title: Typical and atypical pathology in primary progressive aphasia variants.
abstract: OBJECTIVE
  To characterize in vivo signatures of pathological diagnosis in a large cohort of patients with primary progressive aphasia (PPA) variants defined by current diagnostic classification.
  
  
  METHODS
  Extensive clinical, cognitive, neuroimaging, and neuropathological data were collected from 69 patients with sporadic PPA, divided into 29 semantic (svPPA), 25 nonfluent (nfvPPA), 11 logopenic (lvPPA), and 4 mixed PPA. Patterns of gray matter (GM) and white matter (WM) atrophy at presentation were assessed and tested as predictors of pathological diagnosis using support vector machine (SVM) algorithms.
  
  
  RESULTS
  A clinical diagnosis of PPA was associated with frontotemporal lobar degeneration (FTLD) with transactive response DNA-binding protein (TDP) inclusions in 40.5%, FTLD-tau in 40.5%, and Alzheimer disease (AD) pathology in 19% of cases. Each variant was associated with 1 typical pathology; 24 of 29 (83%) svPPA showed FTLD-TDP type C, 22 of 25 (88%) nfvPPA showed FTLD-tau, and all 11 lvPPA had AD. Within FTLD-tau, 4R-tau pathology was commonly associated with nfvPPA, whereas Pick disease was observed in a minority of subjects across all variants except for lvPPA. Compared with pathologically typical cases, svPPA-tau showed significant extrapyramidal signs, greater executive impairment, and severe striatal and frontal GM and WM atrophy. nfvPPA-TDP patients lacked general motor symptoms or significant WM atrophy. Combining GM and WM volumes, SVM analysis showed 92.7% accuracy to distinguish FTLD-tau and FTLD-TDP pathologies across variants.
  
  
  CONCLUSIONS
  Each PPA clinical variant is associated with a typical and most frequent cognitive, neuroimaging, and neuropathological profile. Specific clinical and early anatomical features may suggest rare and atypical pathological diagnosis in vivo. Ann Neurol 2017;81:430-443.
authors.affiliation: Memory and Aging Center, University of California, San Francisco, San Francisco, CA.|Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Edoardo G
authors.initials: EG
authors.lastname: Spinelli
authors.affiliation: Memory and Aging Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Mandelli
authors.affiliation: Memory and Aging Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Miller
authors.affiliation: Memory and Aging Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Santos-Santos
authors.affiliation: Memory and Aging Center, University of California, San Francisco, San Francisco, CA.|Department of Hearing and Speech Sciences, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Wilson
authors.affiliation: Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Agosta
authors.affiliation: Memory and Aging Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Lea T
authors.initials: LT
authors.lastname: Grinberg
authors.affiliation: Memory and Aging Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Memory and Aging Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Marita
authors.initials: M
authors.lastname: Meyer
authors.affiliation: Department of Communication Sciences and Disorders, University of Texas, Austin, TX.
authors.forename: Maya L
authors.initials: ML
authors.lastname: Henry
authors.affiliation: Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.affiliation: Memory and Aging Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Gil
authors.initials: G
authors.lastname: Rabinovici
authors.affiliation: Memory and Aging Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Rosen
authors.affiliation: Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Filippi
authors.affiliation: Memory and Aging Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Memory and Aging Center, University of California, San Francisco, San Francisco, CA.
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
authors.affiliation: Memory and Aging Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Gorno-Tempini
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000145:classification / Q000473:pathology / Q000503:physiopathology; D018888:Aphasia, Primary Progressive / Q000145:classification / Q000473:pathology / Q000503:physiopathology; D001284:Atrophy / Q000473:pathology; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000145:classification / Q000473:pathology / Q000503:physiopathology; D066128:Gray Matter / Q000000981:diagnostic imaging*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020774:Pick Disease of the Brain / Q000473:pathology / Q000503:physiopathology; D057178:Primary Progressive Nonfluent Aphasia / Q000473:pathology / Q000503:physiopathology; D060388:Support Vector Machine; D066127:White Matter / Q000000981:diagnostic imaging*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016875:tau Proteins