Revisiting Glutamate Excitotoxicity in Amyotrophic Lateral Sclerosis and Age-Related Neurodegeneration.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder. While there are five FDA-approved drugs for treating this disease, each has only modest benefits. To design new and more effective therapies for ALS, particularly for sporadic ALS of unknown and diverse etiologies, we must identify key, convergent mechanisms of disease pathogenesis. This review focuses on the origin and effects of glutamate-mediated excitotoxicity in ALS (the cortical hyperexcitability hypothesis), in which increased glutamatergic signaling causes motor neurons to become hyperexcitable and eventually die. We characterize both primary and secondary contributions to excitotoxicity, referring to processes taking place at the synapse and within the cell, respectively. 'Primary pathways' include upregulation of calcium-permeable AMPA receptors, dysfunction of the EAAT2 astrocytic glutamate transporter, increased release of glutamate from the presynaptic terminal, and reduced inhibition by cortical interneurons-all of which have been observed in ALS patients and model systems. 'Secondary pathways' include changes to mitochondrial morphology and function, increased production of reactive oxygen species, and endoplasmic reticulum (ER) stress. By identifying key targets in the excitotoxicity cascade, we emphasize the importance of this pathway in the pathogenesis of ALS and suggest that intervening in this pathway could be effective for developing therapies for this disease.

Amyotrophic lateral sclerosis care and research in the United States during the COVID-19 pandemic: Challenges and opportunities.

Coronavirus disease 2019 has created unprecedented challenges for amyotrophic lateral sclerosis (ALS) clinical care and research in the United States. Traditional evaluations for making an ALS diagnosis, measuring progression, and planning interventions rely on in-person visits that may now be unsafe or impossible. Evidence- and experience-based treatment options, such as multidisciplinary team care, feeding tubes, wheelchairs, home health, and hospice, have become more difficult to obtain and in some places are unavailable. In addition, the pandemic has impacted ALS clinical trials by impairing the ability to obtain measurements for trial eligibility, to monitor safety and efficacy outcomes, and to dispense study drug, as these also often rely on in-person visits. We review opportunities for overcoming some of these challenges through telemedicine and novel measurements. These can reoptimize ALS care and research in the current setting and during future events that may limit travel and face-to-face interactions.

Diaphragm pacing in amyotrophic lateral sclerosis: a literature review.

Amyotrophic lateral sclerosis (ALS) remains a rapidly progressive fatal degenerative disease of motor neurons for which there are few interventions to slow disease progression or improve quality of life. A diaphragm pacing system was approved by the U.S. Food and Drug Administration in September 2011 for ALS under a Humanitarian Device Exemption. News of this approval has been met with a combination of excitement and uncertainty by members of the ALS community. We review the currently available data on the diaphragm pacing system and its use in ALS. Diaphragm pacing appears to be reasonably safe in carefully selected patients, but flaws in the reporting on it thus far preclude conclusions regarding efficacy. Further study is needed.

Creatine for amyotrophic lateral sclerosis/motor neuron disease.

BACKGROUND: Creatine, a naturally-occurring nitrogenous organic acid involved in adenosine triphosphate (ATP) production, has been shown to increase survival in mouse models of amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND). Results from human trials, however, have been mixed. Given conflicting results regarding the efficacy of creatine, we conducted a systematic review, which was updated in 2012. OBJECTIVES: To systematically examine the efficacy of creatine efficacy in prolonging ALS survival and in slowing ALS disease progression. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (16 July 2012), CENTRAL (2012, issue 7 in the Cochrane Library), MEDLINE (January 1966 to July 2012) and EMBASE (January 1980 to July 2012) for any trial involving creatine in the treatment of ALS. We also contacted experts in the field for any additional studies. SELECTION CRITERIA: Randomized trials of treatment with creatine or placebo in patients diagnosed with ALS. Our primary outcome was tracheostomy-free survival time; secondary outcomes were ALS progression as measured by changes in ALS functional rating revised scores (ALSFRS-R) and per cent predicted forced vital capacity (FVC) over time. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, assessed risk of bias and extracted data. We obtained and analyzed individual participant data from each study. MAIN RESULTS: We included three trials involving 386 participants randomized to either creatine 5 to 10 g per day or placebo. When we updated the searches in 2012 we found no additional trials. Creatine was reportedly well-tolerated in all three included studies, with no evidence of renal failure or serious adverse events specifically attributable to creatine. Using a pooled log-rank statistical test, we found no statistical difference in survival between the placebo and creatine groups across all three studies (Chi(2) = 0.09, P = 0.76). In addition, we found no statistical difference in ALSFRS-R slopes between the two groups across all three studies using a pooled linear mixed-effects model (slope difference of +0.03 ALSFRS-R/month in the creatine group; P = 0.76). Interestingly, there was a trend towards slightly worsened FVC slope in the creatine group (slope difference of -0.63 FVC/month in the creatine group) using a pooled linear mixed-effects model across the two studies which included FVC as an outcome, but this difference was not statistically significant (P = 0.054). AUTHORS' CONCLUSIONS: In patients already diagnosed with clinically probable or definite ALS, creatine at doses ranging from 5 to 10 g per day did not have a statistically significant effect on survival, ALSFRS-R progression or percent predicted FVC progression.

Filtered Cerebrospinal Fluid From Patients With Amyotrophic Lateral Sclerosis Displays an Altered Proteome and Affects Motor Phenotype in a Mouse Model.

INTRODUCTION: Cerebrospinal fluid (CSF) has been implicated in amyotrophic lateral sclerosis (ALS) due to its ability to spread inflammatory proteins throughout the nervous system. We hypothesized that filtration of the CSF could remove pathogenic proteins and prevent them from altering motor phenotypes in a mouse model. METHODS: We filtered the CSF from 11 ALS patients via 100 kilodaltons (kD) molecular weight cut-off filters. We used mass spectrometry-based discovery proteomics workflows to compare protein abundances before and after filtration. To test the effects of CSF filtration on motor function, we injected groups of mice with saline, filtered ALS-CSF, or unfiltered ALS-CSF (n=12 per group) and assessed motor function via pole descent and open field tests. RESULTS: We identified proteins implicated in ALS pathogenesis and showed that these were removed in significant amounts in our workflow. Key filtered proteins included complement proteins, chitinases, serine protease inhibitors, and neuro-inflammatory proteins such as amyloid precursor protein, chromogranin A, and glial fibrillary acidic protein. Compared to the filtered ALS-CSF mice, unfiltered ALS-CSF mice took longer to descend a pole (10 days post-injection, 11.14 seconds vs 14.25 seconds, p = 0.02) and explored less on an open field (one day post-injection, 21.81 m vs 16.83 m, p = 0.0004). CONCLUSIONS: We demonstrated the ability to filter proteins from the CSF of ALS patients and identified potentially pathologic proteins that were reduced in quantity. Additionally, we demonstrated the ability of unfiltered ALS-CSF to induce motor deficits in mice on the pole descent and open field tests and showed that filtration could prevent this deficit. Given the lack of effective treatments for ALS, this could be a novel solution for patients suffering from this deadly and irreversible condition.

Pathophysiology and Treatment of Non-motor Dysfunction in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease typically presenting with bulbar or limb weakness. There is increasing evidence that amyotrophic lateral sclerosis is a multisystem disease with early and frequent impacts on cognition, behaviour, sleep, pain and fatigue. Dysfunction of normal physiological and metabolic processes also appears common. Evidence from pre-symptomatic studies and large epidemiological cohorts examining risk factors for the future development of amyotrophic lateral sclerosis have reported a high prevalence of changes in behaviour and mental health before the emergence of motor weakness. This suggests that changes beyond the motor system are underway at an early stage with dysfunction across brain networks regulating a variety of cognitive, behavioural and other homeostatic processes. The full impact of non-motor dysfunction continues to be established but there is now sufficient evidence that the presence of non-motor symptoms impacts overall survival in amyotrophic lateral sclerosis, and with up to 80% reporting non-motor symptoms, there is an urgent need to develop more robust therapeutic approaches. This review provides a contemporary overview of the pathobiology of non-motor dysfunction, offering readers a practical approach with regard to assessment and management. We review the current evidence for pharmacological and non-pharmacological treatment of non-motor dysfunction in amyotrophic lateral sclerosis and highlight the need to further integrate non-motor dysfunction as an important outcome measure for future clinical trial design.

MN-166 (ibudilast) in amyotrophic lateral sclerosis in a Phase IIb/III study: COMBAT-ALS study design.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with motor neuron loss as a defining feature. Despite significant effort, therapeutic breakthroughs have been modest. MN-166 (ibudilast) has demonstrated neuroprotective action by various mechanisms: inhibition of proinflammatory cytokines and macrophage migration inhibitory factor, phosphodiesterase inhibition, and attenuation of glial cell activation in models of ALS. Early-phase studies suggest that MN-166 may improve survival outcomes and slow disease progression in patients with ALS. This article describes the rationale and design of COMBAT-ALS, an ongoing randomized, double-blind, placebo-controlled, multicenter Phase IIb/III study in ALS. This study is designed to evaluate the pharmacokinetics, safety and tolerability and assess the efficacy of MN-166 on function, muscle strength, quality of life and survival in ALS.

Lay abstract Amyotrophic lateral sclerosis (ALS) is a neurological disease defined by the loss of the nerve cells going to the muscles. Despite significant effort, we still do not have good treatments for ALS. MN-166 (ibudilast) can protect nerve cells by calming inflammation in several ways in models of ALS. Early human studies suggest that MN-166 may extend life and slow disease progression in ALS patients. This article describes the rationale and design of COMBAT-ALS, an ongoing randomized, double-blind, placebo-controlled, multicenter Phase IIb/III study. This study will show the drug's safety and tolerability and its effects on physical function, muscle strength, quality of life and survival in people living with ALS. Trial registration number: NCT04057898 (ClinicalTrial.gov).

Amyotrophic lateral sclerosis: current practice and future treatments.

PURPOSE OF REVIEW: Knowledge of amyotrophic lateral sclerosis, and in particular the care of patients with it, is evolving exponentially. More than 1700 articles with the phrase 'amyotrophic lateral sclerosis' have been published in the past 2 years; these form the basis for this timely review. RECENT FINDINGS: In part 1, I give an update on the care of patients with amyotrophic lateral sclerosis, including ways to speed diagnosis, optimal use of riluzole, multidisciplinary teams, mechanical ventilation, gastrostomy tubes, lipid-lowering agents and symptom management. Although care has become more evidence-based, there remain a number of quandaries; for these, I will provide suggestions based upon my own experience. In part 2, I identify some exciting new treatment options that are under study. These include agents designed for novel targets within motor neurons and nonneuronal cells, agents designed for specific amyotrophic lateral sclerosis subtypes and interesting new technologies. Finally, in part 3, I define current barriers to developing even better therapeutics and offer ways around them. SUMMARY: The care of patients with amyotrophic lateral sclerosis has evolved and is now more evidence-based than ever before. Exciting new therapies are currently being tested, which may revolutionize care even further. Barriers exist, but they are surmountable.

Modifiable barriers to enrollment in American ALS research studies.

Enrollment in ALS research studies is surprisingly low. Here we report on two online patient surveys that help identify some of the reasons. These include failure to invite patients to enroll, especially patients who have already participated in prior studies. Also included are patient concerns about the cost of participation, and confusion about several aspects of studies being offered. Along with prior work, these data suggest specific steps that can be taken to improve enrollment.

Time to diagnosis in the National Registry of Veterans with Amyotrophic Lateral Sclerosis.

Our objective was to determine the interval from symptom onset to diagnosis, and to evaluate associated factors in a cohort of U.S. Veterans with motor neuron diseases. We retrospectively evaluated 1359 patients enrolled in the National Registry of Veterans with Amyotrophic Lateral Sclerosis (ALS). The main outcome measures were time from symptom onset to first diagnosis and to second opinion. Predictor variables included age at symptom onset, year of symptom onset, race, onset site, final diagnosis, number of diagnostic tests performed and clinical sites visited. Median time to first diagnosis was 11 months; median time to second opinion was two months. In a multivariable model, more recent calendar year of symptom onset, younger age, bulbar onset and a diagnosis of ALS versus non-ALS motor neuron disease were all significantly associated with a shorter time to first diagnosis. Later year of symptom onset and white race were significantly associated with a shorter time to second opinion. While the interval from symptom onset to diagnosis, and many of the associated factors are similar between our large cohort of U.S. Veterans with ALS and other smaller published cohorts, we found that the diagnostic interval among U.S. Veterans has significantly decreased over time.

Creatine for amyotrophic lateral sclerosis/motor neuron disease.

BACKGROUND: Creatine, a naturally-occurring nitrogenous organic acid involved in adenosine triphosphate (ATP) production, has been shown to increase survival in mouse models of amyotrophic lateral sclerosis (ALS). Results from human trials, however, have been mixed. Given conflicting results regarding creatine's efficacy, we conducted a systematic review. OBJECTIVES: To systematically examine creatine's efficacy in prolonging ALS survival and in slowing ALS disease progression. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library issue 4, 2009), MEDLINE and EMBASE in October 2009 for any trial involving creatine in the treatment of ALS. We also contacted experts in the field for any additional studies. SELECTION CRITERIA: Randomized trials of treatment with creatine or placebo in patients diagnosed with ALS. Our primary outcome was tracheostomy-free survival time; secondary outcomes were ALS progression as measured by changes in ALS functional rating revised scores (ALSFRS-R) and percent predicted forced vital capacity (FVC) over time. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, assessed risk of bias and extracted data. We obtained and analyzed individual participant data from each study. MAIN RESULTS: We included three trials involving 386 participants randomized to either creatine 5 to 10 g per day or placebo. Creatine was reportedly well-tolerated in all three included studies, with no evidence of renal failure or serious adverse events specifically attributable to creatine. Using a pooled log-rank statistical test, we found no statistical difference in survival between the placebo and creatine groups across all three studies (Chi(2) = 0.09, P = 0.76). In addition, we found no statistical difference in ALSFRS-R slopes between the two groups across all three studies using a pooled linear mixed-effects model (slope difference of +0.03 ALSFRS-R/month in the creatine group; P = 0.76). Interestingly, there was a trend towards slightly worsened FVC slope in the creatine group (slope difference of -0.63 FVC/month in the creatine group) using a pooled linear mixed-effects model across the two studies which included FVC as an outcome, but this difference was not statistically significant (P = 0.054). AUTHORS' CONCLUSIONS: In patients already diagnosed with clinically probable or definite amyotrophic lateral sclerosis (ALS), creatine at doses ranging from 5 to 10 g per day did not have a statistically significant effect on survival, ALS functional rating revised scores (ALSFRS-R) progression or percent predicted forced vital capacity (FVC) progression.

Plasma creatinine and oxidative stress biomarkers in amyotrophic lateral sclerosis.

Objective: To determine the associations between plasma creatinine (PCr), plasma uric acid (PUA), and urinary oxidative stress (OS) biomarkers with the ALSFRS-R at baseline and survival in a large epidemiological cohort study (ALS COSMOS) with a well-phenotyped patient population (N = 355).Methods: Fasting plasma and first void urine samples were obtained. PCr, PUA, urinary 8-oxo-deoxy guanosine (8-oxodG), and 15-F2t-isoprostane (IsoP) were analyzed at baseline, near the midpoint of follow-up, and at the final blood draw (before death or withdrawal from study). We estimated associations between these biomarkers and the ALSFRS-R at baseline and survival.Results: At baseline, PCr correlated with ALSFRS-R (Spearman r = 0.30), percent (%) FVC (r = 0.20), PUA (r = 0.37), and 8-oxodG (r = -0.13, all p < 0.05). Baseline PCr significantly predicted survival (adjusted hazard ratio 0.28, p < 0.001). Time to death from baseline was shortest for those in the lowest two PCr quartiles relative to the highest two quartiles. PCr and ALSFRS-R values were significantly correlated at all three time points (baseline: r = 0.29, midpoint: r = 0.23, final: r = 0.38, all p < 0.001). PCr and PUA significantly declined over time, whereas OS biomarkers significantly increased over time.Conclusions: To date, PCr predicted survival the best, compared to PUA, 8-oxodG, and IsoP. Although PCr represents the degree of muscle mass, it may also represent complex biochemical changes in ALS. Because the field has no reliable prognostic biomarkers, the importance of PCr warrants further investigation through clinical studies in ALS.

Open-label pilot trial of levetiracetam for cramps and spasticity in patients with motor neuron disease.

Cramps and spasticity impair quality of life and function in patients with motor neuron diseases, and there are no proven treatments for these problems. We conducted a pilot trial to determine if treatment with levetiracetam was associated with a reduction in cramp severity, cramp frequency, tonic or phasic spasticity. We used an open-label repeated measures pilot trial of 20 patients, comparing cramp and spasticity scores over a 3-month baseline versus nine months on treatment. Cramp and spasticity scores were stable over a 3-month baseline. Shortly after starting levetiracetam, there was a significant reduction in cramp severity and frequency, which persisted for the duration of this year-long study. There was also a reduction in phasic but not tonic spasticity. Levetiracetam was well tolerated. Our results justify a placebo-controlled study of levetiracetam for treatment of cramps and spasticity in patients with motor neuron diseases, and suggest that this can be accomplished with a small number of subjects followed for a short time.

Phase 2 study of sodium phenylbutyrate in ALS.

The objective of the study was to establish the safety and pharmacodynamics of escalating dosages of sodium phenylbutyrate (NaPB) in participants with ALS. Transcription dysregulation may play a role in the pathogenesis of ALS. Sodium phenylbutyrate, a histone deacetylase inhibitor, improves transcription and post-transcriptional pathways, promoting cell survival in a mouse model of motor neuron disease. Forty research participants at eight sites enrolled in an open-label study. Study medication was increased from 9 to 21 g/day. The primary outcome measure was tolerability. Secondary outcome measures included adverse events, blood histone acetylation levels, and NaPB blood levels at each dosage. Twenty-six participants completed the 20-week treatment phase. NaPB was safe and tolerable. No study deaths or clinically relevant laboratory changes occurred with NaPB treatment. Histone acetylation was decreased by approximately 50% in blood buffy-coat specimens at screening and was significantly increased after NaPB administration. Blood levels of NaPB and the primary metabolite, phenylacetate, increased with dosage. While the majority of subjects tolerated higher dosages of NaPB, the lowest dose (9 g/day), was therapeutically efficient in improving histone acetylation levels.

Factors associated with survival in the National Registry of Veterans with ALS.

The clinical course of patients with ALS is highly variable. While the median survival time from symptom onset is 2-4 years, there are reports of survival ranging from less than a year to more than 40 years. Such variability makes planning difficult for patients and physicians, and complicates clinical trial design. We sought to validate previous predictors of survival and search for new ones using a large group of ALS patients in the National Registry of Veterans with ALS. We were especially interested in how various aspects of military service might affect survival. Subjects were those in the National Registry of Veterans with ALS who had probable or definite ALS (according to El Escorial criteria). A multivariable Cox proportional hazard regression model was used to examine variables for statistical association with ventilator-free survival time (determined from date of first diagnosis). Subjects who had not died or started ventilation by 31 October 2006 were censored. Our group of 1085 US military veterans with ALS was primarily male (98%) and white (94%), with mostly sporadic (95%) and extremity-onset (76%) ALS. Symptom onset occurred at a mean age of 59.3 years (60.6 years for diagnosis). Median survival time from symptom onset was 4.7 years (3.3 years from diagnosis). In our multivariable model, older age at diagnosis (HR 1.41 (95% CI 1.27-1.55) per 10-year increase), non-extremity site of onset (HR 1.55 (1.24-1.94)), and past deployment to Vietnam (HR 1.73 (1.36-2.19)) were all associated with shortened survival. A longer time to diagnosis was associated with better survival (HR 0.77 (0.70-0.84) per one year increase in diagnosis time). In this unique cohort of veterans with ALS, traditional factors of reduced survival remained important. In addition, past deployment to Vietnam was found to be associated with shortened survival as well. This finding could be due to a common exposure, a shared characteristic, an unmeasured confounder, or an enrollment bias. More research will be needed to understand the reasons behind this new finding.

Scrutinizing enrollment in ALS clinical trials: room for improvement?

Enrollment in ALS trials has not been systematically studied. We surveyed the ALS Research Group (ALSRG) to learn their impressions of enrollment at ALS clinics across North America. We also reviewed completed ALS trials to determine an enrollment rate (subjects per site per month), its variability across trials, whether it is changing over time, and whether it is influenced by 'trial factors'. ALSRG members were polled via an online survey. ALS trials were identified by literature review and investigator contact. Enrollment rate versus publication year was plotted for each trial. Models were created to examine how 'trial factors' were associated with enrollment rate. By survey, percent enrollment is 25% and highly variable (range 0-75%). By literature review, enrollment rate is 2.2 participants/site/month and highly variable (range 0.1-7.5). Enrollment is not improving over time; no 'trial factor' explains the variability in enrollment across trials. Behaviors among clinic directors and patients were identified that may influence enrollment. In conclusion, ALS trial enrollment rate is low, highly variable and not influenced by trial design factors. 'Patient factors' and 'physician factors' may play more important roles in influencing enrollment, as in oncology trials. Our survey data support this idea, and provide potential mechanisms for improving enrollment.