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Coexistence of Huntington’s disease and amyotrophic lateral sclerosis: a clinicopathologic study

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Abstract

We report a retrospective case series of four patients with genetically confirmed Huntington’s disease (HD) and sporadic amyotrophic lateral sclerosis (ALS), examining the brain and spinal cord in two cases. Neuropathological assessment included a polyglutamine recruitment method to detect sites of active polyglutamine aggregation, and biochemical and immunohistochemical assessment of TDP-43 pathology. The clinical sequence of HD and ALS varied, with the onset of ALS occurring after the mid-50’s in all cases. Neuropathologic features of HD and ALS coexisted in both cases examined pathologically: neuronal loss and gliosis in the neostriatum and upper and lower motor neurons, with Bunina bodies and ubiquitin-immunoreactive skein-like inclusions in remaining lower motor neurons. One case showed relatively early HD pathology while the other was advanced. Expanded polyglutamine-immunoreactive inclusions and TDP-43-immunoreactive inclusions were widespread in many regions of the CNS, including the motor cortex and spinal anterior horn. Although these two different proteinaceous inclusions coexisted in a small number of neurons, the two proteins did not co-localize within inclusions. The regional distribution of TDP-43-immunoreactive inclusions in the cerebral cortex partly overlapped with that of expanded polyglutamine-immunoreactive inclusions. In the one case examined by TDP-43 immunoblotting, similar TDP-43 isoforms were observed as in ALS. Our findings suggest the possibility that a rare subset of older HD patients is prone to develop features of ALS with an atypical TDP-43 distribution that resembles that of aggregated mutant huntingtin. Age-dependent neuronal dysfunction induced by mutant polyglutamine protein expression may contribute to later-life development of TDP-43 associated motor neuron disease in a small subset of patients with HD.

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Acknowledgments

This work was funded by NIH RO1 NS 038712 and RO1 AG034228 (HLP). A grant was received from Hereditary Disease Foundation (APO), Research Committee for CNS Degenerative Diseases, the Ministry of Health, Labour and Welfare, Japan and a Grant-in-Aid (23240049) for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (HT).

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Authors and Affiliations

  1. Department of Neurology, University of Michigan Health System, 109 Zina Pitcher Place, Biomedical Sciences Research Building, Room Number 4160, Ann Arbor, MI, 48109-2200, USA

    Mari Tada & Henry L. Paulson

  2. Department of Neurology, Brain Research Institute, University of Niigata, Niigata, Japan

    Mari Tada, Masayoshi Tada & Masatoyo Nishizawa

  3. Department of Pathology, Brain Research Institute, University of Niigata, Niigata, Japan

    Mari Tada, Atsushi Shiga, Akiyoshi Kakita & Hitoshi Takahashi

  4. Department of Neurology, Mayo Clinic, Rochester, MN, USA

    Elizabeth A. Coon

  5. Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN, USA

    Alexander P. Osmand

  6. Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA

    Patricia A. Kirby

  7. Division of Neurology, University of Alberta, Alberta, Canada

    Wayne Martin & Marguerite Wieler

  8. Shirasaki Clinic, Toyama, Japan

    Hiroe Shirasaki

  9. Department of Clinical Research, Joetsu General Hospital, Niigata, Japan

    Takao Makifuchi

  10. Department of Clinical Research, National Hospital Organization, Saigata National Hospital, Niigata, Japan

    Mitsunori Yamada

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  1. Mari Tada
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Correspondence to Henry L. Paulson.

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Tada, M., Coon, E.A., Osmand, A.P. et al. Coexistence of Huntington’s disease and amyotrophic lateral sclerosis: a clinicopathologic study. Acta Neuropathol 124, 749–760 (2012). https://doi.org/10.1007/s00401-012-1005-5

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  • DOI: https://doi.org/10.1007/s00401-012-1005-5

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