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Effect of topographical distribution of α-synuclein pathology on TDP-43 accumulation in Lewy body disease

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Abstract

It has been reported that the development of TDP-43 pathology in cases of Lewy body disease (LBD) might be associated with the severity of tau pathology. However, the impact of α-synuclein pathology on TDP-43 accumulation in LBD remains unclear. To clarify whether α-synuclein pathology has an effect on TDP-43 accumulation, independent of tau pathology, we examined by immunohistochemistry 56 cases of LBD using a phosphorylation-dependent TDP-43 antibody. The frequency of TDP-43 pathology in all LBD cases was 18% (10/56). In 37 LBD cases with no or low tau burden (LBD-Ltau; Braak NFT stages 0-II), the frequency of TDP-43 pathology was 19% (7/37). The frequency of TDP-43 pathology in diffuse neocortical type LBD-Ltau cases was 36% (4/11), which was higher than those in limbic and brain stem-predominant types (11–14%). The amygdala and entorhinal cortex were the most frequently affected sites of TDP-43 pathology in LBD-Ltau cases. In LBD-Ltau cases, the proportion of diffuse neocortical type LBD was higher in the TDP-43-positive cases, than that in TDP-43-negative cases (57 vs. 23%). In all LBD cases, α-synuclein pathology in the temporal cortex was significantly more severe in TDP-43-positive cases, and significantly correlated with the severity of TDP-43 pathology in the amygdala. In a multivariate model, the presence of severe α-synuclein pathology was significantly associated with the development of TDP-43 pathology independent of age at death and tau pathology. In the amygdala, TDP-43 was often colocalized with α-synuclein or tau. Given these findings, we suggest that α-synuclein pathology is associated with TDP-43 accumulation in LBD cases.

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Acknowledgments

We would like to thank Dr. F. Higaki (Department of Radiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences) for the statistical analysis, Ms. M. Onbe (Department of Neuropsychiatry. Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences) for their excellent technical assistance. We also acknowledge and thank the Parkinson’s Disease Society UK Brain Bank for making available tissue samples for this study. This study was supported in part by a research grant from the Uehara Memorial Foundation.

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Authors and Affiliations

  1. Neurodegeneration and Mental Health Research Group, Faculty of Medical and Human Sciences, School of Community Based Medicine, Greater Manchester Neurosciences Centre, Hope Hospital, University of Manchester, Salford, M6 8HD, UK

    Osamu Yokota, Yvonne Davidson & David M. A. Mann

  2. Neurodegeneration and Mental Health Research Group, Faculty of Medical and Human Sciences, School of Community Based Medicine, A V Hill Building, University of Manchester, Oxford Rd, Manchester, M13 9PL, UK

    Stephen Sikkink & Stuart Pickering-Brown

  3. Department of Psychogeriatrics, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo, 156-8585, Japan

    Tetsuaki Arai & Haruhiko Akiyama

  4. Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo, 156-8585, Japan

    Masato Hasegawa

  5. Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan

    Osamu Yokota, Hideki Ishizu & Seishi Terada

  6. Zikei Institute of Psychiatry, 100-2, Urayasu-honcho, Okayama, 702-8508, Japan

    Hideki Ishizu

Authors
  1. Osamu Yokota
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  2. Yvonne Davidson
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  3. Tetsuaki Arai
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  4. Masato Hasegawa
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  5. Haruhiko Akiyama
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  7. Seishi Terada
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  10. David M. A. Mann
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Correspondence to David M. A. Mann.

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Yokota, O., Davidson, Y., Arai, T. et al. Effect of topographical distribution of α-synuclein pathology on TDP-43 accumulation in Lewy body disease. Acta Neuropathol 120, 789–801 (2010). https://doi.org/10.1007/s00401-010-0731-9

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  • DOI: https://doi.org/10.1007/s00401-010-0731-9

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