Typical and atypical pathology in primary progressive aphasia variants

Ann Neurol. 2017 Mar;81(3):430-443. doi: 10.1002/ana.24885. Epub 2017 Mar 20.


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.

Interpretation: 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.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease* / classification
  • Alzheimer Disease* / pathology
  • Alzheimer Disease* / physiopathology
  • Aphasia, Primary Progressive* / classification
  • Aphasia, Primary Progressive* / pathology
  • Aphasia, Primary Progressive* / physiopathology
  • Atrophy / pathology
  • Female
  • Frontotemporal Lobar Degeneration* / classification
  • Frontotemporal Lobar Degeneration* / pathology
  • Frontotemporal Lobar Degeneration* / physiopathology
  • Gray Matter / diagnostic imaging*
  • Humans
  • Male
  • Middle Aged
  • Pick Disease of the Brain / pathology
  • Pick Disease of the Brain / physiopathology
  • Primary Progressive Nonfluent Aphasia / pathology
  • Primary Progressive Nonfluent Aphasia / physiopathology
  • Support Vector Machine
  • White Matter / diagnostic imaging*
  • tau Proteins / metabolism


  • tau Proteins