Superconditioning TMS for examining upper motor neuron function in MND.

We used transcranial magnetic stimulation (TMS) of motor cortex, including a novel four-pulse superconditioning (TMSsc) paradigm, in repeated examinations of motor-evoked potentials (MEPs) in eight subjects with motor neuron disease (MND), including seven with amyotrophic lateral sclerosis (ALS). The goals were: (1) to look for evidence of cortical hyperexcitability, including a reduction in short-interval intracortical inhibition (SICI); and (2) to examine the utility of using TMSsc for quantifying upper motor neuron function during MND progression. Testing of abductor pollicis brevis (APB) and tibialis anterior (TA) muscles bilaterally was carried out every 3 months in MND subjects for up to 2 years; results were compared to those from a cohort of 15 control subjects. Measures of SICI were not significantly different between control and MND subjects for either APB or TA muscles. Other measures of cortical excitability, including TMS threshold and MEP amplitude, were consistent with lowered cortical excitability in MND subjects. Certain combinations of superconditioning TMS were capable of causing stronger inhibition or facilitation of MEPs compared to dual-pulse TMS, for both APB and TA target muscles. Moreover, there were multiple cases in which target muscles unresponsive to strong single-pulse TMS, whether at rest or when tested with an active contraction, showed an MEP in response to TMSsc optimized for facilitation. Our findings suggest that a multi-faceted neurophysiologic protocol for examining upper motor neuron function in MND subjects might benefit from inclusion of TMSsc testing.

Electrical impedance myography correlates with standard measures of ALS severity.

INTRODUCTION: Electrical impedance myography (EIM) can be used to assess amyotrophic lateral sclerosis (ALS) progression. The relationship between EIM values and standard assessment measures, however, is unknown. METHODS: EIM 50 kHz phase data from 60 subjects who participated in a longitudinal natural history study of ALS were correlated with handheld dynamometry (HHD), the ALS Functional Rating Scale-Revised (ALSFRS-R) score, and motor unit number estimation (MUNE). RESULTS: Moderate strength correlations between EIM parameters and HHD were observed for both whole-body and individual upper and lower extremity values. Similarly, moderate strength correlations were observed between EIM and ALSFRS-R upper and lower extremity subscores, but not total ALSFRS-R scores. MUNE correlated significantly with single muscle EIM data but not with whole body or upper or lower extremity values. CONCLUSIONS: These results support the concept that EIM can serve as a meaningful measure of disease severity in ALS.

Safety, tolerability and pharmacodynamics of a skeletal muscle activator in amyotrophic lateral sclerosis.

This study was designed to evaluate the safety and tolerability of single doses of CK-2017357, an orally bioavailable fast skeletal muscle troponin activator, in patients with amyotrophic lateral sclerosis (ALS), and to explore pharmacodynamic markers related to strength, endurance, and function. Sixty-seven patients with ALS received single doses of placebo, CK-2017357 at 250 mg and 500 mg in random order, separated by one week. Safety measures assessments were performed, as well as tests of pulmonary function, limb muscle strength and endurance, and global impression of change. Pharmacokinetics of both CK-2017357 and riluzole were studied. Sixty-three patients completed all three dosing periods. CK-2017357 was well tolerated, with dizziness and general fatigue being the most frequent adverse events. Both patients and investigators perceived a dose-dependent benefit of CK-2017357 as measured by global impression of change. Maximum voluntary ventilation and submaximal handgrip endurance also improved. Only small changes were seen in maximal strength. In conclusion, single doses of 250 mg and 500 mg of CK-2017357 were safe and well tolerated by patients with ALS. Measures of endurance appear to be improved in a dose-related fashion, and both patients and investigators perceived a global benefit. Further study of this agent is warranted.

Electrical impedance myography as a biomarker to assess ALS progression.

Electrical impedance myography (EIM), a non-invasive, electrophysiological technique, has preliminarily shown value as an ALS biomarker. Here we perform a multicenter study to further assess EIM's potential for tracking ALS. ALS patients were enrolled across eight sites. Each subject underwent EIM, handheld dynamometry (HHD), and the ALS Functional Rating Scale-revised (ALSFRS-R) regularly. Techniques were compared by assessing the coefficient of variation (CoV) in the rate of decline and each technique's correlation to survival. Results showed that in the 60 patients followed for one year, EIM phase measured from the most rapidly progressing muscle in each patient had a CoV in the rate of decline of 0.62, compared to HHD (0.82) and the ALSFRS-R (0.74). Restricting the measurements to the first six months gave a CoV of 0.55 for EIM, 0.93 for HHD, and 0.84 for ALSFRS-R. For both time-periods, all three measures correlated with survival. Based on these data, a six-month clinical trial designed to detect a 20% treatment effect with 80% power using EIM would require only 95 patients/arm compared to the ALSFRS-R, which would require 220 subjects/arm. In conclusion, EIM can serve as a useful ALS biomarker that offers the prospect of greatly accelerating phase 2 clinical trials.

A study to evaluate safety and tolerability of repeated doses of tirasemtiv in patients with amyotrophic lateral sclerosis.

Abstract Tirasemtiv is a fast skeletal muscle activator that increases the sensitivity of the sarcomere to calcium, increasing the efficiency of muscle contraction when the muscle is stimulated at submaximal contraction frequencies. A previous study showed single doses of tirasemtiv to be well tolerated and associated with potentially important improvements in a variety of functional outcomes. This study determined safety of tirasemtiv when given at doses up to 500 mg daily for three weeks. Tirasemtiv was given as a single daily dose up to 375 mg for two weeks, with and without concomitant riluzole. In a separate cohort, an ascending dose protocol evaluated a total dose of 500 mg daily given in two divided doses. Safety and tolerability were assessed, as well as measures of function, muscle strength and endurance. Results showed that tirasemtiv was well tolerated, with dizziness the most common adverse event. Tirasemtiv approximately doubled the serum concentration of riluzole. Trends were noted for improvement in ALSFRS-R, Maximum Minute Ventilation, and Nasal Inspiratory Pressure. In conclusion, tirasemtiv is well tolerated and can be given safely with a reduced dose of riluzole. Positive trends in multiple exploratory outcome measures support the further study of this agent in ALS.