Acta Neuropathologica

, Volume 121, Issue 4, pp 509–517

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

  • Felix Geser
  • Beth Stein
  • Michael Partain
  • Lauren B. Elman
  • Leo F. McCluskey
  • Sharon X. Xie
  • Vivianna M. Van Deerlin
  • Linda K. Kwong
  • Virginia M.-Y. Lee
  • John Q. Trojanowski
Original Paper

DOI: 10.1007/s00401-011-0797-z

Cite this article as:
Geser, F., Stein, B., Partain, M. et al. Acta Neuropathol (2011) 121: 509. doi:10.1007/s00401-011-0797-z

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.

Keywords

Pathological 43 kDa transactive responsive sequence DNA binding proteinMotor neuron disease clinically limited to the lower motor neuronProgressive muscular atrophy

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Felix Geser
    • 1
    • 2
  • Beth Stein
    • 3
  • Michael Partain
    • 1
  • Lauren B. Elman
    • 4
  • Leo F. McCluskey
    • 4
  • Sharon X. Xie
    • 5
  • Vivianna M. Van Deerlin
    • 1
  • Linda K. Kwong
    • 1
  • Virginia M.-Y. Lee
    • 1
  • John Q. Trojanowski
    • 1
    • 6
  1. 1.Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease ResearchAlzheimer’s Disease Core Center, Institute on Aging, University of Pennsylvania School of MedicinePhiladelphiaUSA
  2. 2.Department of Psychiatry, Psychosomatic Medicine and PsychotherapyGoethe-UniversityFrankfurt am MainGermany
  3. 3.Department of Neurology, Division of Neuromuscular Diseases, Montefiore Medical CenterAlbert Einstein College of MedicineBronxUSA
  4. 4.Department of NeurologyUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  5. 5.Department of Biostatistics and EpidemiologyUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  6. 6.Department of Pathology and Laboratory MedicineUniversity of Pennsylvania School of MedicinePhiladelphiaUSA