Combined Pathologies in FTLD-TDP Types A and C

J Neuropathol Exp Neurol. 2018 May 1;77(5):405-412. doi: 10.1093/jnen/nly018.

Abstract

This study investigated the presence of combined pathologies in a large cohort of autopsies that show a primary pathologic diagnosis of phosphorylated 43-kDa TAR DNA-binding protein (FTLD-TDP), the majority of which portrayed clinical phenotypes consistent with primary progressive aphasia or behavioral variant frontotemporal dementia (bvFTD). Thirty-eight cases with FTLD-TDP (30 type-A and 8 type-C) were identified to determine characteristic differences between cases with and without combined pathologies. Findings indicated that combined pathologies co-occur with FTLD-TDP type-A at a high frequency (50%)-greater than when compared to FTLD-TDP type-C cases (12.5%). Those with FTLD-TDP type-A and combined pathologies showed significantly longer lifespans (p < 0.05), and longer disease durations (p < 0.05), than those with only FTLD-TDP type-A. Cases with FTLD-TDP type-A and known genetic mutations tended not to show combined pathology. Those with the GRN mutation and FTLD-TDP type-A showed a significantly younger age of onset (p < 0.05) and younger age at death (p < 0.01) compared to noncarriers. In 1 bvFTD case, we highlight the rare presence of "triple" FTLD-TDP type-A, FTLD-tau, and Alzheimer pathology. The ante- and post-mortem features associated with combined pathologies in FTLD-related disorders are of useful consideration in the stratification of patients to drug trials, and in the development of therapeutic targets for FTLD.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Aged
  • Aged, 80 and over
  • Aphasia, Primary Progressive / genetics
  • Aphasia, Primary Progressive / pathology
  • DNA-Binding Proteins / genetics
  • Female
  • Frontotemporal Dementia / complications
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / pathology*
  • Frontotemporal Lobar Degeneration / complications
  • Frontotemporal Lobar Degeneration / genetics
  • Frontotemporal Lobar Degeneration / pathology*
  • Heterozygote
  • Humans
  • Longevity
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Positron-Emission Tomography
  • Progranulins / genetics
  • Tauopathies / complications
  • Tauopathies / genetics
  • Tauopathies / pathology*

Substances

  • DNA-Binding Proteins
  • GRN protein, human
  • Progranulins
  • TARDBP protein, human