Maximizing the Survival of Amyotrophic Lateral Sclerosis Patients: Current Perspectives.
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ABSTRACT:
SUBMITTER: Khairoalsindi OA
PROVIDER: S-EPMC6109498 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
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Project description:Motor neuron disease includes a heterogeneous group of relentless progressive neurological disorders defined and characterized by the degeneration of motor neurons. Amyotrophic lateral sclerosis is the most common and aggressive form of motor neuron disease with no effective treatment so far. Unfortunately, diagnostic and prognostic biomarkers are lacking in clinical practice. Neurofilaments are fundamental structural components of the axons and neurofilament light chain and phosphorylated neurofilament heavy chain can be measured in both cerebrospinal fluid and serum. Neurofilament light chain and phosphorylated neurofilament heavy chain levels are elevated in amyotrophic lateral sclerosis, reflecting the extensive damage of motor neurons and axons. Hence, neurofilaments are now increasingly recognized as the most promising candidate biomarker in amyotrophic lateral sclerosis. The potential usefulness of neurofilaments regards various aspects, including diagnosis, prognosis, patient stratification in clinical trials and evaluation of treatment response. In this review paper, we review the body of literature about neurofilaments measurement in amyotrophic lateral sclerosis. We also discuss the open issues concerning the use of neurofilaments clinical practice, as no overall guideline exists to date; finally, we address the most recent evidence and future perspectives.
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Project description:Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that results in loss of the upper and lower motor neurons from motor cortex, brainstem, and spinal cord. While the majority of cases are sporadic, approximately 10% show familial inheritance. ALS is usually inherited in an autosomal dominant manner, although autosomal recessive and X-linked inheritance do occur. To date, 24 of the genes at 26 loci have been identified; these include loci linked to ALS and to frontotemporal dementia-ALS, where family pedigrees contain individuals with frontotemporal dementia with/without ALS. The most commonly established genetic causes of familial ALS (FALS) to date are the presence of a hexanucleotide repeat expansion in the C9ORF72 gene (39.3% FALS) and mutation of SOD1, TARDBP, and FUS, with frequencies of 12%-23.5%, 5%, and 4.1%, respectively. However, with the increasing use of next-generation sequencing of small family pedigrees, this has led to an increasing number of genes being associated with ALS. This review provides a comprehensive review on the genetics of ALS and an update of the pathogenic mechanisms associated with these genes. Commonly implicated pathways have been established, including RNA processing, the protein degradation pathways of autophagy and ubiquitin-proteasome system, as well as protein trafficking and cytoskeletal function. Elucidating the role genetics plays in both FALS and sporadic ALS is essential for understanding the subsequent cellular dysregulation that leads to motor neuron loss, in order to develop future effective therapeutic strategies.
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Project description:BACKGROUND:Amyotrophic lateral sclerosis (ALS) is a relatively rare neurodegenerative disorder of both upper and lower motoneurons. Currently, the management of ALS is essentially symptoms-based, and riluzole, an antiglutamatergic agent, is the only drug for the treatment of ALS approved by the food and drug administration. OBJECTIVE:We reviewed current literature concerning emerging treatments for amyotrophic lateral sclerosis. METHODS:A Medline literature search was performed to identify all studies on ALS treatment published from January 1st, 1986 through August 31st, 2009. We selected papers concerning only disease-modifying therapy. RESULTS:Forty-eight compounds were identified and reviewed in this study. CONCLUSIONS:Riluzole is the only compound that demonstrated a beneficial effect on ALS patients, but with only modest increase in survival. Although several drugs showed effective results in the animal models for ALS, none of them significantly prolonged survival or improved quality of life of ALS patients. Several factors have been implicated in explaining the predominantly negative results of numerous randomized clinical trials in ALS, including methodological problems in the use of animal-drug screening, the lack of assessment of pharmacokinetic profile of the drugs, and methodological pitfalls of clinical trials in ALS patients.
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Project description:This SuperSeries is composed of the following subset Series: GSE39642: NanoString nCounter immune-related gene expression in blood sorted CD14+CD16- monocytes from sALS, fALS and HC subjects GSE39643: NanoString miRNA profiling of peripheral blood sorted CD14+CD16- monocytes from amyotrophic lateral sclerosis, multiple sclerosis and healthy control subjects Refer to individual Series
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Project description:Identification of amyotrophic lateral sclerosis (ALS) associated genes. Post mortem spinal cord grey matter from sporadic and familial ALS patients compared with controls. Keywords: other
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Project description:amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that leads to death within a few years after diagnosis. Malnutrition and weight loss are frequent and are indexes of poor prognosis. Total body fat and fat distribution have not been studied in ALS patients.Our aim was to describe adipose tissue content and distribution in ALS patients.We performed a cross-sectional study in a group of ALS patients (n?=?62, mean disease duration 22 months) along with age and gender matched healthy controls (n?=?62) using a MRI-based method to study quantitatively the fat distribution.Total body fat of ALS patients was not changed as compared with controls. However, ALS patients displayed increased visceral fat and an increased ratio of visceral to subcutaneous fat. Visceral fat was not correlated with clinical severity as judged using the ALS functional rating scale (ALS-FRS-R), while subcutaneous fat in ALS patients correlated positively with ALS-FRS-R and disease progression. Multiple regression analysis showed that gender and ALS-FRS-R, but not site of onset, were significant predictors of total and subcutaneous fat. Increased subcutaneous fat predicted survival in male patients but not in female patients (p<0.05).Fat distribution is altered in ALS patients, with increased visceral fat as compared with healthy controls. Subcutaneous fat content is a predictor of survival of ALS patients.
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Project description:Myelin is the lipid-rich structure formed by oligodendrocytes (OLs) that wraps the axons in multilayered sheaths, assuring protection, efficient saltatory signal conduction and metabolic support to neurons. In the last few years, the impact of OL dysfunction and myelin damage has progressively received more attention and is now considered to be a major contributing factor to neurodegeneration in several neurological diseases, including amyotrophic lateral sclerosis (ALS). Upon OL injury, oligodendrocyte precursor cells (OPCs) of adult nervous tissue sustain the generation of new OLs for myelin reconstitution, but this spontaneous regeneration process fails to successfully counteract myelin damage. Of note, the functions of OPCs exceed the formation and repair of myelin, and also involve the trophic support to axons and the capability to exert an immunomodulatory role, which are particularly relevant in the context of neurodegeneration. In this review, we deeply analyze the impact of dysfunctional OLs in ALS pathogenesis. The possible mechanisms underlying OL degeneration, defective OPC maturation, and impairment in energy supply to motor neurons (MNs) have also been examined to provide insights on future therapeutic interventions. On this basis, we discuss the potential therapeutic utility in ALS of several molecules, based on their remyelinating potential or capability to enhance energy metabolism.
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Project description:IntroductionThe Irish ALS register is a valuable resource for examining survival factors in Irish ALS patients. Cox regression has become the default tool for survival analysis, but recently new classes of flexible parametric survival analysis tools known as Royston-Parmar models have become available.MethodsWe employed Cox proportional hazards and Royston-Parmar flexible parametric modeling to examine factors affecting survival in Irish ALS patients. We further examined the effect of choice of timescale on Cox models and the proportional hazards assumption, and extended both Cox and Royston-Parmar models with time varying components.ResultsOn comparison of models we chose a Royston-Parmar proportional hazards model without time varying covariates as the best fit. Using this model we confirmed the association of known survival markers in ALS including age at diagnosis (Hazard Ratio (HR) 1.34 per 10 year increase; 95% CI 1.26-1.42), diagnostic delay (HR 0.96 per 12 weeks delay; 95% CI 0.94-0.97), Definite ALS (HR 1.47 95% CI 1.17-1.84), bulbar onset disease (HR 1.58 95% CI 1.33-1.87), riluzole use (HR 0.72 95% CI 0.61-0.85) and attendance at an ALS clinic (HR 0.74 95% CI 0.64-0.86).DiscussionOur analysis explored the strengths and weaknesses of Cox proportional hazard and Royston-Parmar flexible parametric methods. By including time varying components we were able to gain deeper understanding of the dataset. Variation in survival between time periods appears to be due to missing data in the first time period. The use of age as timescale to account for confounding by age resolved breaches of the proportional hazards assumption, but in doing so may have obscured deficiencies in the data. Our study demonstrates the need to test for, and fully explore, breaches of the Cox proportional hazards assumption. Royston-Parmar flexible parametric modeling proved a powerful method for achieving this.
| S-EPMC3786977 | biostudies-literature
Project description:BackgroundCystatin C (CysC) levels in amyotrophic lateral sclerosis (ALS) have been found changes, however, the associations between serum CysC levels and the progression and survival of ALS remain largely unknown.MethodsA total of 1,086 ALS patients and 1,026 sex-age matched healthy controls (HCs) were enrolled in this study. Serum CysC, other renal function, and metabolic parameters were measured. Correlation analysis and binary logistic regression were used to explore the factors related to serum CysC. Kaplan-Meier curve and Cox regression model were used for survival analysis.ResultsCysC levels were significantly higher in ALS patients compared to HCs (0.94 vs. 0.85 mg/L, p < 0.001). Compared with ALS patients with lower CysC levels, those with higher CysC levels had an older age of onset, significantly lower ALSFRS-R scores (40.1 vs. 41.3, p < 0.001), a faster disease progression rate (0.75 vs. 0.67, p = 0.011), and lower frontal lobe function scores (15.8 vs. 16.1, p = 0.020). In the correlation analysis, CysC levels were significantly negatively correlated with ALSFRS-R scores (r = -0.16, p < 0.001). Additionally, ALS patients with higher CysC levels had significantly shorter survival time (40.0 vs. 51.8, p < 0.001) compared to patients with lower CysC levels. Higher CysC levels were associated with a higher risk of death in Cox analysis (HR: 1.204, 95% CI: 1.012-1.433). However, when treatment was included in the model, the result was no longer significant.ConclusionCysC levels in ALS patients were higher compared to HCs. Higher CysC levels were associated with greater disease severity, faster progression rate and shorter survival, needing early intervention.
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