Increased variability of axonal excitability in amyotrophic lateral sclerosis

Shibuta, Yoshiko; Shimatani, Yoshimitsu; Nodera, Hiroyuki; Izumi, Yuishin; Kaji, Ryuji

doi:10.1016/j.clinph.2013.02.117

Cited by 15 publications

(15 citation statements)

References 29 publications

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“…Indices used in threshold-tracking axonal excitability testing have provided information of pathological significance in ALS (338). Upregulation of persistent Na + conductances and reduction of slow and fast K + channel conductances have been demonstrated, with the net result being motor axonal hyperexcitability (340).…”

Section: Electrophysiology Biomarkersmentioning

confidence: 99%

Biomarkers in Motor Neuron Disease: A State of the Art Review

et al. 2019

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Motor neuron disease can be viewed as an umbrella term describing a heterogeneous group of conditions, all of which are relentlessly progressive and ultimately fatal. The average life expectancy is 2 years, but with a broad range of months to decades. Biomarker research deepens disease understanding through exploration of pathophysiological mechanisms which, in turn, highlights targets for novel therapies. It also allows differentiation of the disease population into sub-groups, which serves two general purposes: (a) provides clinicians with information to better guide their patients in terms of disease progression, and (b) guides clinical trial design so that an intervention may be shown to be effective if population variation is controlled for. Biomarkers also have the potential to provide monitoring during clinical trials to ensure target engagement. This review highlights biomarkers that have emerged from the fields of systemic measurements including biochemistry (blood, cerebrospinal fluid, and urine analysis); imaging and electrophysiology, and gives examples of how a combinatorial approach may yield the best results. We emphasize the importance of systematic sample collection and analysis, and the need to correlate biomarker findings with detailed phenotype and genotype data.

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Section: Electrophysiology Biomarkersmentioning

confidence: 99%

Biomarkers in Motor Neuron Disease: A State of the Art Review

et al. 2019

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“…In addition, "pseudonormalization" of TE changes has also been reported with disease progression and associated with axonal degeneration [4], with the most hyperexcitable axons degenerating with advanced disease. Underscoring this notion is the greater variability of axonal excitability at different target amplitudes, with preferential hyperexcitability evident in low-threshold axons [78]. Importantly, these longitudinal changes in TE could account for the variability reported in previous axonal excitability studies in ALS [5,78], and suggest that targeting the "hyperexcitable" axons early in the disease process could prove therapeutically useful.…”

Section: Axonal Excitability Changes In Alsmentioning

confidence: 95%

“…Underscoring this notion is the greater variability of axonal excitability at different target amplitudes, with preferential hyperexcitability evident in low-threshold axons [78]. Importantly, these longitudinal changes in TE could account for the variability reported in previous axonal excitability studies in ALS [5,78], and suggest that targeting the "hyperexcitable" axons early in the disease process could prove therapeutically useful. Separately, the TE changes in ALS appear to be more prominent in distal axonal segments [79], suggesting a propensity for axonal hyperexcitability to develop distally, and potentially explaining the notion that fasciculations are generated distally in the axon [59,80].…”

Section: Axonal Excitability Changes In Alsmentioning

confidence: 95%

Axonal Excitability in Amyotrophic Lateral Sclerosis

2017

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Axonal excitability testing provides in vivo assessment of axonal ion channel function and membrane potential. Excitability techniques have provided insights into the pathophysiological mechanisms underlying the development of neurodegeneration and clinical features of amyotrophic lateral sclerosis (ALS) and related neuromuscular disorders. Specifically, abnormalities of Na and K conductances contribute to development of membrane hyperexcitability in ALS, thereby leading to symptom generation of muscle cramps and fasciculations, in addition to promoting a neurodegenerative cascade via Ca-mediated processes. Modulation of axonal ion channel function in ALS has resulted in significant symptomatic improvement that has been accompanied by stabilization of axonal excitability parameters. Separately, axonal ion channel dysfunction evolves with disease progression and correlates with survival, thereby serving as a potential therapeutic biomarker in ALS. The present review provides an overview of axonal excitability techniques and the physiological mechanisms underlying membrane excitability, with a focus on the role of axonal ion channel dysfunction in motor neuron disease and related neuromuscular diseases.

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“…(Kaji, 2003). Abnormal axonal excitability suggestive of depolarized shift of the resting potential was reported in ALS, especially in the low-threshold axons (Shibuta et al, 2013). If membrane depolarization and distal conduction failure are general features in ALS, these findings should be present in other nerves.…”

Section: Unique Excitability Feature In the Distal Segment Of The Medmentioning

confidence: 97%