A Phase 1 study of GDC-0134, a dual leucine zipper kinase inhibitor, in ALS.

Objective: Dual leucine zipper kinase (DLK), which regulates the c-Jun N-terminal kinase pathway involved in axon degeneration and apoptosis following neuronal injury, is a potential therapeutic target in amyotrophic lateral sclerosis (ALS). This first-in-human study investigated safety, tolerability, and pharmacokinetics (PK) of oral GDC-0134, a small-molecule DLK inhibitor. Plasma neurofilament light chain (NFL) levels were explored in GDC-0134-treated ALS patients and DLK conditional knockout (cKO) mice.

A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis.

Introduction/aims: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative illness with great unmet patient need. We aimed to evaluate whether mesenchymal stem cells induced to secrete high levels of neurotrophic factors (MSC-NTF), a novel autologous cell-therapy capable of targeting multiple pathways, could safely slow ALS disease progression.

Methods: This randomized, double-blind, placebo-controlled study enrolled ALS participants meeting revised El Escorial criteria, revised ALS Functional Rating Scale (ALSFRS-R) ≥25 (screening) and ≥3 ALSFRS-R points decline prior to randomization.

Plasma creatinine and oxidative stress biomarkers in amyotrophic lateral sclerosis.

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 ( = 355). Fasting plasma and first void urine samples were obtained. PCr, PUA, urinary 8-oxo-deoxy guanosine (8-oxodG), and 15-F-isoprostane (IsoP) were analyzed at baseline, near the midpoint of follow-up, and at the final blood draw (before death or withdrawal from study).

Review process for IVIg treatment: Lessons learned from INSIGHTS neuropathy study.

Background: This project is an effort to understand how orders for IV immunoglobulin (IVIg) are documented and prescribed by physicians, and subsequently, how they are reviewed by insurance companies for the treatment of immune neuropathies.

Methods: A panel of neuromuscular specialists reviewed case records from 248 IVIg-naive patients whose in-home IVIg infusion treatment was submitted to insurance for authorization. After reviewing a case record, 1 panelist was asked to make a diagnosis and to answer several questions about the treatment.

Phase I clinical trial of safety of L-serine for ALS patients.

We performed a randomized, double-blind phase I clinical trial for six months on the effects of oral L-serine in patients with ALS. The protocol called for enrollment of patients with a diagnosis of probable or definite ALS, age 18-85 years, disease duration of less than three years and forced vital capacity (FVC) ≥ 60%. Patients were randomly assigned to four different oral twice-daily dose regimens (0.

Cognitive-behavioral screening reveals prevalent impairment in a large multicenter ALS cohort.

Objectives: To characterize the prevalence of cognitive and behavioral symptoms using a cognitive/behavioral screening battery in a large prospective multicenter study of amyotrophic lateral sclerosis (ALS).

Methods: Two hundred seventy-four patients with ALS completed 2 validated cognitive screening tests and 2 validated behavioral interviews with accompanying caregivers. We examined the associations between cognitive and behavioral performance, demographic and clinical data, and C9orf72 mutation data.

Phrenic nerve conduction studies as a biomarker of respiratory insufficiency in amyotrophic lateral sclerosis.

Our objective was to examine the value of phrenic nerve conduction studies (PNCS) in quantifying diaphragm dysfunction in ALS, as no ideal test of respiratory insufficiency exists in ALS. We prospectively recorded bilateral PNCS, forced vital capacity (FVC), maximum inspiratory pressure (MIP), sniff nasal inspiratory pressure (SNIP), respiratory rate, ALSFRS-R, and respiratory symptoms in 100 ALS patients attending our clinic over a nine-month period. Survival data were collected for two years.

The Dilemma of the Clinical Trialist in Amyotrophic Lateral Sclerosis: The Hurdles to Finding a Cure.

Amyotrophic lateral sclerosis can be described as a disease with a poorly understood pathophysiologic mechanism and no treatment that dramatically impacts the course of the disease. Clinical trialists are faced with finding small treatment effects against a background of multiple potential treatments, a past history of failed trials, and heterogenous clinical outcomes. This article summarizes this environment and provides a rationale for drug development going forward.

Amyotrophic Lateral Sclerosis Regional Variants (Brachial Amyotrophic Diplegia, Leg Amyotrophic Diplegia, and Isolated Bulbar Amyotrophic Lateral Sclerosis).

Amyotrophic lateral sclerosis (ALS), a rapidly progressive, invariably fatal disease, involves mixed upper and lower motor neurons in different spinal cord regions. Patients with bulbar onset progress more rapidly than patients with limb onset or with a lower motor neuron presentation. Recent descriptions of regional variants suggest some patients have ALS isolated to a single spinal region for many years, including brachial amyotrophic diplegia, leg amyotrophic diplegia, and isolated bulbar palsy.

Patterns of Weakness, Classification of Motor Neuron Disease, and Clinical Diagnosis of Sporadic Amyotrophic Lateral Sclerosis.

When approaching a patient with suspected motor neuron disease (MND), the pattern of weakness on examination helps distinguish MND from other diseases of peripheral nerves, the neuromuscular junction, or muscle. MND is a clinical diagnosis supported by findings on electrodiagnostic testing. MNDs exist on a spectrum, from a pure lower motor neuron to mixed upper and lower motor neuron to a pure upper motor neuron variant.

Amyotrophic Lateral Sclerosis: A Historical Perspective.

This article looks back in time to see where the foundational basis for the understanding of amyotrophic lateral sclerosis originated. This foundation was created primarily in France by Jean-Martin Charcot and his fellow countrymen and disciples, along with key contributions from early clinicians in England and Germany. The early work on amyotrophic lateral sclerosis provides a useful foundation for today's clinicians with respect to tying together genetic and biologic aspects of the disorder that have been discovered over the past few decades.

Echocardiography and Cardiac Rupture: Is Contrast Extravasation an Indication for Surgery?

Contrast echocardiography demonstrating microbubbles in the pericardial space has often been cited as evidence of ventricular rupture requiring emergent surgical intervention. We report a case where no myocardial perforation was found during post-myocardial infarction surgery despite prior echocardiographic evidence of contrast extravasation into the pericardial effusion. Clinical decision making requires balancing imaging evidence with clinical circumstances to determine the optimal timing for surgical intervention.

Randomized phase 2 trial of NP001-a novel immune regulator: Safety and early efficacy in ALS.

Objective: To assess the safety, tolerability, and preliminary efficacy of NP001, a novel immune regulator of inflammatory monocytes/macrophages, for slowing progression of amyotrophic lateral sclerosis (ALS).

Methods: This was a phase 2 randomized, double-blind, placebo-controlled trial of NP001 in 136 patients with ALS of <3 years' duration and forced vital capacity ≥70%. Participants received NP001 2 mg/kg, NP001 1 mg/kg, or placebo for 6 months.

ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS): study methodology, recruitment, and baseline demographic and disease characteristics.

Abstract In a multicenter study of newly diagnosed ALS patients without a reported family history of ALS, we are prospectively investigating whether markers of oxidative stress (OS) are associated with disease progression. Methods utilize an extensive structured telephone interview ascertaining environmental, lifestyle, dietary and psychological risk factors associated with OS. Detailed assessments were performed at baseline and at 3-6 month intervals during the ensuing 30 months.

Genetic CJD with a novel E200G mutation in the prion protein gene and comparison with E200K mutation cases.

A novel point mutation resulting in a glutamate-to-glycine substitution in PRNP at codon 200, E200G with codon 129 MV polymorphism (cis valine) and type 2 PrPSc was identified in a patient with a prolonged disease course leading to pathology-proven Jakob-Creutzfeldt disease. Despite the same codon as the most common genetic form of human PRNP mutation, E200K, this novel mutation (E200G) presented with a different clinical and pathological phenotype, including prolonged duration, large vacuoles, no vacuolation in the hippocampus, severe neuronal loss in the thalamus, mild cerebellar involvement, and abundant punctate linear and curvilinear deposition of PrPSc in synaptic boutons and axonal terminals along the dendrites.

Leg amyotrophic diplegia: prevalence and pattern of weakness at US neuromuscular centers.

Objective: To identify the frequency of leg amyotrophic diplegia (LAD) at a US academic center, describe the pattern of weakness, and provide comparative data from 8 additional major US academic institutions.

Background: LAD is a leg onset variant of progressive muscular atrophy (PMA). LAD weakness is confined to the legs for at least 2 years, and there are no upper motor neuron signs.

Effects of noninvasive ventilation on sleep outcomes in amyotrophic lateral sclerosis.

Study Objectives: The objective was to study the effects on noninvasive ventilation on sleep outcomes in patient with ALS, specifically oxygenation and overall sleep quality.

Methods: Patients with ALS who met criteria for initiation of NIV were studied with a series of 2 home PSG studies, one without NIV and a follow-up study while using NIV. Primary outcome was a change in the maximum overnight oxygen saturation; secondary outcomes included change in mean overnight oxygen saturation, apnea and hypopnea indexes, sleep latency, sleep efficiency, sleep arousals, and sleep architecture.

Combined fulminant frontotemporal dementia and amyotrophic lateral sclerosis associated with an I113T SOD1 mutation.

Mutations in the gene for superoxide dismutase type 1 cause amyotrophic lateral sclerosis (ALS), but are not thought to be associated with frontotemporal dementia (FTD). A lack of detailed case reports is one reason, among others, for this skepticism. This case report comments on a patient with familial ALS caused by I113T mutation in the SOD1 gene presenting with progressive cognitive and behavioral decline two years before developing progressive motor degeneration.

Progression of white matter degeneration in amyotrophic lateral sclerosis: A diffusion tensor imaging study.

Whether longitudinal diffusion tensor MRI imaging (DTI) can capture disease progression in patients with amyotrophic lateral sclerosis (ALS) is unclear. The primary goal of this study was to determine if DTI detects progression of the corticospinal tracts (CST) degeneration in ALS. Seventeen ALS patients and 19 age- and gender-matched healthy controls were scanned with DTI at baseline for cross-sectional analyses.

Molecular diagnosis of hereditary inclusion body myopathy by linkage analysis and identification of a novel splice site mutation in GNE.

Background: Many myopathies share clinical features in common, and diagnosis often requires genetic testing. We ascertained a family in which five siblings presented with distal muscle weakness of unknown etiology.

Methods: We performed high-density genomewide linkage analysis and mutation screening of candidate genes to identify the genetic defect in the family.

Neuroanatomical correlates of apathy in ALS using 4 Tesla diffusion tensor MRI.

Our objective was to determine whether apathy in amyotrophic lateral sclerosis (ALS) relates to structural changes associated with the degenerative process or disease related factors such as illness duration, physical disability, or hypoxia. Using diffusion tensor imaging (DTI) with fractional anisotropy (FA), we conducted a voxel-based analysis of whole-brain changes to investigate decline in white matter integrity as it correlates with apathy in ALS. Twenty-four patients enrolled in the study were compared with 24 age- and gender-matched controls.

Detecting frontotemporal dysfunction in ALS: utility of the ALS Cognitive Behavioral Screen (ALS-CBS).

Up to half of patients with ALS develop cognitive impairment during the course of the illness. Despite this, there is no simple tool for screening patients in the clinical setting. This study examines the sensitivity, specificity and accuracy of the ALS Cognitive Behavioral Screen (ALS-CBS).

Insight in ALS: awareness of behavioral change in patients with and without FTD.

Unlabelled: Although impaired insight is a core diagnostic criterion for establishing the diagnosis of frontotemporal dementia (FTD), insight has rarely been studied in amyotrophic lateral sclerosis (ALS).

Objective: To determine differences between patient and informant (caregiver) reports of behavior and behavioral change in amyotrophic lateral sclerosis.

Methods: Behavioral data for 17 patients with ALS and 4 patients with ALS-FTD were analyzed.

Cognitive and behavioral impairment in amyotrophic lateral sclerosis.

Cognitive impairment in amyotrophic lateral sclerosis (ALS) is correlated with pathologic and radiographic changes in cerebral cortex beyond the motor regions. Clinically, evidence of impairment can be detected in up to 50 percent of patients through direct neuropsychological testing, although frank frontotemporal dementia (FTD) occurs in a limited percentage. Behavioral changes are also common and can be characterized primarily by the presence of increased apathy.