55 research outputs found
Symptom management in amyotrophic lateral sclerosis: We can do better
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141321/1/mus25740_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141321/2/mus25740.pd
Use of AngleâIndependent MâMode Sonography for Assessment of Diaphragm Displacement
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137196/1/jum14204.pd
Speckle tracking as a method to measure hemidiaphragm excursion
Introduction: Diaphragm excursion measured via ultrasound may be an important imaging outcome measure of respiratory function. We developed a new method for measuring diaphragm movement and compared it to the more traditional Mâmode method. Methods: Ultrasound images of the right and left hemidiaphragms were collected to compare speckle tracking and Mâmode measurements of diaphragm excursion. Speckle tracking was performed using EchoInsight (Epsilon Imaging, Ann Arbor, Michigan). Results: Six healthy subjects without a history of pulmonary diseases were included in this proofâofâconcept study. Speckle tracking of the diaphragm is technically possible. Unlike Mâmode, speckle tracking carries the advantage of reliable visualization and measurement of the left hemidiaphragm. Conclusions: Speckle tracking accounted for diaphragm movement simultaneously in the cephalocaudad and mediolateral directions, unlike Mâmode, which is 1âdimensional. Diaphragm speckle tracking may represent a novel, more robust method for measuring diaphragm excursion, especially for the left hemidiaphragm. Muscle Nerve 55: 125â127, 2017Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135149/1/mus25380.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135149/2/mus25380_am.pd
Early life metal dysregulation in amyotrophic lateral sclerosis
ObjectiveDeficiencies and excess of essential elements and toxic metals are implicated in amyotrophic lateral sclerosis (ALS), but the age when metal dysregulation appears remains unknown. This study aims to determine whether metal uptake is dysregulated during childhood in individuals eventually diagnosed with ALS.MethodsLaser ablation- inductively coupled plasma- mass spectrometry was used to obtain time series data of metal uptake using biomarkers in teeth from autopsies or dental extractions of ALS (nĂÂ =ĂÂ 36) and control (nĂÂ =ĂÂ 31) participants. Covariate data included sex, smoking, occupational exposures, and ALS family history. Case- control differences were identified in temporal profiles of metal uptake for individual metals using distributed lag models. Weighted quantile sum (WQS) regression was used for metals mixture analyses. Similar analyses were performed on an ALS mouse model to further verify the relevance of dysregulation of metals in ALS.ResultsMetal levels were higher in cases than in controls: 1.49 times for chromium (1.11- 1.82; at 15ĂÂ years), 1.82 times for manganese (1.34- 2.46; at birth), 1.65 times for nickel (1.22- 2.01; at 8ĂÂ years), 2.46 times for tin (1.65- 3.30; at 2ĂÂ years), and 2.46 times for zinc (1.49- 3.67; at 6ĂÂ years). Co- exposure to 11 elements indicated that childhood metal dysregulation was associated with ALS. The mixture contribution of metals to disease outcome was likewise apparent in tooth biomarkers of an ALS mouse model, and differences in metal distribution were evident in ALS mouse brains compared to brains from littermate controls.InterpretationOverall, our study reveals direct evidence that altered metal uptake during specific early life time windows is associated with adult- onset ALS.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155978/1/acn351006_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155978/2/acn351006.pd
Amyotrophic lateral sclerosisâspecific quality of lifeâshort form (ALSSQOLâSF): A brief, reliable, and valid version of the ALSSQOLâR
Introduction: The Amyotrophic Lateral Sclerosis (ALS)âSpecific Quality of Life instrument and its revised version (ALSSQOL and ALSSQOLâR) have strong psychometric properties, and have demonstrated research and clinical utility. In this study we aimed to develop a short form (ALSSQOLâSF) suitable for limited clinic time and patient stamina. Methods: The ALSSQOLâSF was created using Item Response Theory and confirmatory factor analysis on 389 patients. A crossâvalidation sample of 162 patients assessed convergent, divergent, and construct validity of the ALSSQOLâSF compared with psychosocial and physical functioning measures. Results: The ALSSQOLâSF consisted of 20 items. Compared with the ALSSQOLâR, optimal precision was retained, and completion time was reduced from 15â25 minutes to 2â4 minutes. Psychometric properties for the ALSSQOLâSF and its subscales were strong. Discussion: The ALSSQOLâSF is a diseaseâspecific global QOL instrument that has a short administration time suitable for clinical use, and can provide clinically useful, valid information about persons with ALS. Muscle Nerve 58: 646â654, 2018Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146574/1/mus26203_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146574/2/mus26203.pd
Longâterm Phase 1/2 intraspinal stem cell transplantation outcomes in ALS
ObjectiveIntraspinal human spinal cordâderived neural stem cell (HSSC) transplantation is a potential therapy for amyotrophic lateral sclerosis (ALS); however, previous trials lack controls. This post hoc analysis compared ambulatory limbâonset ALS participants in Phase 1 and 2 (Ph1/2) openâlabel intraspinal HSSC transplantation studies up to 3 years after transplant to matched participants in Pooled Resource OpenâAccess ALS Clinical Trials (PROâACT) and ceftriaxone datasets to provide required analyses to inform future clinical trial designs.MethodsSurvival, ALSFRSâR, and a composite statistic (ALS/SURV) combining survival and ALS Functional Rating Scale revised (ALSFRSâR) functional status were assessed for matched participant subsets: PROâACT n = 1108, Ph1/2 n = 21 and ceftriaxone n = 177, Ph1/2 n = 20.ResultsSurvival did not differ significantly between cohorts: Ph1/2 median survival 4.7 years, 95% CI (1.2, â) versus PROâACT 2.3 years (1.9, 2.5), P = 1.0; Ph1/2 3.0 years (1.2, 5.6) versus ceftriaxone 2.3 years (1.8, 2.8), P = 0.88. Mean ALSFRSâR at 24 months significantly differed between Ph1/2 and both comparison cohorts (Ph1/2 30.1 ± 8.6 vs. PROâACT 24.0 ± 10.2, P = 0.048; Ph1/2 30.7 ± 8.8 vs. ceftriaxone 19.2 ± 9.5, P = 0.0023). Using ALS/SURV, median PROâACT and ceftriaxone participants died by 24 months, whereas median Ph1/2 participant ALSFRSâRs were 23 (P = 0.0038) and 19 (P = 0.14) in PROâACT and ceftriaxone comparisons at 24 months, respectively, supporting improved functional outcomes in the Ph1/2 study.InterpretationComparison of Ph1/2 studies to historical datasets revealed significantly improved survival and function using ALS/SURV versus PROâACT controls. While results are encouraging, comparison against historical populations demonstrate limitations in noncontrolled studies. These findings support continued evaluation of HSSC transplantation in ALS, support the benefit of control populations, and enable necessary power calculations to design a randomized, sham surgeryâcontrolled efficacy study.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144287/1/acn3567_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144287/2/acn3567.pd
Cumulative Genetic Score and C9orf72 Repeat Status Independently Contribute to Amyotrophic Lateral Sclerosis Risk in 2 Case-Control Studies
[Background and Objectives] Most patients with amyotrophic lateral sclerosis (ALS) lack a monogenic mutation. This study evaluates ALS cumulative genetic risk in an independent Michigan and Spanish replication cohort using polygenic scores.[Methods] Participant samples from University of Michigan were genotyped and assayed for the chromosome 9 open reading frame 72 hexanucleotide expansion. Final cohort size was 219 ALS and 223 healthy controls after genotyping and participant filtering. Polygenic scores excluding the C9 region were generated using an independent ALS genome-wide association study (20,806 cases, 59,804 controls). Adjusted logistic regression and receiver operating characteristic curves evaluated the association and classification between polygenic scores and ALS status, respectively. Population attributable fractions and pathway analyses were conducted. An independent Spanish study sample (548 cases, 2,756 controls) was used for replication.[Results] Polygenic scores constructed from 275 single-nucleotide variation (SNV) had the best model fit in the Michigan cohort. An SD increase in ALS polygenic score associated with 1.28 (95% CI 1.04â1.57) times higher odds of ALS with area under the curve of 0.663 vs a model without the ALS polygenic score (p value = 1 Ă 10â6). The population attributable fraction of the highest 20th percentile of ALS polygenic scores, relative to the lowest 80th percentile, was 4.1% of ALS cases. Genes annotated to this polygenic score enriched for important ALS pathomechanisms. Meta-analysis with the Spanish study, using a harmonized 132 single nucleotide variation polygenic score, yielded similar logistic regression findings (odds ratio: 1.13, 95% CI 1.04â1.23).[Discussion] ALS polygenic scores can account for cumulative genetic risk in populations and reflect disease-relevant pathways. If further validated, this polygenic score will inform future ALS risk models.National ALS Registry/CDC/ATSDR (1R01TS000289); National ALS Registry/CDC/ATSDR CDCP-DHHS-US (CDC/ATSDR 200-2013-56856); NIEHS K23ES027221; NIEHS R01ES030049; NINDS R01NS127188, ALS Association (20-IIA-532), the Dr. Randall W. Whitcomb Fund for ALS Genetics, the Peter R. Clark Fund for ALS Research, the Scott L. Pranger ALS Clinic Fund, and the NeuroNetwork for Emerging Therapies at the University of Michigan. This work was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (Z01-AG000949-02). Project âALS Genetic study in Madrid Autonomous Communityâ funded by âESTRATEGIAS FRENTE A ENFERMEDADES NEURODEGENERATIVASâ from Spanish Ministry of Health.Peer reviewe
Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe
A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS
To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (â€2 years since diagnosis) with slow upright vital capacity (SVC) of â„60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength mega-score, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898)
- âŠ