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.

Differential motor neuron involvement in progressive muscular atrophy: a comparative study with amyotrophic lateral sclerosis

“…Our pathological results revealed differential UMN involvement between patients with PMA and indicated that PMA and ALS are continuous pathological entities. Regarding immunohistochemical aspects, several studies have revealed that TDP-43 pathology is commonly observed in the cerebral cortices or the subcortical grey matter of patients with PMA 7 8. In our results, TDP-43-positive neuronal or glial inclusions in the motor cortices or hippocampus were common in the clinical ALS and PMA groups and were found even in patients apparently lacking UMN degenerative changes.…”

“…Postmortem histopathological studies have revealed corticospinal tract (CST) degeneration in more than half of the patients with MND clinically limited to LMN symptoms/signs 5 6. TDP-43-immunoreactive inclusions have been detected in the LMNs and cortical neurons of patients with PMA 7 8. The disease course of PMA is relentlessly progressive, although somewhat longer than that of ALS 2 4 9 10…”

Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights

“…Of further relevance, subclinical UMN dysfunction has been reported in progressive muscular atrophy (PMA),101–103 suggesting that PMA may be a phenotype of ALS. While corticomotoneuronal integrity was recently reported to be intact in PMA using a β-band intermuscular coherence technique,104 assessment of cortical function with TMS techniques may be of diagnostic utility, especially in light of presence of subclinical UMN pathology in PMA 102 103…”

An Autopsy Case Involving a 12-year History of Amyotrophic Lateral Sclerosis with CIDP-like Polyneuropathy

“…The lack of upper motor neuron signs made the diagnosis more difficult. Although a small number of ALS patients are known to exhibit slow disease progression of up to 10 years or more (12)(13)(14) and present with only lower motor neuron signs clinically (14,15), the neuropathy may have partially contributed to the present patient's symptoms, which improved with IVIG therapy. After 45 years of age, when the IVIG therapy no longer achieved any objective improvements, the muscle weakness may have been attributable to ALS, because we did not find any typical CIDP lesions at autopsy, such as onion bulb formation or inflammatory infiltration, although we can not exclude the possibility that such lesions existed in the peripheral nervous system at sites other than those we were able to examine.…”