Motor neuron disease clinically limited to the lower motor neuron is a diffuse TDP43 proteinopathy

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 19104-4283, USA.
Acta Neuropathologica (Impact Factor: 10.76). 04/2011; 121(4):509-517. 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.

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