Current therapeutic development in amyotrophic lateral sclerosis (ALS) relies on individual randomized clinical trials to test a specific investigational product in a single patient population. This approach has intrinsic limitations, including cost, time, and lack of flexibility. Adaptive platform trials represent a novel approach to investigate several interventions for a single disease in a continuous manner. Already in use in oncology, this approach is now being employed more often in neurology. Here, we describe a newly launched platform trial for ALS. The Healey ALS Platform Trial is testing multiple investigational products concurrently in people with ALS, with the goal of rapidly identifying novel treatments, biomarkers, and trial endpoints.

Alzheimer disease (AD) is a feared and stigmatized condition, with relentlessly progressive impact not only on the independence and health of people with dementia, but also on the health and financial well-being of their families, and the overall health care system and society. Further research towards effective treatment for AD is urgently needed, and patients with AD deserve more support from clinicians and from their communities. One essential condition of this support is trust. Whereas it is important to offer hope to patients and families, these efforts will ring hollow if trust is lost. Neurologists and others who serve patients and the broader public health must continually ask: Are the statements and actions of our profession worthy of the trust placed in us by patients and the public?Neurologists have often depended upon US Food and Drug Administration (FDA) approval as a sign of a medication's safety and effectiveness, but recent decisions indicate a lowering of the standards of scientific evidence used for drug approvals, 1-3 which will require clinicians to scrutinize approved medications more carefully. One recent example is the approval of aducanumab, a monoclonal antibody directed at β-amyloid aggregates implicated in the pathogenesis of AD. Although drug approval has traditionally depended on support from 2 well-conducted clinical trials, aducanumab was approved based upon 2 studies that were both stopped prematurely for futility. In later post hoc analyses of the available data, 1 trial indicated a statistically significant but small benefit with high-dose aducanumab, while the other study continued to indicate no benefit. The clinical importance of the small statistical benefit in 1 trial for daily function is unclear, and aducanumab was also associated with brain swelling and hemorrhage in more than one-third of patients who received the dose approved by the FDA. An advisory committee of outside experts convened by the FDA reviewed the available evidence and decisively concluded (10 votes no, 1 uncertain) that these data did not support a conclusion that aducanumab slows cognitive decline.The FDA approved aducanumab by invoking the accelerated approval pathway rather than the traditional approval process. This contradicted prior assurances by the agency that the determination would depend on clinical endpoints. 4 Instead, as an accelerated approval, the FDA based its decision on the effects of aducanumab on brain β-amyloid levels as a surrogate marker MORE ONLINE

Upper and lower motor neuron pathologies are critical to the autopsy diagnosis of amyotrophic lateral sclerosis (ALS). Further investigation is needed to determine how the relative burden of these pathologies affects the disease course. We performed a blinded, retrospective study of 38 ALS patients, examining the association between pathologic measures in motor cortex, hypoglossal nucleus, and lumbar cord with clinical data, including progression rate and disease duration, site of symptom onset, and upper and lower motor neuron signs. The most critical finding in our study was that TAR DNA-binding protein 43 kDa (TDP-43) pathologic burden in lumbar cord and hypoglossal nucleus was significantly associated with a faster progression rate with reduced survival (p < 0.02). There was no correlation between TDP-43 burden and the severity of cell loss, and no significant clinical associations were identified for motor cortex TDP-43 burden or severity of cell loss in motor cortex. C9orf72 expansion was associated with shorter disease duration (p < 0.001) but was not significantly associated with pathologic measures in these regions. The association between lower motor neuron TDP-43 burden and fast progression with reduced survival in ALS provides further support for the study of TDP-43 as a disease biomarker.

Background: Repeated neuromuscular electrical stimulation in type 1 Myotonic Dystrophy (DM1) has previously been shown to cause an increase in strength and a decrease in hyperexcitability of the tibialis anterior muscle. Objective: In this proof-of-principle study our objective was to test the hypothesis that noninvasive repetitive transcranial magnetic stimulation of the primary motor cortex (M1) with a new portable wearable multifocal stimulator causes improvement in muscle function in DM1 patients. Methods: We performed repetitive stimulation of M1, localized by magnetic resonance imaging, with a newly developed Transcranial Rotating Permanent Magnet Stimulator (TRPMS). Using a randomized within-patient placebo-controlled double-blind TRPMS protocol, we performed unilateral active stimulation along with contralateral sham stimulation every weekday for two weeks in 6 adults. Methods for evaluation of muscle function involved electromyography (EMG), hand dynamometry and clinical assessment using the Medical Research Council scale. Results: All participants tolerated the treatment well. While there were no significant changes clinically, EMG showed significant improvement in nerve stimulus-evoked compound muscle action potential amplitude of the first dorsal interosseous muscle and a similar but non-significant trend in the trapezius muscle, after a short exercise test, with active but not sham stimulation. Conclusions: We conclude that two-week repeated multifocal cortical stimulation with a new wearable transcranial magnetic stimulator can be safely conducted in DM1 patients to investigate potential improvement of muscle strength and activity. The results obtained, if confirmed and extended by future safety and efficacy trials with larger patient samples, could offer a potential supportive TRPMS treatment in DM1.