations, but the mechanisms underlying these phenotypic variants remain elusive. Aging-related astrogliopathy (ARTAG) is a relatively recent term encompassing a broad array of tau deposition in astroglia outside the range of traditional tauopathies. White matter thorn-shaped astrocyte (WM-TSA) clusters, a specific ARTAG subtype, has been associated with atypical language presentation of AD in a small study lacking replication. To interrogate the impact of WM-TSA in modifying clinical phenotype in AD, we investigated a clinicopathologic sample of 83 persons with pure cortical AD pathology and heterogeneous clinical presentations. METHODS: We mapped WM-TSA presence and density throughout cortical areas and interrogated whether WM-TSA correlated with atypical AD presentation or worse performance in neuropsychological testing. RESULTS: WM-TSA was present in nearly half of the cases and equally distributed in typical and atypical AD presentations. Worsening language and visuospatial functions were correlated with higher WM-TSA density in language-related and visuospatial-related regions, respectively. These findings were unrelated to regional neurofibrillary tangle burden. Next, unsupervised clustering divided the participants into 2 groups: a high-WM-TSA (n = 9) and low-WM-TSA (n = 74) pathology signature. The high-WM-TSA group scored significantly worse in language but not in other cognitive domains. CONCLUSIONS: The negative impact of WM-TSA pathology to language and possibly visuospatial networks suggests that WM-TSA is not as benign as other ARTAG types and may be explored as a framework to understand the mechanisms and impact of astrocytic tau deposition in AD in humans.
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