TDP-43 pathologic lesions and clinical phenotype in frontotemporal lobar degeneration with ubiquitin-positive inclusions

Arch Neurol. 2007 Oct;64(10):1449-54. doi: 10.1001/archneur.64.10.1449.


Background: TDP-43 is a major ubiquitinated disease protein in the pathologic condition of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U).

Objective: To investigate the demographic, clinical, and neuropsychological features associated with subtypes of FTLD-U with TDP-43 inclusions (FTLD-U/TDP-43).

Design: Retrospective clinical-pathologic study.

Setting: Academic medical center. Patients Twenty-three patients with histopathologically proven FTLD-U.

Main outcome measures: Demographic, symptom, neuropsychological, and autopsy characteristics.

Results: There are notably different clinical and neuropsychological patterns of impairment in FTLD-U subtypes. Patients with FTLD-U/TDP-43 characterized by numerous neuronal intracytoplasmic inclusions have shorter survival; patients with FTLD-U/TDP-43 featuring numerous neurites have difficulty with object naming; and patients with FTLD-U/TDP-43 in whom neuronal intranuclear inclusions are present have substantial executive deficits. There are also different anatomical distributions of ubiquitin pathologic features in FTLD-U subgroups, consistent with their cognitive deficits.

Conclusion: Distinct TDP-43 profiles may affect clinical phenotypes differentially in patients with FTLD-U.

Publication types

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

MeSH terms

  • Aged
  • Autopsy
  • Brain / pathology
  • Cognition / physiology
  • DNA-Binding Proteins / genetics*
  • Data Interpretation, Statistical
  • Dementia / genetics*
  • Dementia / pathology*
  • Dementia / psychology
  • Female
  • Humans
  • Immunohistochemistry
  • Inclusion Bodies / genetics*
  • Inclusion Bodies / pathology*
  • Male
  • Middle Aged
  • Neuropsychological Tests
  • Phenotype
  • Psychomotor Performance / physiology
  • Retrospective Studies
  • Ubiquitin / metabolism*


  • DNA-Binding Proteins
  • Ubiquitin