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Deep clinical and neuropathological phenotyping of P ick disease
Author(s) -
Irwin David J.,
Brettschneider Johannes,
McMillan Corey T.,
Cooper Felicia,
Olm Christopher,
Arnold Steven E.,
Van Deerlin Vivianna M.,
Seeley William W.,
Miller Bruce L.,
Lee Edward B.,
Lee Virginia M.Y.,
Grossman Murray,
Trojanowski John Q.
Publication year - 2016
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24559
Subject(s) - neuropathology , pathology , white matter , frontotemporal dementia , tauopathy , tau protein , frontotemporal lobar degeneration , limbic system , neuroscience , psychology , alzheimer's disease , dementia , medicine , neurodegeneration , magnetic resonance imaging , disease , central nervous system , radiology
Objective To characterize sequential patterns of regional neuropathology and clinical symptoms in a well‐characterized cohort of 21 patients with autopsy‐confirmed Pick disease. Methods Detailed neuropathological examination using 70μm and traditional 6μm sections was performed using thioflavin‐S staining and immunohistochemistry for phosphorylated tau, 3R and 4R tau isoforms, ubiquitin, and C‐terminally truncated tau. Patterns of regional tau deposition were correlated with clinical data. In a subset of cases (n = 5), converging evidence was obtained using antemortem neuroimaging measures of gray and white matter integrity. Results 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–positive and 4R tau–negative in sporadic cases. There was a relative abundance of mature tau pathology markers in frontotemporal limbic/paralimbic regions compared to neocortical regions. Interpretation 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‐mediated neurodegeneration. Ann Neurol 2016;79:272–287