Progressive axonal dysfunction and clinical impairment in amyotrophic lateral sclerosis

Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology (Impact Factor: 3.1). 08/2012; 123(12). DOI: 10.1016/j.clinph.2012.06.020
Source: PubMed


OBJECTIVE: To elucidate longitudinal changes in axonal function in amyotrophic lateral sclerosis (ALS) patients, and to relate such changes with motor unit loss and functional impairment. METHODS: 37 ALS patients (age, 53.7±1.7years; 22 males) were studied using axonal excitability techniques at baseline and 12weeks follow-up. RESULTS: Longitudinal measurements across excitability parameters suggested increasing K(+) channel dysfunction, with further increases in depolarising threshold electrotonus (90-100ms, baseline, 46.8±1.0%; follow-up, 48.7±0.8%; P=0.02) and superexcitability (baseline, -24.0±1.2%; 12weeks, -26.0±1.2%; P=0.04). Patients with preserved compound muscle action potential (CMAP) amplitude at follow-up developed more severe changes in axonal excitability than those in whom CMAP decreased from baseline, suggesting that the most pronounced disease effects were on motor axons immediately prior to axonal loss in ALS patients. Fine motor decline was associated with more severe changes in axonal excitability, suggesting that functional impairment was related to axonal dysfunction. CONCLUSIONS: Longitudinal changes in axonal excitability in ALS patients suggest increasing K(+) channel dysfunction in motor axons. SIGNIFICANCE: Axonal excitability studies enable investigation of longitudinal changes in axonal ion channel dysfunction, and thereby the processes that potentially contribute to axonal degeneration in ALS.

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    • "Threshold tracking has been used to investigate axonal excitability in peripheral nerve motor axons in ALS (Vucic and Kiernan, 2006). Increased persistent Na + conductance and reduced K + conductance have been described (Vucic and Kiernan, 2006), which tend to become more marked with disease duration and may be a predictor of survival (Cheah et al., 2012). More recently, it has been suggested that motor neurons have an abnormal function of the membrane ion channels, in ALS (Devlin et al., 2015). "

    Full-text · Article · Dec 2015 · EBioMedicine

  • No preview · Article · Aug 2012 · Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology
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    ABSTRACT: The development of hyperexcitability in amyotrophic lateral sclerosis (ALS) is a well-known phenomenon. Despite controversy as to the underlying mechanisms, cortical hyperexcitability appears to be closely related to the interplay between excitatory corticomotoneurons and inhibitory interneurons. Hyperexcitability is not a static phenomenon but rather shows a pattern of progression in a spatiotemporal aspect. Cortical hyperexcitability may serve as a trigger to the development of anterior horn cell degeneration through a 'dying forward' process. Hyperexcitability appears to develop during the early disease stages and gradually disappears in the advanced stages of the disease, linked to the destruction of corticomotorneuronal pathways. As such, a more precise interpretation of these unique processes may provide new insight regarding the pathophysiology of ALS and its clinical features. Recently developed technologies such as threshold tracking transcranial magnetic stimulation and automated nerve excitability tests have provided some clues about underlying pathophysiological processes linked to hyperexcitability. Additionally, these novel techniques have enabled clinicians to use the specific finding of hyperexcitability as a useful diagnostic biomarker, enabling clarification of various ALS-mimic syndromes, and the prediction of disease development in pre-symptomatic carriers of familial ALS. In terms of nerve excitability tests for peripheral nerves, an increase in persistent Na(+) conductances has been identified as a major determinant of peripheral hyperexcitability in ALS, inversely correlated with the survival in ALS. As such, the present Review will focus primarily on the puzzling theory of hyperexcitability in ALS and summarize clinical and pathophysiological implications for current and future ALS research.
    Full-text · Article · Apr 2013 · Journal of Clinical Neurology
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