Leo H. Wang

MIXED LINEAGE KINASE INHIBITOR CEP- 1347 FAILS TO DELAY DISABILITY IN EARLY PARKINSON DISEASE

We read the Parkinson Study Group’s article with interest.1 The disappointing result in PRECEPT that used mixed-lineage kinase (MLK) inhibitor CEP-1347 for treatment of Parkinson disease (PD) may be because 1) the hypothesis that MLK inhibitors retard disease progression is incorrect; 2) the inhibitor does not reach therapeutic levels in the CNS; or 3) MLK inhibitors require an additional signal to maintain dopaminergic neuronal survival. Based on our research into the molecular mechanism of MLK inhibitors, we propose the third possibility as why MLK inhibitors did not maintain neuronal survival.nnSmall-molecule MLK inhibitors such as CEP-1347 and CEP-11004 inhibit activation of the c-Jun NH2-terminal kinase (JNK) and neuronal cell death pathway in many cell culture and animal models. However, in three well-defined cell culture models of trophic factor-withdrawal neuronal cell death, neurons maintained by MLK inhibitors require additional activation of the phosphatidylinositol 3-kinase (PI3-kinase) pathway for survival.2,3nnIn sympathetic neurons deprived of nerve growth factor, MLK inhibitors induce TrkA receptor overexpression.3 Increases in TrkA expression cause ligand-independent activation of the receptor and, consequently, the PI3-kinase-Akt-GSK (glycogen synthase kinase)-3 pathway. Inhibition of PI3-kinase negates the long-term cell survival and trophic effects of MLK inhibitors.nnIn contrast, MLK inhibitors only maintain short-term survival in trophic-deprived cerebellar granule neurons (CGNs) that express TrkB, another Trk-receptor family member. While MLK inhibitors increase TrkB expression, this does …

MR nerve imaging in a prospective cohort of patients with suspected carpal tunnel syndrome

Objectives To evaluate the reliability and diagnostic accuracy of high-resolution MRI of the median nerve in a prospectively assembled cohort of subjects with clinically suspected carpal tunnel syndrome (CTS). Methods The authors prospectively identified 120 subjects with clinically suspected CTS from five Seattle-area clinics. All subjects completed a hand-pain diagram and underwent a standardized nerve conduction study (NCS). The reference standard for determining CTS status was a classic or probable hand pain diagram and NCS with a difference >0.3 ms between the 8-cm median and ulnar peak latencies. Readers graded multiple imaging parameters of the MRI on four-point scales. The authors also performed quantitative measurements of both the median nerve and carpal tunnel cross-sectional areas. NCS and MRI were interpreted without knowledge of the other study or the hand pain diagram. Results Intrareader reliability was substantial to near perfect (kappa = 0.76 to 0.88). Interreader agreement was lower but still substantial (kappa = 0.60 to 0.67). Sensitivity of MRI was greatest for the overall impression of the images (96%) followed by increased median nerve signal (91%); however, specificities were low (33 to 38%). The length of abnormal signal on T2-weighted images was significantly correlated with nerve conduction latency, and median nerve area was larger at the distal radioulnar joint (15.8 vs 11.8 mm2) in patients with CTS. A logistic regression model combining these two MR variables had a receiver operating characteristic area under the curve of 0.85. Conclusions The reliability of MRI is high but the diagnostic accuracy is only moderate compared with a research-definition reference standard.

Role of Magnetic Resonance Imaging, Cerebrospinal Fluid, and Electroencephalogram in Diagnosis of Sporadic Creutzfeldt-Jakob Disease

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive dementia (RPD) that can be difficult to identify antemortem, with definitive diagnosis requiring tissue confirmation. We describe the clinical, magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and electroencephalogram (EEG) measures of a small cohort of 30 patients evaluated for RPD. Clinical and diagnostic measures were cross-sectionally obtained from 17 sCJD patients (15 definite, two probable), 13 non-prion rapidly progressive dementia patients (npRPD), and 18 unimpaired controls. In a subset of patients (nine sCJD and nine npRPD) diffusion tensor imaging (DTI) measures [fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD)] were also obtained for the caudate, corpus callosum, posterior limb of the internal capsule, pulvinar, precuneus, and frontal lobe. Differences among groups were assessed by an analysis of variance. Compared to npRPD individuals, sCJD patients had cerebellar dysfunction, significantly higher CSF tau, “positive” CSF 14-3-3, and hyperintensities on diffusion-weighted imaging (DWI) that met previously established imaging criteria for sCJD. EEG changes were similar for the two groups. In addition, sCJD patients had significant decreases in DTI measures (MD, AD, RD but not FA) within the caudate and pulvinar compared to either npRPD patients or unimpaired controls. Our results confirm that CSF abnormalities and MRI (especially DWI) can assist in distinguishing sCJD patients from npRPD patients. Future longitudinal studies using multiple measures (including CSF and MRI) are needed for evaluating pathological changes seen in sCJD patients.

Defining SOD1 ALS natural history to guide therapeutic clinical trial design

Importance Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALSSOD1) will provide key information for optimising clinical trials in this patient population. Objective To establish an updated natural history of ALSSOD1. Design, setting and participants Retrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000. Main outcomes and measures Age of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1A4V), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1non-A4V) for analysis. Results Mean age of disease onset was 49.7±12.3u2005years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1A4V and SOD1non-A4V (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7u2005years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7u2005years for SOD1A4V. SOD1A4V survival probability (median survival 1.2u2005years) was significantly decreased compared with SOD1non-A4V (median survival 6.8u2005years; p<0.0001, log-rank). A statistically significant increase in ALS-FRS decline in SOD1A4V compared with SOD1non-A4V participants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1A4V compared with SOD1non-A4V (p=0.02). Conclusions and relevance SOD1A4V is an aggressive, but relatively homogeneous form of ALS. These SOD1-specific ALS natural history data will be important for the design and implementation of clinical trials in the ALSSOD1 patient population.

Sleep Pathology in Creutzfeldt-Jakob Disease.

STUDY OBJECTIVESnAssociations between sleep and neurodegenerative diseases have become increasingly evident. This study aims to characterize the prevalence and type of sleep pathology in Creutzfeldt-Jakob disease (CJD), a rapidly progressive, fatal neurodegenerative disease.nnnMETHODSnIn this observational cross-sectional cohort study, we performed a retrospective analysis of sleep signs and symptoms in a consecutive group of patients with definite CJD at a tertiary care medical center (n = 28). Polysomnography was performed in 14 patients.nnnRESULTSnAlthough only 5 of 28 patients carried a premorbid sleep diagnosis, signs/symptoms of sleep pathology were present in 25 patients. Eleven reported hypersomnia whereas 13 reported insomnia. Seven had restless legs symptoms and/or periodic limb movements of sleep, and nine reported parasomnias. Of the 14 patients who underwent polysomnography, 1 did not show sleep, 9 (69%) had poorly formed or absent sleep spindles and/or K-complexes, and 10 (77%) had sleep-disordered breathing. Of the 8 patients who experienced rapid eye movement (REM) sleep during the polysomnography, 3 (38%) showed REM sleep without atonia, and 2 patients met criteria for REM sleep behavior disorder. Median total sleep time was 226 (interquartile range [IQR] = 195-282) min. Median sleep efficiency was 58.5% (IQR = 41-65.5 %). Median REM time was 0.35% (IQR = 0-7.125%). Five patients (38%) demonstrated periodic limb movements during polysomnography. One case is presented.nnnCONCLUSIONSnSleep pathology is common in CJD, and screening for sleep pathology is indicated in the evaluation of patients with rapidly progressive dementias. Early identification and treatment of sleep pathology may provide an intervenable target for CJD.

Death with dignity in Washington patients with amyotrophic lateral sclerosis

Objectives: To describe the amyotrophic lateral sclerosis (ALS) patients who sought medication under the Washington State Death with Dignity (DWD) Act since its inception in 2009. Methods: Chart review at 3 tertiary medical centers in the Seattle/Puget Sound region and comparison to publicly available data of ALS and all-cause DWD cohorts from Washington and Oregon. Results: In Washington State, 39 patients with ALS requested DWD from the University of Washington, Virginia Mason, and Swedish Medical Centers beginning in 2009. The median age at death was 65 years (range 46–86). Seventy-seven percent of the patients used the prescriptions. All of the patients who used the medications passed away without complications. The major reasons for patients to request DWD as reported by participating physicians were loss of autonomy and dignity and decrease in enjoyable activities. Inadequate pain control, financial cost, and loss of bodily control were less commonly indicated. These findings were similar to those of the 92 patients who sought DWD in Oregon. In Washington and Oregon, the percentage of patients with ALS seeking DWD is higher compared to the cancer DWD cohort. Furthermore, compared to the all-cause DWD cohort, patients with ALS are more likely to be non-Hispanic white, married, educated, enrolled in hospice, and to have died at home. Conclusions: Although a small number, ALS represents the disease with the highest proportion of patients seeking to participate in DWD. Patients with ALS who choose DWD are well-educated and have access to palliative or life-prolonging care. The use of the medications appears to be able to achieve the patients goals without complications.

Molecular Therapies for Muscular Dystrophies

Purpose of reviewTo construct a framework to understand the different molecular interventions for muscular dystrophy.Recent findingsThe recent approval of antisense oligonucleotides treatment for Duchenne muscular dystrophy and spinal muscular atrophy and current clinical trials using recombinant adeno-associated virus for the treatment of those diseases suggests that we are at a tipping point where we are able to treat and potentially cure muscular dystrophies.SummaryUnderstanding the basic molecular pathogenesis of muscular dystrophies and the molecular biology of the treatment allows for critical evaluation of the proposed therapies.

MRI change metrics of facioscapulohumeral muscular dystrophy: Stir and T1: FSHD MRI STIR and T1

Introduction: MRI evaluation in facioscapulohumeral muscular dystrophy (FSHD) demonstrates fatty replacement and inflammation/edema in muscle. Our previous work demonstrated short T1 inversion recovery (STIR)‐hyperintense (STIR+) signal in muscle 2 years before fatty replacement. We evaluated leg muscle STIR changes and fatty replacement within 14 months. Methods: FSHD subjects received 2 MRI scans of thigh and calf over a 6.9‐ to 13.8‐month interval. Quality of life measures were collected. One Radiologist rated muscle changes on a semi‐quantitative scale. Results: Fifteen subjects completed longitudinal imaging. Four STIRu2009+u2009muscles and 3 STIR‐normal (STIR−) muscles were rated as progressing to fatty tissue over the study period. Discussion: STIRu2009+u2009muscles with confluent regions of fat at baseline increased more in fat, while STIR− muscles had increases in septal‐fat over the study period. These changes may reflect two phases of FSHD, demonstrating MRI sensitivity is weighted toward gross pathological phases of the disease. Muscle Nerve 57: 905–912, 2018

A muscle strength enhancer for all seasons?: A Muscle Enhancer

Fast skeletal muscle troponin activators (FSTAs) are a new class of therapeutic agents that have the potential to improve strength and function in patients with weakness due to various pathophysiological defects, possibly serving as treatment for a number of neuromuscular conditions such as amyotrophic lateral sclerosis (ALS), neuromuscular junction disorders, and muscle disease. FTSAs are small-molecule drugs that slow the rate of calcium release from troponin C, sensitizing the sarcomere of fast skeletal muscle to calcium and producing greater muscle force at submaximal nerve input. When a motor unit action potential is triggered, calcium is released from the sarcoplasmic reticulum, inducing a structural change in troponin C and allowing for assemblage of the 3subunit troponin complex. This allows for translocation of the 3-subunit troponin and tropomyosin complex to a different part of the actin filament. Together, these changes expose the myosin-binding site on the actin filament. The motor head of myosin is then able to bind to actin and, in an adenosine triphosphate-dependent manner, undergo a power stroke to slide the oppositely anchored thin filaments across the centrally located thick filaments, resulting in muscle contraction. FTSAs are specific to fast skeletal muscle because fast skeletal muscles express their own troponin C isoform from the TNNC2 gene that is distinct from the cardiac and slow skeletal muscle troponin C isoforms encoded from the TNNC1 gene. The prolonged presence of calcium on troponin C allows for a lower threshold of actin-myosin interaction and more force output at submaximal nerve stimulation. An early generation FSTA, tirasemtiv, was previously shown to enhance skeletal muscle contractile force in a dose-, concentration-, and frequencydependent manner, potentially translating into improved muscle strength in patients with neuromuscular diseases. FSTAs have been shown to improve muscle performance and force of muscular contraction in murine models of nemaline myopathy, myasthenia gravis, and amyotrophic lateral sclerosis (ALS), and exercise tolerance in a rat model of heart failure. In humans, tirasemtiv has been studied in a small, double-blind, randomized, controlled phase 2 trial of acetylcholine receptor binding antibody-positive myasthenia gravis patients, demonstrating significant dose-dependent improvements on the Quantitative Myasthenia Gravis scale as well as in forced vital capacity. In randomized, double-blind, placebo-controlled phase 2b and phase 3 trials in ALS, tirasemtiv slowed the rate of deterioration of the slow vital capacity (SVC) but did not meet the primary endpoint of change from baseline of the ALS Functional Rating Scale (ALSFRS-R) in the phase 2 trial or the primary SVC endpoint in the phase 3 trial. There was a high rate of adverse events with the study medication, leading to a number of dropouts in the phase 2 trial, most notably due to dizziness but also to fatigue, confusion, and nausea. In this issue of Muscle & Nerve, Andrews et al. report the results of three phase 1 trials investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of a second-generation FSTA, CK2127107, in healthy volunteers. In the first study, CY 5011, a pharmacokinetic analysis of a single dose of the medication, ranging from 30 to 4,000 mg, there was a dose-dependent increase in maximum observed plasma concentration, and a steady median half-life of 8–12 hours at doses above 270 mg. The second study, CY 5012, established that CK-2127107 displayed similar pharmacokinetic parameters, achieving steady-state blood concentrations in both sexes and across different age groups (18–55 and 65– 85 years of age), with doses of 300 or 500 mg twice daily for 10–17 days. The third study, CY 5013, explored the pharmacodynamic properties of the study medication, evaluating the effects of CK2127107 on muscle contraction. Specifically, the study assessed the ability of a single dose of CK2127107 to augment the force generated by the tibialis anterior muscle. Using a strain-gauge to measure muscle force generated by electrical stimulation of the deep fibular nerve, CK-2127107 was found to increase tibialis anterior motor responses in a generally doseand plasma-concentration–dependent manner at all stimulation frequencies (5–50 HZ), Conflict of Interest: M.D.W. is on the speaker’s bureau for Soleo Health.

MRI-informed muscle biopsies correlate MRI with pathology and DUX4 target gene expression in FSHD

Abstract Facioscapulohumeral muscular dystrophy (FSHD) is a common, dominantly inherited disease caused by the epigenetic de‐repression of the DUX4 gene, a transcription factor normally repressed in skeletal muscle. As targeted therapies are now possible in FSHD, a better understanding of the relationship between DUX4 activity, muscle pathology and muscle magnetic resonance imaging (MRI) changes is crucial both to understand disease mechanisms and for the design of future clinical trials. Here, we performed MRIs of the lower extremities in 36 individuals with FSHD, followed by needle muscle biopsies in safely accessible muscles. We examined the correlation between MRI characteristics, muscle pathology and expression of DUX4 target genes. Results show that the presence of elevated MRI short tau inversion recovery signal has substantial predictive value in identifying muscles with active disease as determined by histopathology and DUX4 target gene expression. In addition, DUX4 target gene expression was detected only in FSHD‐affected muscles and not in control muscles. These results support the use of MRI to identify FSHD muscles most likely to have active disease and higher levels of DUX4 target gene expression and might be useful in early phase therapeutic trials to demonstrate target engagement in therapies aiming to suppress DUX4 expression.