Motor axonal excitability properties are strong predictors for survival in amyotrophic lateral sclerosis

Kanai, Kazuaki; Shibuya, Kazumoto; Sato, Yasunori; Misawa, Sonoko; Nasu, Saiko; Sekiguchi, Yukari; Mitsuma, Satsuki; Isose, Sagiri; Fujimaki, Yumi; Ohmori, Satoshi; Koga, Shunsuke; Kuwabara, Satoshi

doi:10.1136/jnnp-2011-301782

Cited by 107 publications

(73 citation statements)

References 30 publications

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“…Hyperexcitability of MNs in ALS has been shown in vitro and in vivo [87, 99, 118, 186]. However, it has been reported that if any shifts are observed at all, they point towards overall hypoexcitability, irrespective of MN subtype [39].…”

Section: Differential Vulnerability Between Spinal Motor Unitsmentioning

confidence: 99%

Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis

2017

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In the fatal disease—amyotrophic lateral sclerosis (ALS)—upper (corticospinal) motor neurons (MNs) and lower somatic MNs, which innervate voluntary muscles, degenerate. Importantly, certain lower MN subgroups are relatively resistant to degeneration, even though pathogenic proteins are typically ubiquitously expressed. Ocular MNs (OMNs), including the oculomotor, trochlear and abducens nuclei (CNIII, IV and VI), which regulate eye movement, persist throughout the disease. Consequently, eye-tracking devices are used to enable paralysed ALS patients (who can no longer speak) to communicate. Additionally, there is a gradient of vulnerability among spinal MNs. Those innervating fast-twitch muscle are most severely affected and degenerate first. MNs innervating slow-twitch muscle can compensate temporarily for the loss of their neighbours by re-innervating denervated muscle until later in disease these too degenerate. The resistant OMNs and the associated extraocular muscles (EOMs) are anatomically and functionally very different from other motor units. The EOMs have a unique set of myosin heavy chains, placing them outside the classical characterization spectrum of all skeletal muscle. Moreover, EOMs have multiple neuromuscular innervation sites per single myofibre. Spinal fast and slow motor units show differences in their dendritic arborisations and the number of myofibres they innervate. These motor units also differ in their functionality and excitability. Identifying the molecular basis of cell-intrinsic pathways that are differentially activated between resistant and vulnerable MNs could reveal mechanisms of selective neuronal resistance, degeneration and regeneration and lead to therapies preventing progressive MN loss in ALS. Illustrating this, overexpression of OMN-enriched genes in spinal MNs, as well as suppression of fast spinal MN-enriched genes can increase the lifespan of ALS mice. Here, we discuss the pattern of lower MN degeneration in ALS and review the current literature on OMN resistance in ALS and differential spinal MN vulnerability. We also reflect upon the non-cell autonomous components that are involved in lower MN degeneration in ALS.

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Section: Differential Vulnerability Between Spinal Motor Unitsmentioning

confidence: 99%

Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis

2017

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“…Changes in axonal excitability evolve with disease progression,57 and may be a predictor of survival in ALS patients 58. Axonal excitability parameters may be useful biomarkers of axonal degeneration.…”

Section: Candidate Biomarkers Of Disease Progressionmentioning

confidence: 99%

Quantifying disease progression in amyotrophic lateral sclerosis

Simon

Turner

Vucic

et al. 2014

Annals of Neurology

140

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Amyotrophic lateral sclerosis (ALS) exhibits characteristic variability of onset and rate of disease progression, with inherent clinical heterogeneity making disease quantitation difficult. Recent advances in understanding pathogenic mechanisms linked to the development of ALS impose an increasing need to develop strategies to predict and more objectively measure disease progression. This review explores phenotypic and genetic determinants of disease progression in ALS, and examines established and evolving biomarkers that may contribute to robust measurement in longitudinal clinical studies. With targeted neuroprotective strategies on the horizon, developing efficiencies in clinical trial design may facilitate timely entry of novel treatments into the clinic.

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“…In terms of clinical-prognostic correlation, one previous study showed that the amount of the SICI decrease correlated with disease duration and motor deficit score 66. However, studies with TT-TMS or NET showed that functional status or survival was instead correlated with peripheral NET or NCS parameters, such as CMAP or strength-duration time constant (SDTC) 45,67…”

Section: Hyperexcitability and Its Clinical Implications In Alsmentioning

confidence: 99%

The Puzzling Case of Hyperexcitability in Amyotrophic Lateral Sclerosis

et al. 2013

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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.

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Motor axonal excitability properties are strong predictors for survival in amyotrophic lateral sclerosis

Cited by 107 publications

References 30 publications

Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis

Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis

Quantifying disease progression in amyotrophic lateral sclerosis

The Puzzling Case of Hyperexcitability in Amyotrophic Lateral Sclerosis

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