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

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.

Fig. 1

Dot- or dash-like cytoplasmic 43 kDa transactive responsive sequence DNA binding protein (TDP-43) pathology in a case of motor neuron disease (MND) clinically limited to lower motor neuron (LMN). Anti-TDP-43 immunohistochemistry using phosphorylation independent anti-TDP-43 antibodies in (a), i.e., commercial polyclonal anti-TDP-43, Proteintech Group Inc, as well as in (b), i.e., 171-anti-TDP-43, and the anti-phosphorylated S409/410 TDP-43 antibody in (c) showing dot-or dash-like inclusion formation in spinal cord lower motor neurons (examples denoted by arrows, bars 20 µm)

Fig. 2

Lower and upper motor neuron 43 kDa transactive responsive sequence DNA binding protein (TDP-43) pathology in a patients with MND/LMN. Anti-TDP-43 immunohistochemistry using anti-phosphorylated S409/410 TDP-43 antibodies showing TDP-43 pathology (examples arrows) in the dorsal motor plate in the medulla oblongata (a) and motor cortex (b) (bars 100 µm). Since this antibody does not stain normal TDP-43, all of the immunoreactivity in brown reflects pathology

Fig. 3

Cortical 43 kDa transactive responsive sequence DNA binding protein (TDP-43) pathology in a case of MND/LMN (same patient as in Fig. 1). Anti-TDP-43 immunohistochemistry using anti-phosphorylated S409/410 showing TDP-43 pathology (examples arrows) in the amygdala (a), dentate gyrus of the hippocampus (b), cingulate cortex (c), orbitofrontal cortex (d), and rarely visual cortex (e) (e.g., arrows) (bars 100 µm). As in Fig. 2, all of the immunoreactivity in brown here reflects pathology