Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invaria... more Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invariably fatal neurodegenerative disease. Limited knowledge of the underlying causes of ALS has made it difficult to target upstream biological mechanisms of disease, and therapeutic interventions are usually administered relatively late in the course of disease. Genetic forms of ALS offer a unique opportunity for therapeutic development, as genetic associations may reveal potential insights into disease etiology. Genetic ALS may also be amenable to investigating earlier intervention given the possibility of identifying clinically presymptomatic, at-risk individuals with causative genetic variants. There is increasing evidence for a presymptomatic phase of ALS, with biomarker data from the Pre-Symptomatic Familial ALS (Pre-fALS) study showing that an elevation in blood neurofilament light chain (NfL) precedes phenoconversion to clinically manifest disease. Tofersen is an investigational antis...
Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic late... more Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer’s disease based on inferred underlying histopathology. Parkinson’s disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers ...
ObjectiveTo define the natural history of the C9orf72 amyotrophic lateral sclerosis (C9ALS) patie... more ObjectiveTo define the natural history of the C9orf72 amyotrophic lateral sclerosis (C9ALS) patient population, develop disease biomarkers, and characterize patient pathologies.MethodsWe prospectively collected clinical and demographic data from 116 symptomatic C9ALS and 12 non–amyotrophic lateral sclerosis (ALS) full expansion carriers across 7 institutions in the United States and the Netherlands. In addition, we collected blood samples for DNA repeat size assessment, CSF samples for biomarker identification, and autopsy samples for dipeptide repeat protein (DPR) size determination. Finally, we collected retrospective clinical data via chart review from 208 individuals with C9ALS and 450 individuals with singleton ALS.ResultsThe mean age at onset in the symptomatic prospective cohort was 57.9 ± 8.3 years, and median duration of survival after onset was 36.9 months. The monthly change was −1.8 ± 1.7 for ALS Functional Rating Scale–Revised and −1.4% ± 3.24% of predicted for slow vit...
Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology, Jan 3, 2018
Motor Unit Number Index (MUNIX) is a quantitative neurophysiological method that reflects loss of... more Motor Unit Number Index (MUNIX) is a quantitative neurophysiological method that reflects loss of motor neurons in Amyotrophic Lateral Sclerosis (ALS) in longitudinal studies. It has been utilized in one natural history ALS study and one drug trial (Biogen USA) after training and qualification of raters. Prior to testing patients, evaluators had to submit test-retest data of 4 healthy volunteers. Twenty-seven centres with 36 raters measured MUNIX in 4 sets of 6 different muscles twice. Coefficient of variation of all measurements had to be <20% to pass the qualification process. MUNIX COV of the first attempt, number of repeated measurements and muscle specific COV were evaluated. COV varied considerably between raters. Mean COV of all raters at the first measurements was 12.9% ± 13.5 (median 8.7%). Need of repetitions ranged from 0 to 43 (mean 10.7 ± 9.1, median 8). Biceps and first dorsal interosseus muscles showed highest repetition rates. MUNIX variability correlated consider...
Clinical trials in neurodegenerative disorders are facing high futility rates and rising developm... more Clinical trials in neurodegenerative disorders are facing high futility rates and rising development costs. We aim to review and exemplify the value of group sequential trial designs (i.e. designs with one or more prospectively planned interim analyses) within the field of amyotrophic lateral sclerosis (ALS). We reviewed the literature to identify sequentially conducted trials. Subsequently, we re-analyzed the dexpramipexole trial (EMPOWER), a classically designed and conducted trial involving 942 participants, by sequentially monitoring the functional questionnaire and survival endpoint. Finally, we simulated the performance of the sequential methodology under different treatment effects. Only six (12%) randomized, placebo-controlled trials incorporated stopping rules for both futility and superiority. Despite its high enrollment rate, sequential re-analysis of the EMPOWER study reduced the total trial duration with 140 days (23.4%, 95% CI 13.2% - 34.4%), the number of follow-ups w...
Proceedings of the National Academy of Sciences, 2015
Significance Dual leucine-zipper kinase (DLK) is essential for responses to nerve injury and subs... more Significance Dual leucine-zipper kinase (DLK) is essential for responses to nerve injury and subsequent neural regeneration by controlling transfer of signals from damaged distal axons to neuronal cell bodies. However, DLK is predicted to be freely diffusible, raising the question of how it conveys long-distance, directional signals. Here we report that direct modification of DLK with the lipid palmitate, a process called palmitoylation, is critical for retrograde injury signaling. At the molecular level, palmitoylation targets DLK to retrograde trafficking vesicles, assembles DLK-dependent signaling complexes, and is also essential for DLK kinase activity. This “multifunctional” palmitoylation explains how DLK mediates injury responses and may be a previously unappreciated mechanism that ensures the specificity of enzymatic signaling in diverse cell types.
Abstract For successful regeneration to occur, axons not only need to grow past the lesion, but t... more Abstract For successful regeneration to occur, axons not only need to grow past the lesion, but they also must be targeted to their appropriate synaptic locations. Here we review the basic response of a peripheral neuron to injury, emphasizing the communication of the injury response to the cell body and the initially robust cell body response to injury that often stands in contrast to the injury response of central nervous system neurons. However, despite the high potential for regeneration, patients with peripheral nervous system (PNS) injuries often recover poorly. Failure of PNS regeneration arises not only because of the time and distance over which axon growth must occur but also because of misdirected axon growth even if regenerative potential remains robust. This is more evident with increasing disruption of the nerve integrity by the injury, which progressively decreases the functional outcome. For example, a crush injury shows the highest levels of function recovery, whereas complete transection and nerve excision lesions show the lowest. The low probability of a good outcome after any transection lesion is primarily caused by the misdirected regeneration of motor and sensory axons to inappropriate peripheral targets. However, some preferential re-formation of appropriate synapses after injury exists. Furthermore, modulation of both spinal cord plasticity in response to erroneous motor reinnervation and treatments to increase the specificity of axon regeneration at an injury site have improved regenerative recovery in some cases. Together these observations suggest the possibility of rational strategies to improve recovery of PNS injuries.
After central nervous system (CNS) injury axons fail to regenerate often leading to persistent ne... more After central nervous system (CNS) injury axons fail to regenerate often leading to persistent neurologic deficit although injured peripheral nervous system (PNS) axons mount a robust regenerative response that may lead to functional recovery. Some of the failures of CNS regeneration arise from the many glial-based inhibitory molecules found in the injured CNS, whereas the intrinsic regenerative potential of some CNS neurons is actively curtailed during CNS maturation and limited after injury. In this review, the molecular basis for extrinsic and intrinsic modulation of axon regeneration within the nervous system is evaluated. A more complete understanding of the factors limiting axonal regeneration will provide a rational basis, which is used to develop improved treatments for nervous system injury.
We report on 2 patients with cerebrovascular events associated with sexual activity and PFO who s... more We report on 2 patients with cerebrovascular events associated with sexual activity and PFO who subsequently underwent endovascular patent foramen ovale (PFO) closure. The concurrence of sexual activity (a Valsalva equivalent) at symptom onset, together with supporting data, prior paradoxical embolus in 1 case, elevated D-dimer in another, supported paradoxical embolization as the most likely mechanism of the cerebrovascular events. These cases emphasize that clinicians evaluating patients for PFO closure should explicitly inquire about sexual activity at stroke onset.
Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invaria... more Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invariably fatal neurodegenerative disease. Limited knowledge of the underlying causes of ALS has made it difficult to target upstream biological mechanisms of disease, and therapeutic interventions are usually administered relatively late in the course of disease. Genetic forms of ALS offer a unique opportunity for therapeutic development, as genetic associations may reveal potential insights into disease etiology. Genetic ALS may also be amenable to investigating earlier intervention given the possibility of identifying clinically presymptomatic, at-risk individuals with causative genetic variants. There is increasing evidence for a presymptomatic phase of ALS, with biomarker data from the Pre-Symptomatic Familial ALS (Pre-fALS) study showing that an elevation in blood neurofilament light chain (NfL) precedes phenoconversion to clinically manifest disease. Tofersen is an investigational antis...
Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic late... more Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer’s disease based on inferred underlying histopathology. Parkinson’s disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers ...
ObjectiveTo define the natural history of the C9orf72 amyotrophic lateral sclerosis (C9ALS) patie... more ObjectiveTo define the natural history of the C9orf72 amyotrophic lateral sclerosis (C9ALS) patient population, develop disease biomarkers, and characterize patient pathologies.MethodsWe prospectively collected clinical and demographic data from 116 symptomatic C9ALS and 12 non–amyotrophic lateral sclerosis (ALS) full expansion carriers across 7 institutions in the United States and the Netherlands. In addition, we collected blood samples for DNA repeat size assessment, CSF samples for biomarker identification, and autopsy samples for dipeptide repeat protein (DPR) size determination. Finally, we collected retrospective clinical data via chart review from 208 individuals with C9ALS and 450 individuals with singleton ALS.ResultsThe mean age at onset in the symptomatic prospective cohort was 57.9 ± 8.3 years, and median duration of survival after onset was 36.9 months. The monthly change was −1.8 ± 1.7 for ALS Functional Rating Scale–Revised and −1.4% ± 3.24% of predicted for slow vit...
Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology, Jan 3, 2018
Motor Unit Number Index (MUNIX) is a quantitative neurophysiological method that reflects loss of... more Motor Unit Number Index (MUNIX) is a quantitative neurophysiological method that reflects loss of motor neurons in Amyotrophic Lateral Sclerosis (ALS) in longitudinal studies. It has been utilized in one natural history ALS study and one drug trial (Biogen USA) after training and qualification of raters. Prior to testing patients, evaluators had to submit test-retest data of 4 healthy volunteers. Twenty-seven centres with 36 raters measured MUNIX in 4 sets of 6 different muscles twice. Coefficient of variation of all measurements had to be <20% to pass the qualification process. MUNIX COV of the first attempt, number of repeated measurements and muscle specific COV were evaluated. COV varied considerably between raters. Mean COV of all raters at the first measurements was 12.9% ± 13.5 (median 8.7%). Need of repetitions ranged from 0 to 43 (mean 10.7 ± 9.1, median 8). Biceps and first dorsal interosseus muscles showed highest repetition rates. MUNIX variability correlated consider...
Clinical trials in neurodegenerative disorders are facing high futility rates and rising developm... more Clinical trials in neurodegenerative disorders are facing high futility rates and rising development costs. We aim to review and exemplify the value of group sequential trial designs (i.e. designs with one or more prospectively planned interim analyses) within the field of amyotrophic lateral sclerosis (ALS). We reviewed the literature to identify sequentially conducted trials. Subsequently, we re-analyzed the dexpramipexole trial (EMPOWER), a classically designed and conducted trial involving 942 participants, by sequentially monitoring the functional questionnaire and survival endpoint. Finally, we simulated the performance of the sequential methodology under different treatment effects. Only six (12%) randomized, placebo-controlled trials incorporated stopping rules for both futility and superiority. Despite its high enrollment rate, sequential re-analysis of the EMPOWER study reduced the total trial duration with 140 days (23.4%, 95% CI 13.2% - 34.4%), the number of follow-ups w...
Proceedings of the National Academy of Sciences, 2015
Significance Dual leucine-zipper kinase (DLK) is essential for responses to nerve injury and subs... more Significance Dual leucine-zipper kinase (DLK) is essential for responses to nerve injury and subsequent neural regeneration by controlling transfer of signals from damaged distal axons to neuronal cell bodies. However, DLK is predicted to be freely diffusible, raising the question of how it conveys long-distance, directional signals. Here we report that direct modification of DLK with the lipid palmitate, a process called palmitoylation, is critical for retrograde injury signaling. At the molecular level, palmitoylation targets DLK to retrograde trafficking vesicles, assembles DLK-dependent signaling complexes, and is also essential for DLK kinase activity. This “multifunctional” palmitoylation explains how DLK mediates injury responses and may be a previously unappreciated mechanism that ensures the specificity of enzymatic signaling in diverse cell types.
Abstract For successful regeneration to occur, axons not only need to grow past the lesion, but t... more Abstract For successful regeneration to occur, axons not only need to grow past the lesion, but they also must be targeted to their appropriate synaptic locations. Here we review the basic response of a peripheral neuron to injury, emphasizing the communication of the injury response to the cell body and the initially robust cell body response to injury that often stands in contrast to the injury response of central nervous system neurons. However, despite the high potential for regeneration, patients with peripheral nervous system (PNS) injuries often recover poorly. Failure of PNS regeneration arises not only because of the time and distance over which axon growth must occur but also because of misdirected axon growth even if regenerative potential remains robust. This is more evident with increasing disruption of the nerve integrity by the injury, which progressively decreases the functional outcome. For example, a crush injury shows the highest levels of function recovery, whereas complete transection and nerve excision lesions show the lowest. The low probability of a good outcome after any transection lesion is primarily caused by the misdirected regeneration of motor and sensory axons to inappropriate peripheral targets. However, some preferential re-formation of appropriate synapses after injury exists. Furthermore, modulation of both spinal cord plasticity in response to erroneous motor reinnervation and treatments to increase the specificity of axon regeneration at an injury site have improved regenerative recovery in some cases. Together these observations suggest the possibility of rational strategies to improve recovery of PNS injuries.
After central nervous system (CNS) injury axons fail to regenerate often leading to persistent ne... more After central nervous system (CNS) injury axons fail to regenerate often leading to persistent neurologic deficit although injured peripheral nervous system (PNS) axons mount a robust regenerative response that may lead to functional recovery. Some of the failures of CNS regeneration arise from the many glial-based inhibitory molecules found in the injured CNS, whereas the intrinsic regenerative potential of some CNS neurons is actively curtailed during CNS maturation and limited after injury. In this review, the molecular basis for extrinsic and intrinsic modulation of axon regeneration within the nervous system is evaluated. A more complete understanding of the factors limiting axonal regeneration will provide a rational basis, which is used to develop improved treatments for nervous system injury.
We report on 2 patients with cerebrovascular events associated with sexual activity and PFO who s... more We report on 2 patients with cerebrovascular events associated with sexual activity and PFO who subsequently underwent endovascular patent foramen ovale (PFO) closure. The concurrence of sexual activity (a Valsalva equivalent) at symptom onset, together with supporting data, prior paradoxical embolus in 1 case, elevated D-dimer in another, supported paradoxical embolization as the most likely mechanism of the cerebrovascular events. These cases emphasize that clinicians evaluating patients for PFO closure should explicitly inquire about sexual activity at stroke onset.
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