Acta Neuropathologica

, Volume 115, Issue 1, pp 133–145

Pathological TDP-43 in parkinsonism–dementia complex and amyotrophic lateral sclerosis of Guam

  • Felix Geser
  • Matthew J. Winton
  • Linda K. Kwong
  • Yan Xu
  • Sharon X. Xie
  • Lionel M. Igaz
  • Ralph M. Garruto
  • Daniel P. Perl
  • Douglas Galasko
  • Virginia M.-Y. Lee
  • John Q. Trojanowski
Original Paper

DOI: 10.1007/s00401-007-0257-y

Cite this article as:
Geser, F., Winton, M.J., Kwong, L.K. et al. Acta Neuropathol (2008) 115: 133. doi:10.1007/s00401-007-0257-y

Abstract

Pathological TDP-43 is the major disease protein in frontotemporal lobar degeneration characterized by ubiquitin inclusions (FTLD-U) with/without motor neuron disease (MND) and in amyotrophic lateral sclerosis (ALS). As Guamanian parkinsonism–dementia complex (PDC) or Guamanian ALS (G-PDC or G-ALS) of the Chamorro population may present clinically similar to FTLD-U and ALS, TDP-43 pathology may be present in the G-PDC and G-ALS. Thus, we examined cortical or spinal cord samples from 54 Guamanian subjects for evidence of TDP-43 pathology. In addition to cortical neurofibrillary and glial tau pathology, G-PDC was associated with cortical TDP-43 positive dystrophic neurites and neuronal and glial inclusions in gray and/or white matter. Biochemical analyses showed the presence of FTLD-U-like insoluble TDP-43 in G-PDC, but not in Guam controls (G-C). Spinal cord pathology of G-PDC or G-ALS was characterized by tau positive tangles as well as TDP-43 positive inclusions in lower motor neurons and glial cells. G-C had variable tau and negligible TDP-43 pathology. These results indicate that G-PDC and G-ALS are associated with pathological TDP-43 similar to FTLD-U with/without MND as well as ALS, and that neocortical or hippocampal TDP-43 pathology distinguishes controls from disease subjects better than tau pathology. Finally, we conclude that the spectrum of TDP-43 proteinopathies should be expanded to include neurodegenerative cognitive and motor diseases, affecting the Chamorro population of Guam.

Keywords

Parkinsonism–dementia complexAmyotrophic lateral sclerosisGuamTDP-43

Supplementary material

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Felix Geser
    • 1
  • Matthew J. Winton
    • 1
  • Linda K. Kwong
    • 1
  • Yan Xu
    • 1
  • Sharon X. Xie
    • 2
  • Lionel M. Igaz
    • 1
  • Ralph M. Garruto
    • 3
  • Daniel P. Perl
    • 4
  • Douglas Galasko
    • 5
  • Virginia M.-Y. Lee
    • 1
  • John Q. Trojanowski
    • 1
  1. 1.Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Alzheimer’s Disease Core Center, Institute on AgingUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  2. 2.Department of Biostatistics and EpidemiologyUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  3. 3.Department of Anthropology and Biological SciencesState University of New York at BinghamtonBinghamtonUSA
  4. 4.Department of PathologyMt. Sinai School of MedicineNew YorkUSA
  5. 5.Department of NeurologyUniversity of California at San DiegoSan DiegoUSA