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

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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.

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Acknowledgments

The authors would like to thank T. Schuck, A. Truax, M. Getahun, J. Robinson, J. McBride, and N. Camacho for their expert technical assistance. Further, they thank their patients and families and the dedicated efforts of the research team at the University of Guam who made this research possible. This work was funded by the National Institutes of Health (AG10124, AG17586, AG14382).

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Authors and Affiliations

  1. Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Alzheimer’s Disease Core Center, Institute on Aging, University of Pennsylvania School of Medicine, HUP, Maloney 3rd Floor, 36th and Spruce Streets, Philadelphia, PA, 19104-4283, USA

    Felix Geser, Matthew J. Winton, Linda K. Kwong, Yan Xu, Lionel M. Igaz, Virginia M.-Y. Lee & John Q. Trojanowski

  2. Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Sharon X. Xie

  3. Department of Anthropology and Biological Sciences, State University of New York at Binghamton, Binghamton, NY, USA

    Ralph M. Garruto

  4. Department of Pathology, Mt. Sinai School of Medicine, New York, NY, USA

    Daniel P. Perl

  5. Department of Neurology, University of California at San Diego, San Diego, CA, USA

    Douglas Galasko

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  1. Felix Geser
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  2. Matthew J. Winton
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  10. Virginia M.-Y. Lee
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Correspondence to John Q. Trojanowski.

Additional information

VM-YL is the John H. Ware III Chair of Alzheimer’s Research and JQT is the William Maul Measey-Truman G. Schnabel, Jr., MD, Professor of Geriatric Medicine and Gerontology.

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Geser, F., Winton, M.J., Kwong, L.K. et al. Pathological TDP-43 in parkinsonism–dementia complex and amyotrophic lateral sclerosis of Guam. Acta Neuropathol 115, 133–145 (2008). https://doi.org/10.1007/s00401-007-0257-y

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  • DOI: https://doi.org/10.1007/s00401-007-0257-y

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