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Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases

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Abstract

Here, we investigated if TAR-DNA-binding protein-43 (TDP-43), the disease protein in frontotemporal lobar degeneration and ubiquitin inclusions with or without motor neuron disease as well as amyotrophic lateral sclerosis, also formed inclusions in Lewy body (LB) disorders including Parkinson’s disease (PD) without or with dementia (PDD), and dementia with LBs (DLB) alone or in association with Alzheimer’s disease (AD). Immunohistochemical analyses of TDP-43 in clinically well characterized and pathologically confirmed cases of DLB + AD, PD and PDD demonstrated TDP-43 pathology in the following percentage of cases: DLB + AD = 25/80 (31.3%); PD = 5/69 (7.2%); PDD = 4/21 (19%), while DLB and normal controls exhibited no (0/10, 0%) and one cases (1/33, 3%) presenting TDP-43 pathology, respectively. Significant differences in the prevalence of TDP-43 lesions were noted between disease versus normal brains (P < 0.001) as well as demented versus non-demented brains (P < 0.001). Statistical analyses revealed a positive relationship between TDP-43 lesions and several clinical and pathological parameters in these disorders suggesting the TDP-43 pathology may have co-morbid effects in LB diseases. This study expands the concept of TDP-43 proteinopathies by implicating TDP-43 lesions in mechanisms of neurodegeneration in LB disorders.

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Acknowledgments

We thank colleagues for technical support and advice in the Center for Neurodegenerative Disease Research. We thank the families of patients whose generosity made this research possible. This work was supported by grants from the National Institutes of Health (AG-09215, AG-10124, AG-17586). V.M.-Y.L. is the John H. Ware III Professor of Alzheimer’s disease research; and J.Q.T. is the William Maul Measey-Truman G. Schnabel Jr, Professor of Geriatric Medicine and Gerontology.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, HUP/Maloney 3rd Floor, Philadelphia, PA, 19104-4283, USA

    Hanae Nakashima-Yasuda, Kunihiro Uryu, John Robinson, Virginia M. -Y. Lee & John Q. Trojanowski

  2. Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    John Q. Trojanowski

  3. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Howard Hurtig, John E. Duda, Andrew Siderowf, Murray Grossman & Christopher M. Clark

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

    Sharon X. Xie

  5. Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Steven E. Arnold

  6. Parkinson’s Disease Research, Education and Clinical Center, Philadelphia VAMC, Philadelphia, PA, USA

    John E. Duda

  7. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA

    James B. Leverenz & Debby W. Tsuang

  8. Department of Neurology, University of Washington, Seattle, WA, USA

    James B. Leverenz

  9. Department of Pathology, University of Washington, Seattle, WA, USA

    Randy Woltjer & Thomas J. Montine

  10. Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA

    James B. Leverenz

  11. Parkinson’s Disease Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA

    James B. Leverenz & Debby W. Tsuang

  12. Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA

    Oscar L. Lopez

  13. Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA

    Ronald Hamilton

  14. Department of Neuroscience, University of California-San Diego, San Diego, CA, USA

    Douglas Galasko & Eliezer Masliah

  15. Department of Pathology, University of California-San Diego, San Diego, CA, USA

    Eliezer Masliah

  16. Department of Neurology, Oregon Health & Sciences University, Portland, OR, USA

    Jeffrey Kaye

Authors
  1. Hanae Nakashima-Yasuda
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  2. Kunihiro Uryu
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  3. John Robinson
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  4. Sharon X. Xie
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  6. John E. Duda
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  9. Murray Grossman
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  10. James B. Leverenz
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  11. Randy Woltjer
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  12. Oscar L. Lopez
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  13. Ronald Hamilton
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  14. Debby W. Tsuang
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  15. Douglas Galasko
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  16. Eliezer Masliah
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  17. Jeffrey Kaye
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  18. Christopher M. Clark
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  19. Thomas J. Montine
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  20. Virginia M. -Y. Lee
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  21. John Q. Trojanowski
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Corresponding author

Correspondence to John Q. Trojanowski.

Additional information

Hanae Nakashima-Yasuda and Kunihiro Uryu are equally contributed first authors.

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Nakashima-Yasuda, H., Uryu, K., Robinson, J. et al. Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol 114, 221–229 (2007). https://doi.org/10.1007/s00401-007-0261-2

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  • DOI: https://doi.org/10.1007/s00401-007-0261-2

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