title: Deep clinical and neuropathological phenotyping of Pick disease.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Pennsylvania Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA.|Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Irwin
authors.affiliation: Department of Neurology, Herford Hospital, Herford, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Brettschneider
authors.affiliation: University of Pennsylvania Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA.
authors.forename: Corey T
authors.initials: CT
authors.lastname: McMillan
authors.affiliation: University of Pennsylvania Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA.|Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Felicia
authors.initials: F
authors.lastname: Cooper
authors.affiliation: University of Pennsylvania Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Olm
authors.affiliation: Brain-Behavior Laboratory, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Arnold
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.affiliation: Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA.
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
authors.affiliation: Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.|Translational Neuropathology Research Laboratory, University of Pennsylvania, Philadelphia, PA.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Lee
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.affiliation: University of Pennsylvania Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA.
authors.forename: Murray
authors.initials: M
authors.lastname: Grossman
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D052160:Benzothiazoles; D002540:Cerebral Cortex / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008032:Limbic System / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020774:Pick Disease of the Brain / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D013194:Staining and Labeling; D013844:Thiazoles; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D052160:Benzothiazoles; C054369:MAPT protein, human; D013844:Thiazoles; D016875:tau Proteins; C009462:thioflavin T