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Sporadic amyotrophic lateral sclerosis of long duration is associated with relatively mild TDP-43 pathology

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Abstract

Recently, sporadic amyotrophic lateral sclerosis (SALS), a fatal neurological disease, has been shown to be a multisystem proteinopathy of TDP-43 in which both neurons and glial cells in the central nervous system are widely affected. In general, the natural history of SALS is short (<5 years). However, it is also known that a few patients may survive for 10 years or more, even without artificial respiratory support (ARS). In the present study using TDP-43 immunohistochemistry, we examined various regions of the nervous system in six patients with SALS of long duration (10–20 years) without ARS, in whom lower motor-predominant disease with Bunina bodies and ubiquitinated inclusions (UIs) in the affected lower motor neurons was confirmed. One case also showed UIs in the hippocampal dentate granule cells (UDG). In all cases, except one with UDG, the occurrence of TDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs) was confined to a few regions in the spinal cord and brainstem, including the anterior horns. In one case with UDG, TDP-43-ir NCIs were also detected in the substantia nigra, and some regions of the cerebrum, including the hippocampal dentate gyrus (granule cells). The number of neurons displaying NCIs in each region was very small (1–3 per region, except the dentate gyrus). On the other hand, the occurrence of TDP-43-ir glial cytoplasmic inclusions (GCIs) was more widespread in the central nervous system, including the cerebral white matter. Again, however, the number of glial cells displaying GCIs in each region was very small (1–3 per region). In conclusion, compared to the usual form of SALS, TDP-43 pathology shown in SALS of long duration was apparently mild in degree and limited in distribution, corresponding to the relatively benign clinical courses observed. It is now apparent that SALS of long duration is actually part of a TDP-43 proteinopathy spectrum.

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Acknowledgments

We thank C. Tanda, J. Takasaki and S. Egawa for their technical assistance, and M. Machida for her help in preparing the manuscript. This work was supported by a Grant-in-Aid for Scientific Research (20240037) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan, and a grant from the Research Committee of CNS Degenerative Diseases, the Ministry of Health, Labour and Welfare, Japan.

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Authors and Affiliations

  1. Department of Pathology, Brain Research Institute, University of Niigata, 1-757 Asahimachi, Chuo-ku, Niigata, 951-8585, Japan

    Yasushi Nishihira, Chun-Feng Tan, Yasuhiro Hoshi & Hitoshi Takahashi

  2. Section of Neurology, Nagasaki Kita Hospital, Nagasaki, 851-2103, Japan

    Keisuke Iwanaga & Mitsuhiro Tsujihata

  3. Department of Neurology and Geriatrics, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan

    Megumi Yamada & Isao Hozumi

  4. Department of Neurology, Brain Research Institute, University of Niigata, Niigata, 951-8585, Japan

    Izumi Kawachi & Masatoyo Nishizawa

  5. Department of Pathology, Shinrakuen Hospital, Niigata, 905-2087, Japan

    Takashi Morita

  6. Department of Molecular Neuroscience, Brain Research Institute, University of Niigata, Niigata, 951-8585, Japan

    Osamu Onodera

  7. Department of Pathology Neuroscience, Brain Research Institute, University of Niigata, Niigata, 951-8585, Japan

    Akiyoshi Kakita

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  1. Yasushi Nishihira
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  2. Chun-Feng Tan
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  3. Yasuhiro Hoshi
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  11. Masatoyo Nishizawa
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  13. Hitoshi Takahashi
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Correspondence to Yasushi Nishihira.

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Nishihira, Y., Tan, CF., Hoshi, Y. et al. Sporadic amyotrophic lateral sclerosis of long duration is associated with relatively mild TDP-43 pathology. Acta Neuropathol 117, 45–53 (2009). https://doi.org/10.1007/s00401-008-0443-6

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  • DOI: https://doi.org/10.1007/s00401-008-0443-6

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