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Motor neuron disease clinically limited to the lower motor neuron is a diffuse TDP-43 proteinopathy

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Abstract

Motor neuron disease (MND) may present as an isolated lower motor neuron (LMN) disorder. Although the significance of pathological 43 kDa transactive responsive sequence DNA binding protein (TDP-43) for amyotrophic lateral sclerosis (ALS) was appreciated only recently, the topographical distribution of TDP-43 pathology in MND clinically isolated to the LMN versus normal controls (COs) is only incompletely described. Therefore, we performed longitudinal clinical evaluation and retrospective chart review of autopsied patients diagnosed with isolated LMN disease. Cases with a disease duration over 4 years were designated as progressive muscular atrophy (PMA), and those with a more rapid course as MND/LMN. Immunohistochemistry was employed to identify neuronal and glial TDP-43 pathology in the central nervous system (CNS) in patients and COs. We examined 19 subjects including six patients (i.e., four with MND/LMN and two with PMA) and 13 COs. All patients showed significant TDP-43 linked degeneration of LMNs, and five cases showed a lesser degree of motor cortex degeneration. Additional brain areas were affected in varying degrees, ranging from predominantly brainstem pathology to significant involvement of the whole CNS including neocortical and limbic areas. Pathological TDP-43 was present only rarely in the CO group. We conclude that MND limited to the LMN and PMA is part of a disease continuum that includes ALS and FTLD-TDP, all of which are characterized by widespread TDP-43 pathology. Hence, we suggest that the next revision of the El Escorial criteria for the diagnosis of ALS include MND patients with disease clinically limited to the LMN and PMA as variants of ALS, which like classical ALS, are TDP-43 proteinopathies.

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Acknowledgments

We thank the families of patients whose generosity made this research possible. Manuela Neumann, MD, provided the anti-phosphorylated TDP-43 antibody (S409/410). We thank our colleagues at the Center for Neurodegenerative Disease Research and Department of Psychiatry, University of Pennsylvania School of Medicine, for technical support and advice, particularly Theresa Schuck, BA, and John L. Robinson, BS. Supported by AG10124 and AG32953.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Alzheimer’s Disease Core Center, Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Felix Geser, Michael Partain, Vivianna M. Van Deerlin, Linda K. Kwong, Virginia M.-Y. Lee & John Q. Trojanowski

  2. Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe-University, Frankfurt am Main, Germany

    Felix Geser

  3. Department of Neurology, Division of Neuromuscular Diseases, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA

    Beth Stein

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

    Lauren B. Elman & Leo F. McCluskey

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

    Sharon X. Xie

  6. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, HUP, Maloney 3rd Floor, 36th and Spruce Streets, Philadelphia, PA, 19104-4283, USA

    John Q. Trojanowski

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  1. Felix Geser
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  2. Beth Stein
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  4. Lauren B. Elman
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  8. Linda K. Kwong
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  9. Virginia M.-Y. Lee
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Correspondence to John Q. Trojanowski.

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Geser, F., Stein, B., Partain, M. et al. Motor neuron disease clinically limited to the lower motor neuron is a diffuse TDP-43 proteinopathy. Acta Neuropathol 121, 509–517 (2011). https://doi.org/10.1007/s00401-011-0797-z

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  • DOI: https://doi.org/10.1007/s00401-011-0797-z

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