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TDP-43 pathology and neuronal loss in amyotrophic lateral sclerosis spinal cord

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Abstract

We examined the phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) inclusions as well as neuronal loss in full-length spinal cords and five selected regions of the central nervous system from 36 patients with amyotrophic lateral sclerosis (ALS) and 10 age-matched normal controls. The most severe neuronal loss and pTDP-43 lesions were seen in lamina IX motor nuclei columns 4, 6, and 8 of lower cervical segments and in columns 9–11 of lumbosacral segments. Severity of pTDP-43 pathology and neuronal loss correlated closely with gray and white matter oligodendroglial involvement and was linked to onset of disease, with severe involvement of columns 4, 6, and 8 of upper extremity onset cases and severe involvement of columns of 9, 10, and 11 in cases with lower extremity onset. Severe TDP-43 lesions and neuronal loss were observed in stage 4 cases and sometimes included Onuf’s nucleus. Notably, three cases displayed pTDP-43 aggregates in the midbrain oculomotor nucleus, which we had not seen previously even in cases with advanced (i.e., stage 4) pathology. pTDP-43 aggregates were observed in neurons of Clarke’s column in 30.6 % of cases but rarely in the intermediolateral nucleus (IML). Gray matter oligodendroglial pTDP-43 inclusions were present in areas devoid of neuronal pTDP-43 aggregates and neuronal loss. Taken together, our findings indicate that (1) the dorsolateral motor nuclei columns of the cervical and lumbosacral anterior horn may be the earliest foci of pTDP-43 pathology in the spinal cord, (2) gray matter oligodendroglial involvement is an early event in the ALS disease process that possibly heralds subsequent involvement of neurons by pTDP-43 pathology, and (3) in some very advanced cases, there is oculomotor nucleus involvement, which may constitute an additional neuropathological stage (designated here as stage 5) of pTDP-43 pathology in ALS.

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Acknowledgments

We thank the patients who contributed to this study. We are also grateful to Kevin Raible, Terry Schuck, Sigrid Baumann, Gabriele Ehmke, Simone Feldengut, Julia Straub, and Thi Phuong Thu Brettschneider for technical support, together with David Ewert (University of Ulm) for assistance with the graphics. This study was supported by the NIH (AG033101, AG017586, AG010124, AG032953, AG039510, NS044266), the Wyncote Foundation, and the Koller Family Foundation, as well as by the German Motor Neuron Disease Network. VM-YL is the John H. Ware, 3rd, Professor of Alzheimer’s Disease Research. JQT is the William Maul Measey-Truman G. Schnabel, Jr. Professor of Geriatric Medicine and Gerontology. DJI is supported by the Penn Institute for Translational Medicine & Therapeutics (ITMAT). HB and KDT are supported by the Michael J. Fox Foundation for Parkinson’s Research.

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Authors and Affiliations

  1. Clinical Neuroanatomy Section, Department of Neurology, Center for Biomedical Research, University of Ulm, Helmholtzstrasse 8/1, 89081, Ulm, Germany

    Kelly Del Tredici, Lubin Fang & Heiko Braak

  2. Center for Neurodegenerative Disease Research (CNDR), University of Pennsylvania School of Medicine, 3rd Floor Maloney Building, 3600 Spruce Street, Philadelphia, PA, 19104, USA

    Johannes Brettschneider, Jon B. Toledo, John L. Robinson, Edward B. Lee, David J. Irwin, Vivianna M. Van Deerlin, Virginia M.-Y. Lee & John Q. Trojanowski

  3. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA, 19104, USA

    David J. Irwin, Vivianna M. Van Deerlin, Virginia M.-Y. Lee & John Q. Trojanowski

  4. Department of Neurology, University of Pennsylvania School of Medicine, 3 W Gates, 3400 Spruce Street, Philadelphia, PA, 19104, USA

    Lauren Elman & Leo McCluskey

  5. Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081, Ulm, Germany

    Albert C. Ludolph

  6. Chiba-East Hospital, Nitona-cho 673, Chuo-ku, Chiba, 260-8712, Japan

    Kimihito Arai

  7. Department of Neurology, Chiba University School of Medicine, Chiba, Japan

    Kimihito Arai, Satoshi Kuwabara & Kazumoto Shibuya

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  1. Johannes Brettschneider
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Correspondence to John Q. Trojanowski.

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J. Brettschneider, K. Arai, and K. Del Tredici contributed equally.

H. Braak and J. Q. Trojanowski are Senior authors.

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Brettschneider, J., Arai, K., Del Tredici, K. et al. TDP-43 pathology and neuronal loss in amyotrophic lateral sclerosis spinal cord. Acta Neuropathol 128, 423–437 (2014). https://doi.org/10.1007/s00401-014-1299-6

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  • DOI: https://doi.org/10.1007/s00401-014-1299-6

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