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In a subset of cases (n = 5), converging evidence was obtained using antemortem neuroimaging measures of gray and white matter integrity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Four sequential patterns of pathological tau deposition were identified starting in frontotemporal limbic\/paralimbic and neocortical regions (phase I). Sequential involvement was seen in subcortical structures, including basal ganglia, locus coeruleus, and raphe nuclei (phase II), followed by primary motor cortex and precerebellar nuclei (phase III) and finally visual cortex in the most severe (phase IV) cases. Behavioral variant frontotemporal dementia was the predominant clinical phenotype (18 of 21), but all patients eventually developed a social comportment disorder. Pathological tau phases reflected the evolution of clinical symptoms and degeneration on serial antemortem neuroimaging, directly correlated with disease duration and inversely correlated with brain weight at autopsy. The majority of neuronal and glial tau inclusions were 3R tau\u2013positive and 4R tau\u2013negative in sporadic cases. There was a relative abundance of mature tau pathology markers in frontotemporal limbic\/paralimbic regions compared to neocortical regions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Pick disease tau neuropathology may originate in limbic\/paralimbic cortices. The patterns of tau pathology observed here provide novel insights into the natural history and biology of tau\u2010mediated neurodegeneration. Ann Neurol 2016;79:272\u2013287<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.24559","type":"journal-article","created":{"date-parts":[[2015,11,19]],"date-time":"2015-11-19T23:02:39Z","timestamp":1447974159000},"page":"272-287","source":"Crossref","is-referenced-by-count":209,"title":["Deep clinical and neuropathological phenotyping of <scp>P<\/scp>ick disease"],"prefix":"10.1002","volume":"79","author":[{"given":"David J.","family":"Irwin","sequence":"first","affiliation":[{"name":"University of Pennsylvania Frontotemporal Degeneration Center, Department of Neurology University of Pennsylvania Philadelphia PA"},{"name":"Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine University of Pennsylvania Philadelphia PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Brettschneider","sequence":"additional","affiliation":[{"name":"Department of Neurology Herford Hospital Herford 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