Sporadic amyotrophic lateral sclerosis of long duration is associated with relatively mild TDP-43 pathology

Abstract

Recently, sporadic amyotrophic lateral sclerosis (SALS), a fatal neurological disease, has been shown to be a multisystem proteinopathy of TDP-43 in which both neurons and glial cells in the central nervous system are widely affected. In general, the natural history of SALS is short (<5 years). However, it is also known that a few patients may survive for 10 years or more, even without artificial respiratory support (ARS). In the present study using TDP-43 immunohistochemistry, we examined various regions of the nervous system in six patients with SALS of long duration (10-20 years) without ARS, in whom lower motor-predominant disease with Bunina bodies and ubiquitinated inclusions (UIs) in the affected lower motor neurons was confirmed. One case also showed UIs in the hippocampal dentate granule cells (UDG). In all cases, except one with UDG, the occurrence of TDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs) was confined to a few regions in the spinal cord and brainstem, including the anterior horns. In one case with UDG, TDP-43-ir NCIs were also detected in the substantia nigra, and some regions of the cerebrum, including the hippocampal dentate gyrus (granule cells). The number of neurons displaying NCIs in each region was very small (1-3 per region, except the dentate gyrus). On the other hand, the occurrence of TDP-43-ir glial cytoplasmic inclusions (GCIs) was more widespread in the central nervous system, including the cerebral white matter. Again, however, the number of glial cells displaying GCIs in each region was very small (1-3 per region). In conclusion, compared to the usual form of SALS, TDP-43 pathology shown in SALS of long duration was apparently mild in degree and limited in distribution, corresponding to the relatively benign clinical courses observed. It is now apparent that SALS of long duration is actually part of a TDP-43 proteinopathy spectrum.

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…”

Sporadic amyotrophic lateral sclerosis: Widespread multisystem degeneration with TDP‐43 pathology in a patient after long‐term survival on a respirator

“…In a previous study, we also showed that, compared to the usual form of SALS, the TDP-43 neuronal pathology detected in long-duration SALS without ARS (disease duration, 10-20 years) was mild in degree and limited in distribution. 22 Significantly, it has also been reported recently that mutations in the TDP-43 gene can cause familial ALS with neuropathology indistinguishable from that observed in SALS, including TDP-43 pathology. [23][24][25] All these findings, including the present TDP-43 pathology with ubiquitination, strongly suggest that there is a close link between TDP-43 abnormality and neuronal cell death in SALS.…”

Molecular Dissection of TDP-43 Proteinopathies

“…Type 1 is associated with semantic dementia, type 2 with FTLD with motor neuron disease (MND), ALS or clinical signs of MND, and type 3 with progressive nonfluent aphasia or FTD with mutation in the progranulin gene. Recent studies of ALS have clarified the wide distribution of neuronal and glial TDP-43 pathology in multiple areas of the central nervous systems (Geser et al 2008;Nishihira et al 2009), suggesting that ALS does not selectively affect only the motor system, but rather is a multisystem neurodegenerative TDP-43 proteinopathy affecting both neurons and glial cells.…”