Dissecting the Mechanisms Underlying Short-Interval Intracortical Inhibition Using Exercise

Recently, 2 physiologically distinct phases of short-interval intracortical inhibition (SICI) have been identified, a larger phase at interstimulus interval (ISI) 3 ms and a smaller phase at ISI 1 ms. While the former is mediated by synaptic processes, the mechanisms underlying the first phase of SICI remain a matter of debate. Separately, it is known that fatiguing hand exercise reduces SICI, a measure of cortical excitability. Consequently, the present study assessed effects of fatiguing hand exercise on the 2 SICI phases, using threshold tracking transcranial magnetic stimulation techniques, to yield further information on underlying mechanisms. Studies were undertaken on 22 subjects, with SICI assessed at baseline, after each voluntary contraction (VC) period of 120 s and 5, 10, and 20 min after last VC, with responses recorded over abductor pollicis brevis. Exercise resulted in significant reduction of SICI at ISI 1 ms (SICIbaseline 9.5 ± 2.7%; SICIMAXIMUM REDUCTION 2.5 ± 2.5%, P < 0.05) and 3 ms (SICIbaseline 16.8 ± 1.7%; SICIMAXIMUM REDUCTION 11.6 ± 2.1%, P < 0.05), with the time course of reduction being different for the 2 phases. Taken together, findings from the present study suggest that synaptic processes were the predominant mechanism underlying the different phases of SICI

Soluble Beta-Amyloid Precursor Protein Is Related to Disease Progression in Amyotrophic Lateral Sclerosis

Background: Biomarkers of disease progression in amyotrophic lateral sclerosis (ALS) could support the identification of beneficial drugs in clinical trials. We aimed to test whether soluble fragments of beta-amyloid precursor protein (sAPPa and sAPPß) correlated with clinical subtypes of ALS and were of prognostic value. Methodology/Principal Findings: In a cross-sectional study including patients with ALS (N = 68) with clinical follow-up data over 6 months, Parkinson’s disease (PD, N = 20), and age-matched controls (N = 40), cerebrospinal fluid (CSF) levels of sAPPa a, sAPPß and neurofilaments (NfH SMI35) were measured by multiplex assay, Progranulin by ELISA. CSF sAPPa and sAPPß levels were lower in ALS with a rapidly-progressive disease course (p = 0.03, and p = 0.02) and with longer disease duration (p = 0.01 and p = 0.01, respectively). CSF NfH SMI35 was elevated in ALS compared to PD and controls, with highest concentrations found in patients with rapid disease progression (p,0.01). High CSF NfH SMI3 was linked to low CSF sAPPa and sAPPß (p = 0.001, and p = 0.007, respectively). The ratios CSF NfH SMI35 /CSF sAPPa,-ß were elevated in patients with fast progression of disease (p = 0.002 each). CSF Progranulin decreased with ongoing disease (p = 0.04). Conclusions: This study provides new CSF candidate markers associated with progression of disease in ALS. The data suggest that a deficiency of cellular neuroprotective mechanisms (decrease of sAPP) is linked to progressive neuro-axona

Plasma Neurofilament Heavy Chain Levels Correlate to Markers of Late Stage Disease Progression and Treatment Response in SOD1(G93A) Mice that Model ALS

Background: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder characterised by progressive degeneration of motor neurons leading to death, typically within 3–5 years of symptom onset. The diagnosis of ALS is largely reliant on clinical assessment and electrophysiological findings. Neither specific investigative tools nor reliable biomarkers are currently available to enable an early diagnosis or monitoring of disease progression, hindering the design of treatment trials. Methodology/Principal Findings: In this study, using the well-established SOD1G93A mouse model of ALS and a new in-house ELISA method, we have validated that plasma neurofilament heavy chain protein (NfH) levels correlate with both functional markers of late stage disease progression and treatment response. We detected a significant increase in plasma levels of phosphorylated NfH during disease progression in SOD1G93A mice from 105 days onwards. Moreover, increased plasma NfH levels correlated with the decline in muscle force, motor unit survival and, more significantly, with the loss of spinal motor neurons in SOD1 mice during this critical period of decline. Importantly, mice treated with the disease modifying compound arimoclomol had lower plasma NfH levels, suggesting plasma NfH levels could be validated as an outcome measure for treatment trials. Conclusions/Significance: These results show that plasma NfH levels closely reflect later stages of disease progression and therapeutic response in the SOD1G93A mouse model of ALS and may potentially be a valuable biomarker of later disease progression in ALS

Corticomotoneuronal function in asymptomatic SOD-1 mutation carriers

Objective: Diffusion tensor imaging (DTI) recently identified structural abnormalities of corticomotoneurons in asymptomatic copper/zinc superoxide-dismutase-1 (SOD-1) gene mutation carriers. The potential existence of longstanding corticomotoneuronal dysfunction would clearly have consequences for the medical management of asymptomatic SOD-1 mutation carriers. To clarify this unexpected finding, DTI techniques were combined with threshold tracking transcranial magnetic stimulation (TMS) to assess the anatomical and functional integrity of corticomotoneurons in asymptomatic SOD-1 mutation carriers. Methods: TMS studies were undertaken using a 90 mm circular coil on seven asymptomatic SOD-1 mutation carriers and results were compared to 62 healthy controls. DTI studies were carried out using a 3 T magnetic resonance device in the same asymptomatic SOD-1 mutation carriers. Results were compared to age-matched healthy controls. Results: In contrast to previous findings, there were no significant differences in fractional anisotropy (SOD-1 mutation carriers, 0.62 ± 0.01; controls, 0.61 ± 0.02, P = 0.2) and trace apparent diffusion coefficient (SOD-1 mutation carriers, 0.003 ± 0.0001; controls, 0.003 ± 0.0001) in asymptomatic SOD-1 mutation carriers. Of further relevance, there were no significant differences in short-interval intracortical inhibition (SOD-1 mutation carriers, 7.9 ± 3.4%; controls, 8.5 ± 1.1%, P = 0.26), intracortical facilitation (P = 0.5), MEP amplitude (P = 0.44), resting motor threshold (P = 0.36) and cortical silent period duration (P = 0.29). Conclusions: Combined anatomical and functional modalities established normal integrity of corticomotoneurons in asymptomatic SOD-1 mutation carrier subjects. Significance: Additional factors other than simply SOD-1 mutation expression are required to trigger cortical hyperexcitability and neurodegeneration in FALS.5 page(s

Nocturnal hypoxia in motor neuron disease is not predicted by standard respiratory function tests

Background: With increasing awareness of motor neuron disease (MND) in Australia, the approach to respiratory management of patients with this disease will more commonly face the respiratory physician. Aim: The aim of this study was to determine if standard respiratory function tests could determine the presence of nocturnal hypoxia (NH) in patients with MND. Methods: Respiratory function tests were used to examine daytime respiratory function, and sleep studies were used to detect NH in 16 consecutive patients with MND and in 9 healthy control subjects. Demographic data, clinical parameters, respiratory function tests and sleep studies were obtained. Statistical analyses were carried out using t-tests and anova, where appropriate. Results: NH was detected in 50% of patients with MND, with no hypoxic events detected in the control group. Standard respiratory function tests were not able to predict the presence of NH. Conclusion: There was no correlation between respiratory function tests and NH. This study emphasizes the inability of standard respiratory function tests to predict NH that may arise early in the course of MND.4 page(s

Flecainide in Amyotrophic Lateral Sclerosis as a Neuroprotective Strategy (FANS): A Randomized Placebo-Controlled Trial

Background: Abnormalities in membrane excitability and Na+ channel function are characteristic of amyotrophic lateral sclerosis (ALS). We aimed to examine the neuroprotective potential, safety and tolerability of the Na+ channel blocker and membrane stabiliser flecainide in ALS. Methods: A double-blind, placebo-controlled, randomised clinical trial of flecainide (200 mg/day) for 32-weeks with a 12-week lead-in phase was conducted in participants with probable or definite ALS recruited from multiple Australian centres (ANZCT Registry number ACTRN12608000338369). Patients were reviewed by a cardiologist to rule out cardiac contraindications. Participants were randomly assigned (1:1) to flecainide or placebo using stratified permuted blocks by a central pharmacy. The primary outcome measure was the slope of decline of the ALS Functional Rating Scale-revised (ALS FRS-r) during the treatment period. Findings: Between March 11, 2008 and July 1, 2010, 67 patients were screened, 54 of whom were randomly assigned to receive flecainide (26 patients) or placebo (28 patients). Four patients in the flecainide group and three patients in the placebo group withdrew from the study. One patient in the flecainide group died during the study, attributed to disease progression. Flecainide was generally well tolerated, with no serious adverse events reported in either group. There was no significant difference in the rate of decline in the primary outcome measure ALS-FRS-r between placebo and flecainide treated patients (Flecainide 0.65 [95% CI 0.49 to 0.98]; Placebo 0.81 [0.49 to 2.12] P = 0.50). However, the rate of decline of the neurophysiological index was significantly reduced in the flecainide group (Flecainide 0.06 [0.01 to 0.11]; Placebo 0.14 [0.09 to 0.19], P = 0.02). Placebo-treated patients demonstrated greater CMAP amplitude reduction during the course of the study in the subset of patients with a reduced baseline CMAP amplitude (Flecainide: −15 ± 12%; Placebo −59 ± 12%; P = 0.03). Flecainide-treated patients maintained stabilized peripheral axonal excitability over the study compared to placebo. Interpretation: This pilot study indicated that flecainide was safe and potentially biologically effective in ALS. There was evidence that flecainide stabilized peripheral axonal membrane function in ALS. While the study was not powered to detect evidence of benefit of flecainide on ALS-FRS-r decline, further studies may demonstrate clinical efficacy of flecainide in ALS