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Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger-containing (PIKfyve) inhibitor with a favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis (ALS) models. In this ALS clinical trial, the safety, tolerability, CNS penetrance and modulation of pharmacodynamic target engagement biomarkers were evaluated. This phase 2a, randomized, double-blind, placebo-controlled, biomarker-end-point clinical trial was conducted in four US centres (ClinicalTrials.gov NCT05163886). Participants with C9orf72 repeat expansions were randomly assigned (2:1) to receive twice-daily oral treatment with 125 mg apilimod dimesylate capsules or matching placebo for 12 weeks, followed by a 12-week open-label extension. Safety was measured as the occurrence of treatment-emergent or serious adverse events attributable to the study drug and tolerability at trial completion or treatment over 12 weeks. Changes from baseline in plasma and CSF and concentrations of apilimod dimesylate and its active metabolites and of pharmacodynamic biomarkers of PIKfyve inhibition [soluble glycoprotein nonmetastatic melanoma protein B (sGPNMB) upregulation] and disease-specific CNS target engagement [poly(GP)] were measured. Between 16 December 2021 and 7 July 2022, 15 eligible participants were enrolled. There were no drug-related serious adverse events reported in the trial. Fourteen (93%) participants completed the double-blind period with 99% dose compliance [n = 9 (90%) apilimod dimesylate; n = 5 (100%) placebo]. At Week 12, apilimod dimesylate was measurable in CSF at 1.63 ng/ml [standard deviation (SD): 0.937]. At Week 12, apilimod dimesylate increased plasma sGPNMB by >2.5-fold (P < 0.001), indicating PIKfyve inhibition, and lowered CSF poly(GP) protein levels by 73% (P < 0.001), indicating CNS tissue-level proof of mechanism. Apilimod dimesylate met prespecified key safety and biomarker end-points in this phase 2a trial and demonstrated CNS penetrance and pharmacodynamic target engagement. Apilimod dimesylate was observed to result in the greatest reduction in CSF poly(GP) levels observed to date in C9orf72 clinical trials.
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Esclerosis Amiotrófica Lateral , Proteína C9orf72 , Humanos , Masculino , Femenino , Persona de Mediana Edad , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/genética , Método Doble Ciego , Adulto , Anciano , Proteína C9orf72/genética , Pirazoles/uso terapéutico , Pirazoles/farmacocinética , Resultado del Tratamiento , Biomarcadores/sangre , Hidrazonas , Morfolinas , PirimidinasRESUMEN
BACKGROUND: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known. METHODS: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization. RESULTS: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal. CONCLUSIONS: Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).
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Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Fenilbutiratos/uso terapéutico , Ácido Tauroquenodesoxicólico/uso terapéutico , Anciano , Progresión de la Enfermedad , Método Doble Ciego , Combinación de Medicamentos , Femenino , Humanos , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , Fenilbutiratos/efectos adversos , Índice de Severidad de la Enfermedad , Ácido Tauroquenodesoxicólico/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: Coformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) was shown to prolong survival and slow functional decline in amyotrophic lateral sclerosis (ALS). OBJECTIVE: Determine whether PB/TURSO prolonged tracheostomy/ventilation-free survival and/or reduced first hospitalisation in participants with ALS in the CENTAUR trial. METHODS: Adults with El Escorial Definite ALS ≤18 months from symptom onset were randomised to PB/ TURSO or placebo for 6 months. Those completing randomised treatment could enrol in an open-label extension (OLE) phase and receive PB/TURSO for ≤30 months. Times to the following individual or combined key events were compared in the originally randomised treatment groups over a period spanning trial start through July 2020 (longest postrandomisation follow-up, 35 months): death, tracheostomy, permanent assisted ventilation (PAV) and first hospitalisation. RESULTS: Risk of any key event was 47% lower in those originally randomised to PB/TURSO (n=87) versus placebo (n=48, 71% of whom received delayed-start PB/TURSO in the OLE phase) (HR=0.53; 95% CI 0.35 to 0.81; p=0.003). Risks of death or tracheostomy/PAV (HR=0.51; 95% CI 0.32 to 0.84; p=0.007) and first hospitalisation (HR=0.56; 95% CI 0.34 to 0.95; p=0.03) were also decreased in those originally randomised to PB/TURSO. CONCLUSIONS: Early PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS. TRIAL REGISTRATION NUMBER: NCT03127514; NCT03488524.
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An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo. Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension. An all-cause mortality analysis (35-month maximum follow-up post-randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow-up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB-TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34-0.92; P = .023). Initiation of PB-TURSO treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB-TURSO has both functional and survival benefits in ALS.
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Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/mortalidad , Fármacos Neuroprotectores/uso terapéutico , Fenilbutiratos/uso terapéutico , Ácido Tauroquenodesoxicólico/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tiempo , Adulto JovenRESUMEN
INTRODUCTION: Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin-antibody-positive double-seronegative myasthenia gravis (DNMG). METHODS: DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected. RESULTS: Of 181 DNMG patients, 27 (14.9%) were positive for either low-density lipoprotein receptor-related protein 4 (LRP4) or agrin antibodies. Twenty-three DNMG patients (12.7%) were positive for both antibodies. More antibody-positive patients presented with generalized symptoms (69%) compared with antibody-negative patients (43%) (P ≤ .02). Antibody-positive patients' maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody-negative patients (P ≤ .005). Seventy percent of antibody-positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody-negative patients. Most LRP4- and agrin-antibody-positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow-up of 11 years. DISCUSSION: Antibody-positive patients had more severe clinical disease than antibody-negative patients. Most DNMG patients responded to standard therapy regardless of antibody status.
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Agrina/inmunología , Autoanticuerpos , Proteínas Relacionadas con Receptor de LDL/inmunología , Miastenia Gravis/diagnóstico , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miastenia Gravis/epidemiología , Miastenia Gravis/inmunología , Prevalencia , Evaluación de Síntomas , Estados UnidosRESUMEN
INTRODUCTION: A calpain-3 (CAPN3) gene heterozygous deletion (c.643_663del21) was recently linked to autosomal dominant (AD) limb-girdle muscular dystrophy. However, the possibility of digenic disease was raised. We describe 3 families with AD calpainopathy carrying this isolated mutation. METHODS: Probands heterozygous for CAPN3 c.643_663del21 were identified by targeted next generation or whole exome sequencing. Clinical findings were collected for probands and families. Calpain-3 muscle Western blots were performed in 3 unrelated individuals. RESULTS: Probands reported variable weakness in their 40s or 50s, with myalgia, back pain, or hyperlordosis. Pelvic girdle muscles were affected with adductor and hamstring sparing. Creatine kinase was normal to 1,800 U/L, independent of weakness severity. Imaging demonstrated lumbar paraspinal muscle atrophy. Electromyographic findings and muscle biopsies were normal to mildly myopathic. Muscle calpain-3 expression was reduced. DISCUSSION: This study provides further evidence for AD calpainopathy associated with CAPN3 c.643_663del21. No pathogenic variants in other genes known to cause myopathy were detected. Muscle Nerve 57: 679-683, 2018.
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Calpaína/genética , Proteínas Musculares/genética , Debilidad Muscular/fisiopatología , Atrofia Muscular/diagnóstico por imagen , Distrofia Muscular de Cinturas/genética , Músculos Paraespinales/diagnóstico por imagen , Adulto , Anciano , Calpaína/metabolismo , Creatina Quinasa/metabolismo , Análisis Mutacional de ADN , Electromiografía , Femenino , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Proteínas Musculares/metabolismo , Debilidad Muscular/etiología , Atrofia Muscular/etiología , Atrofia Muscular/patología , Distrofia Muscular de Cinturas/complicaciones , Distrofia Muscular de Cinturas/metabolismo , Distrofia Muscular de Cinturas/fisiopatología , Mutación , Linaje , Análisis de Secuencia de ADN , Eliminación de SecuenciaRESUMEN
INTRODUCTION: To evaluate the sensitivity of F-wave minimal latencies, we compared F-waves with motor and sensory nerve conduction studies (MNCS and SNCS) in patients with peripheral neuropathy. METHODS: A retrospective chart review conducted in 484 patients confirmed the clinical evidence of a polyneuropathy, and studies of F-wave minimal latencies as well as MNCS and SNCS in each patient. RESULTS: Overall rate of abnormality reached 469/484 (96.9%) for F-wave minimal latencies as compared to 374/484 (77%) for nerve conduction studies ( p < 0.0001). Nerve-specific abnormalities of F-waves showed 290/354 (82%), 140/171 (82%), 367/398 (92%) and 357/376 (95%) for median, ulnar, peroneal and tibial nerves, respectively. Corresponding values for MNCS consisted of 108/354 (31%), 29/171 (17%), 258/398 (65%) and 189/376 (50%) (all p < 0.0001). In contrast, SNCS revealed abnormalities in 120/333 (36%), 60/159 (38%) and 266/474 (56%) of median, ulnar and sural nerves. CONCLUSION: F-wave minimal latencies serve as the best predictor of polyneuropathy followed by SNCS and then MNCS.
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INTRODUCTION: We describe a 6-year-old girl with a T118M PMP22 mutation and heterozygous deletion of PMP22 on chromosome 17 (17p11.2-p12) resulting in a severe sensorimotor polyneuropathy. METHODS: This study is a case report in which the relevant mutations are described. RESULTS: Foot pain, cavovarus feet, tibialis anterior atrophy, absent reflexes, and inability to walk were found when the patient was age 6 years. Nerve conduction studies showed evidence of a sensorimotor polyneuropathy and compressive mononeuropathies of bilateral median nerves at the wrist and ulnar nerves at the elbow. Genetic testing revealed deletion of a PMP22 allele and T118M PMP22 mutation in the remaining allele. CONCLUSIONS: The severe sensorimotor polyneuropathy and hereditary neuropathy with liability to pressure palsies (HNPP) in this patient was likely a consequence of both decreased expression of PMP22 causing features consistent with HNPP and unopposed expression of the T118M mutant form of PMP22 that is relatively benign in the heterozygous state. The T118M mutant form of PMP22 can be disease-modifying in the appropriate circumstances.
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Mutación Missense/genética , Proteínas de la Mielina/genética , Polineuropatías/diagnóstico , Polineuropatías/genética , Síndrome de Smith-Magenis/genética , Niño , Deleción Cromosómica , Cromosomas Humanos Par 17/genética , Femenino , Humanos , Linaje , Polineuropatías/cirugíaRESUMEN
Patients with amyotrophic lateral sclerosis (ALS) often show deficits on neuropsychological tests that tap functions related to the integrity of the prefrontal lobes. Various aspects of personality are also known to be mediated by prefrontal regions, particularly ventromedial prefrontal cortex (vmPFC). Other than apathy, personality changes have not been widely reported in patients with ALS, although clinical observations indicate such changes might be relatively common. Here, we report on a middle-aged woman with bulbar onset ALS (diagnosed 06/2011, examined in Spring, 2012) whose neuropsychological exam did not reveal cognitive deficits. She performed normally on tests of executive functioning. Self-report measures of mood and personality were unremarkable. However, significant personality changes subsequent to disease onset were reported by her husband and two daughters, and these changes were quantified with the Iowa Scales of Personality Change. Results show that personality disturbance may manifest in the absence of notable cognitive changes in ALS, and careful assessment of personality may be important for documenting early neurobehavioral changes in some ALS patients. Findings also show that patients with ALS may not have good insight into personality changes, underscoring the importance of acquiring collateral information. More generally, the results provide further evidence that ALS may compromise the integrity of ventromedial prefrontal regions.
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Esclerosis Amiotrófica Lateral/complicaciones , Trastornos de la Personalidad/etiología , Esclerosis Amiotrófica Lateral/patología , Encéfalo/patología , Femenino , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Pruebas Neuropsicológicas , Inventario de PersonalidadRESUMEN
OBJECTIVE: We utilized national claims-based data to identify the change in odds of diagnosis of ALS following possible-ALS-symptoms-and whether the change varies in urban/rural areas. METHODS: Insurance claims were obtained from the Merative MarketScan databases, 2001-2021 in the United States. Individuals with incident ALS were identified and matched on age, sex, and enrollment period to individuals without ALS. For all individuals, claims for 8 possible-ALS-symptoms in the time before any ALS diagnosis were identified. We then used conditional logistic regression to estimate the odds of being diagnosed with ALS following these symptoms and whether the association varied by urban/rural location. RESULTS: 19,226 individuals with ALS were matched to 96,126 controls. Patients with ALS were more likely to live in an urban area (87.0% vs 84.5%). Of those with ALS 84% had 1+ of our 8 possible-ALS-symptom compared to 51% of controls. After adjustment for confounders, having possible-ALS-symptoms increased the odds of a future ALS diagnosis by nearly 5-fold. A dose-response pattern was present with increasing odds as the number of symptoms increased. In all models, urban areas were associated with increased odds of diagnosis with ALS while the effect of having a symptom was smaller in urban places. Urban cases of ALS are diagnosed at younger ages. CONCLUSIONS: These results suggest symptoms may appear and be noted years before the diagnosis of ALS. Additionally, rural patients are diagnosed at later ages with a greater dependence on symptoms than urban patients. These results highlight potential improvements for screening for ALS.
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Esclerosis Amiotrófica Lateral , Población Rural , Humanos , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Población Rural/estadística & datos numéricos , Anciano , Adulto , Estados Unidos/epidemiología , Población Urbana/estadística & datos numéricosAsunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Reguladoras de la Apoptosis/genética , Enfermedad de Charcot-Marie-Tooth/genética , Adulto , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Electromiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Conducción Nerviosa , Linaje , Secuenciación del ExomaRESUMEN
To reduce the prevalence of youth injuries and fatalities in agricultural settings, safety professionals considered developing a guideline-focused intervention for how and when youth should conduct farm chores. In 1996, the process to create guidelines started, which then expanded to include professionals from the United States, Canada, and Mexico. This team used a consensus driven approach to develop the guidelines and launch the North American Guidelines for Children's Agricultural Tasks. By 2015, research related to the published guidelines indicated a need to incorporate new empirical evidence and develop dissemination plans based on new technologies. The process for updating the guidelines was supported by a 16-person steering committee and used content experts and technical advisors. The process yielded updated and new guidelines, now called Agricultural Youth Work Guidelines. This report responds to request for further details on the development and update of the guidelines and describes the genesis of the guidelines as an intervention, the process for creating guidelines, recognition of the need to update guidelines based on research, and the process for updating guidelines to assist in others engaged in similar types of interventions.
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Actividades Cotidianas , Agricultura , Niño , Estados Unidos , Humanos , Adolescente , Canadá , México , ConsensoRESUMEN
Valosin-containing protein (VCP) associated multisystem proteinopathy (MSP) is a rare inherited disorder that may result in multisystem involvement of varying phenotypes including inclusion body myopathy, Paget's disease of bone (PDB), frontotemporal dementia (FTD), parkinsonism, and amyotrophic lateral sclerosis (ALS), among others. An international multidisciplinary consortium of 40+ experts in neuromuscular disease, dementia, movement disorders, psychology, cardiology, pulmonology, physical therapy, occupational therapy, speech and language pathology, nutrition, genetics, integrative medicine, and endocrinology were convened by the patient advocacy organization, Cure VCP Disease, in December 2020 to develop a standard of care for this heterogeneous and under-diagnosed disease. To achieve this goal, working groups collaborated to generate expert consensus recommendations in 10 key areas: genetic diagnosis, myopathy, FTD, PDB, ALS, Charcot Marie Tooth disease (CMT), parkinsonism, cardiomyopathy, pulmonology, supportive therapies, nutrition and supplements, and mental health. In April 2021, facilitated discussion of each working group's conclusions with consensus building techniques enabled final agreement on the proposed standard of care for VCP patients. Timely referral to a specialty neuromuscular center is recommended to aid in efficient diagnosis of VCP MSP via single-gene testing in the case of a known familial VCP variant, or multi-gene panel sequencing in undifferentiated cases. Additionally, regular and ongoing multidisciplinary team follow up is essential for proactive screening and management of secondary complications. The goal of our consortium is to raise awareness of VCP MSP, expedite the time to accurate diagnosis, define gaps and inequities in patient care, initiate appropriate pharmacotherapies and supportive therapies for optimal management, and elevate the recommended best practices guidelines for multidisciplinary care internationally.
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Esclerosis Amiotrófica Lateral , Miositis por Cuerpos de Inclusión , Osteítis Deformante , Esclerosis Amiotrófica Lateral/genética , Proteínas de Ciclo Celular/genética , Humanos , Mutación , Osteítis Deformante/genética , Nivel de Atención , Proteína que Contiene Valosina/genéticaRESUMEN
Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients; however, factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort (N = 327) from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium. We demonstrate that a polygenic risk score derived using sCCA relates to longitudinal cognitive decline in the same cohort and also to in vivo cortical thinning in the orbital frontal cortex, anterior cingulate cortex, lateral temporal cortex, premotor cortex, and hippocampus (N = 90) as well as post-mortem motor cortical neuronal loss (N = 87) in independent ALS cohorts from the University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Our findings suggest that common genetic polymorphisms may exert a polygenic contribution to the risk of cortical disease vulnerability and cognitive dysfunction in ALS.
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Esclerosis Amiotrófica Lateral , Disfunción Cognitiva , Demencia Frontotemporal , Enfermedades Neurodegenerativas , Esclerosis Amiotrófica Lateral/genética , Disfunción Cognitiva/genética , Humanos , Aprendizaje AutomáticoRESUMEN
OBJECTIVE: To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥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).
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Esclerosis Amiotrófica Lateral , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Método Doble Ciego , Humanos , Fuerza MuscularRESUMEN
OBJECTIVE: To identify preferred neurofilament assays and clinically validate serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) as prognostic and potential pharmacodynamic biomarkers relevant to amyotrophic lateral sclerosis (ALS) therapy development. METHODS: In this prospective, multicenter, longitudinal observational study of patients with ALS (n = 229), primary lateral sclerosis (n = 20), and progressive muscular atrophy (n = 11), biological specimens were collected, processed, and stored according to strict standard operating procedures (SOPs). Neurofilament assays were performed in a blinded manner by independent contract research organizations. RESULTS: For serum NfL and pNfH measured using the Simoa assay, there were no missing data (i.e., technical replicates below the lower limit of detection were not encountered). For the Iron Horse and Euroimmun pNfH assays, such missingness was encountered in â¼4% and â¼10% of serum samples, respectively. Mean coefficients of variation for NfL in serum and CSF were both â¼3%. Mean coefficients of variation for pNfH in serum and CSF were â¼4%-5% and â¼2%-3%, respectively, in all assays. Baseline serum NfL concentration, but not pNfH, predicted the future Revised ALS Functional Rating Scale (ALSFRS-R) slope and survival. Incorporation of baseline serum NfL into mixed effects models of ALSFRS-R slopes yields an estimated sample size saving of â¼8%. Depending on the method used to estimate effect size, use of serum NfL (and perhaps pNfH) as pharmacodynamic biomarkers, instead of the ALSFRS-R slope, yields significantly larger sample size savings. CONCLUSIONS: Serum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, has potential utility as a pharmacodynamic biomarker of treatment effect.
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Esclerosis Amiotrófica Lateral/sangre , Biomarcadores/sangre , Filamentos Intermedios/metabolismo , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
Objective: 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 (N = 355).Methods: Fasting plasma and first void urine samples were obtained. PCr, PUA, urinary 8-oxo-deoxy guanosine (8-oxodG), and 15-F2t-isoprostane (IsoP) were analyzed at baseline, near the midpoint of follow-up, and at the final blood draw (before death or withdrawal from study). We estimated associations between these biomarkers and the ALSFRS-R at baseline and survival.Results: At baseline, PCr correlated with ALSFRS-R (Spearman r = 0.30), percent (%) FVC (r = 0.20), PUA (r = 0.37), and 8-oxodG (r = -0.13, all p < 0.05). Baseline PCr significantly predicted survival (adjusted hazard ratio 0.28, p < 0.001). Time to death from baseline was shortest for those in the lowest two PCr quartiles relative to the highest two quartiles. PCr and ALSFRS-R values were significantly correlated at all three time points (baseline: r = 0.29, midpoint: r = 0.23, final: r = 0.38, all p < 0.001). PCr and PUA significantly declined over time, whereas OS biomarkers significantly increased over time.Conclusions: To date, PCr predicted survival the best, compared to PUA, 8-oxodG, and IsoP. Although PCr represents the degree of muscle mass, it may also represent complex biochemical changes in ALS. Because the field has no reliable prognostic biomarkers, the importance of PCr warrants further investigation through clinical studies in ALS.
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Esclerosis Amiotrófica Lateral/sangre , Esclerosis Amiotrófica Lateral/diagnóstico , Creatinina/sangre , Estrés Oxidativo/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/mortalidad , Biomarcadores/sangre , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tasa de Supervivencia/tendencias , Ácido Úrico/sangreRESUMEN
[This corrects the article DOI: 10.1155/2018/5969137.].
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Guided by ecological, work-family spillover and crossover frameworks, this study examined mechanisms linking parental work travel (i.e., nights per year) to youth adjustment (i.e., externalizing and internalizing behaviours) through youth's perceptions of parenting (i.e., knowledge, solicitation) with traveller and youth gender as moderators in a sample of 78 children in 44 two-parent families residing in the United States. The findings from multilevel analyses suggested that mothers' travel nights predicted lower levels of maternal knowledge, with variation by traveller and youth gender. Mothers' and fathers' work travel and perceived parenting were predictors of youth's externalizing behaviours, whereas only fathers' work travel and perceived parenting were predictors of youth's internalizing behaviours. Tests of indirect effects indicated that maternal work travel linked to youth's externalizing behaviours through youth's perceptions of maternal knowledge. These findings add to our limited understanding of work-family issues for parents who have the unique work demand of frequently travelling.