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Revue Neurologique May 2020Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with no known cure. Approximately 90% of ALS cases are sporadic, suggesting there are... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with no known cure. Approximately 90% of ALS cases are sporadic, suggesting there are multiple contributing factors that influence the disease risk, onset, and progression. Diet and sex are two factors that have been reported to alter ALS risk, onset and progression in humans and in animal models, providing potential modifiers of disease. Several epidemiological studies have identified diets that positively affect ALS patients, including various high-calorie fat or sugar-based diets, while animal models have been developed to test how these diets are working on a molecular level. These diets may offset the metabolic alterations that occur in ALS, such as hypermetabolism, lowered body mass index(BMI), and hyperlipidemia. Sex-dependent differences have also come forth from large-scale epidemiological studies as well as mouse-model studies. In addition, sex hormones have been shown to affect disease risk or progression. Herein, studies on the effects of diet and sex on ALS risk, onset, and progression will be reviewed. Understanding these diet- and sex-dependent outcomes may lead to optimized patient-specific therapies for ALS.
Topics: Amyotrophic Lateral Sclerosis; Animals; Body Mass Index; Diet; Disease Models, Animal; Disease Progression; Female; Gonadal Steroid Hormones; Humans; Male; Mice; Sex Characteristics
PubMed: 32147204
DOI: 10.1016/j.neurol.2019.09.008 -
Cells Apr 2023Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the degeneration of motor neurons for which effective therapies are lacking. One of the... (Review)
Review
Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the degeneration of motor neurons for which effective therapies are lacking. One of the most explored areas of research in ALS is the discovery and validation of biomarkers that can be applied to clinical practice and incorporated into the development of innovative therapies. The study of biomarkers requires an adequate theoretical and operational framework, highlighting the "fit-for-purpose" concept and distinguishing different types of biomarkers based on common terminology. In this review, we aim to discuss the current status of fluid-based prognostic and predictive biomarkers in ALS, with particular emphasis on those that are the most promising ones for clinical trial design and routine clinical practice. Neurofilaments in cerebrospinal fluid and blood are the main prognostic and pharmacodynamic biomarkers. Furthermore, several candidates exist covering various pathological aspects of the disease, such as immune, metabolic and muscle damage markers. Urine has been studied less often and should be explored for its possible advantages. New advances in the knowledge of cryptic exons introduce the possibility of discovering new biomarkers. Collaborative efforts, prospective studies and standardized procedures are needed to validate candidate biomarkers. A combined biomarkers panel can provide a more detailed disease status.
Topics: Humans; Amyotrophic Lateral Sclerosis; Neurodegenerative Diseases; Prospective Studies; Biomarkers; Motor Neurons
PubMed: 37190090
DOI: 10.3390/cells12081180 -
Neurological Sciences : Official... Oct 2023The study aims to increase understanding of edaravone's efficacy and safety as an amyotrophic lateral sclerosis (ALS) treatment and provide significant insights... (Meta-Analysis)
Meta-Analysis Review
AIM
The study aims to increase understanding of edaravone's efficacy and safety as an amyotrophic lateral sclerosis (ALS) treatment and provide significant insights regarding this field's future research.
METHODS
We conducted a comprehensive search of the Embase, PubMed, Cochrane Library, Web of Science, and Scopus databases for randomized controlled trials and observational studies up until September 2022. We evaluated the studies' quality using the Cochrane risk of bias tool and the National Institutes of Health tool.
RESULTS
We included 11 studies with 2845 ALS patients. We found that edaravone improved the survival rate at 18, 24, and 30 months (risk ratio (RR) = 1.03, 95% confidence interval (CI) [1.02 to 1.24], P = 0.02), (RR = 1.22, 95% CI [1.06 to 1.41], P = 0.007), and (RR = 1.17, 95% CI [1.01 to 1.34], P = 0.03), respectively. However, the administration of edaravone did not result in any significant difference in adverse effects or efficacy outcomes between the two groups, as indicated by a P value greater than 0.05.
CONCLUSION
Edaravone improves survival rates of ALS patients at 18, 24, and 30 months with no adverse effects. However, edaravone does not affect functional outcomes. In order to ensure the validity of our findings and assess the results in accordance with the disease stage, it is essential to carry out additional prospective, rigorous, and high-quality clinical trials. The current study offers preliminary indications regarding the effectiveness and safety of edaravone. However, further comprehensive research is required to establish the generalizability and sustainability of the findings.
Topics: United States; Humans; Edaravone; Amyotrophic Lateral Sclerosis; Prospective Studies; Quality of Life; Severity of Illness Index
PubMed: 37249667
DOI: 10.1007/s10072-023-06869-8 -
Biomolecules Jun 2021Amyotrophic Lateral Sclerosis (ALS) is a degenerative disorder which affects the motor neurons. Growing evidence suggests that ALS may impact the metabolic system,...
BACKGROUND
Amyotrophic Lateral Sclerosis (ALS) is a degenerative disorder which affects the motor neurons. Growing evidence suggests that ALS may impact the metabolic system, including the glucose metabolism. Several studies investigated the role of Diabetes Mellitus (DM) as risk and/or prognostic factor. However, a clear correlation between DM and ALS has not been defined. In this review, we focus on the role of DM in ALS, examining the different hypotheses on how perturbations of glucose metabolism may interact with the pathophysiology and the course of ALS.
METHODS
We undertook an independent PubMed literature search, using the following search terms: ((ALS) OR (Amyotrophic Lateral Sclerosis) OR (Motor Neuron Disease)) AND ((Diabetes) OR (Glucose Intolerance) OR (Hyperglycemia)). Review and original articles were considered.
RESULTS
DM appears not to affect ALS severity, progression, and survival. Contrasting data suggested a protective role of DM on the occurrence of ALS in elderly and an opposite effect in younger subjects.
CONCLUSIONS
The actual clinical and pathophysiological correlation between DM and ALS is unclear. Large longitudinal prospective studies are needed. Achieving large sample sizes comparable to those of common complex diseases like DM is a challenge for a rare disease like ALS. Collaborative efforts could overcome this specific issue.
Topics: Age Factors; Amyotrophic Lateral Sclerosis; Diabetes Mellitus; Glucose; Humans
PubMed: 34200812
DOI: 10.3390/biom11060867 -
CNS Neuroscience & Therapeutics Sep 2023To study the brain metabolic signature in Chinese amyotrophic lateral sclerosis (ALS) patients and compare the difference in brain metabolic patterns between ALS with...
AIMS
To study the brain metabolic signature in Chinese amyotrophic lateral sclerosis (ALS) patients and compare the difference in brain metabolic patterns between ALS with and without genetic variants.
METHODS
We included 146 patients with ALS and 128 healthy controls (HCs). All patients with ALS underwent genetic testing to screen for ALS related genetic variants and were then divided into genetic (n = 22) and nongenetic ALS (n = 93) subgroups. All participants underwent brain F-FDG-PET scans. Group comparisons were performed using the two-sample t-test model of SPM12.
RESULTS
We identified a large of hypometabolic clusters in ALS patients as compared with HCs, especially in the bilateral basal ganglia, midbrain, and cerebellum. Moreover, hypometabolism in the bilateral temporal lobe, precentral gyrus and hypermetabolism in the left anterior cingulate, occipital lobe, and bilateral frontal lobe were also found in ALS patients as compared with HCs. Compared with nongenetic ALS patients, genetic ALS patients showed hypometabolism in the right postcentral gyrus, precuneus, and middle occipital gyrus. The incidence of sensory disturbance in patients with genetic ALS was higher than that in patients with nongenetic ALS (5 of 22 [22.72%] vs. 7 of 93 [7.52%], p = 0.036).
CONCLUSIONS
Our investigation provided unprecedented evidence of relative hypometabolism in the midbrain and cerebellum in ALS patients. Genetic ALS patients showed a specific signature of brain metabolism and a higher incidence of sensory disturbance, indicating that genetic factors may be an underlying cause affecting the brain metabolism and increasing the risk of sensory disturbance in ALS.
Topics: Humans; Amyotrophic Lateral Sclerosis; Brain; Fluorodeoxyglucose F18; Cerebellum; Mesencephalon
PubMed: 36971206
DOI: 10.1111/cns.14193 -
International Journal of Molecular... Nov 2023Amyotrophic lateral sclerosis (ALS) is a fatal multisystem disease characterized by progressive death of motor neurons, loss of muscle mass, and impaired energy... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a fatal multisystem disease characterized by progressive death of motor neurons, loss of muscle mass, and impaired energy metabolism. More than 40 genes are now known to be associated with ALS, which together account for the majority of familial forms of ALS and only 10% of sporadic ALS cases. To date, there is no consensus on the pathogenesis of ALS, which makes it difficult to develop effective therapy. Accumulating evidence indicates that mitochondria, which play an important role in cellular homeostasis, are the earliest targets in ALS, and abnormalities in their structure and functions contribute to the development of bioenergetic stress and disease progression. Mitochondria are known to be highly dynamic organelles, and their stability is maintained through a number of key regulatory pathways. Mitochondrial homeostasis is dynamically regulated via mitochondrial biogenesis, clearance, fission/fusion, and trafficking; however, the processes providing "quality control" and distribution of the organelles are prone to dysregulation in ALS. Here, we systematically summarized changes in mitochondrial turnover, dynamics, calcium homeostasis, and alterations in mitochondrial transport and functions to provide in-depth insights into disease progression pathways, which may have a significant impact on current symptomatic therapies and personalized treatment programs for patients with ALS.
Topics: Humans; Amyotrophic Lateral Sclerosis; Mitochondria; Motor Neurons; Energy Metabolism; Disease Progression; Superoxide Dismutase-1
PubMed: 38069154
DOI: 10.3390/ijms242316833 -
Molecular Neurodegeneration Jan 2023Amyotrophic lateral sclerosis (ALS) is caused by upper and lower motor neuron loss and has a fairly rapid disease progression, leading to fatality in an average of... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is caused by upper and lower motor neuron loss and has a fairly rapid disease progression, leading to fatality in an average of 2-5 years after symptom onset. Numerous genes have been implicated in this disease; however, many cases remain unexplained. Several technologies are being used to identify regions of interest and investigate candidate genes. Initial approaches to detect ALS genes include, among others, linkage analysis, Sanger sequencing, and genome-wide association studies. More recently, next-generation sequencing methods, such as whole-exome and whole-genome sequencing, have been introduced. While those methods have been particularly useful in discovering new ALS-linked genes, methodological advances are becoming increasingly important, especially given the complex genetics of ALS. Novel sequencing technologies, like long-read sequencing, are beginning to be used to uncover the contribution of repeat expansions and other types of structural variation, which may help explain missing heritability in ALS. In this review, we discuss how popular and/or upcoming methods are being used to discover ALS genes, highlighting emerging long-read sequencing platforms and their role in aiding our understanding of this challenging disease.
Topics: Humans; Amyotrophic Lateral Sclerosis; Genome-Wide Association Study; High-Throughput Nucleotide Sequencing
PubMed: 36635726
DOI: 10.1186/s13024-022-00593-1 -
British Journal of Pharmacology Mar 2021
Topics: Amyotrophic Lateral Sclerosis; Humans
PubMed: 33638898
DOI: 10.1111/bph.15348 -
Muscle & Nerve Aug 2020Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder with complex biology and significant clinical heterogeneity. Many preclinical and early... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder with complex biology and significant clinical heterogeneity. Many preclinical and early phase ALS clinical trials have yielded promising results that could not be replicated in larger phase 3 confirmatory trials. One reason for the lack of reproducibility may be ALS biological and clinical heterogeneity. Therefore, in this review, we explore sources of ALS heterogeneity that may reduce statistical power to evaluate efficacy in ALS trials. We also review efforts to manage clinical heterogeneity, including use of validated disease outcome measures, predictive biomarkers of disease progression, and individual clinical risk stratification. We propose that personalized prognostic models with use of predictive biomarkers may identify patients with ALS for whom a specific therapeutic strategy may be expected to be more successful. Finally, the rapid application of emerging clinical and biomarker strategies may reduce heterogeneity, increase trial efficiency, and, in turn, accelerate ALS drug development.
Topics: Amyotrophic Lateral Sclerosis; Biological Variation, Population; Biomarkers; Clinical Trials as Topic; Disease Progression; Drug Development; Humans; Muscle Strength; Outcome Assessment, Health Care; Physical Functional Performance; Precision Medicine; Prognosis; Reproducibility of Results; Respiratory Function Tests; Risk Assessment; Speech; Transcranial Magnetic Stimulation
PubMed: 31899540
DOI: 10.1002/mus.26801 -
Classification of amyotrophic lateral sclerosis by brain volume, connectivity, and network dynamics.Human Brain Mapping Feb 2022Emerging studies corroborate the importance of neuroimaging biomarkers and machine learning to improve diagnostic classification of amyotrophic lateral sclerosis (ALS)....
Emerging studies corroborate the importance of neuroimaging biomarkers and machine learning to improve diagnostic classification of amyotrophic lateral sclerosis (ALS). While most studies focus on structural data, recent studies assessing functional connectivity between brain regions by linear methods highlight the role of brain function. These studies have yet to be combined with brain structure and nonlinear functional features. We investigate the role of linear and nonlinear functional brain features, and the benefit of combining brain structure and function for ALS classification. ALS patients (N = 97) and healthy controls (N = 59) underwent structural and functional resting state magnetic resonance imaging. Based on key hubs of resting state networks, we defined three feature sets comprising brain volume, resting state functional connectivity (rsFC), as well as (nonlinear) resting state dynamics assessed via recurrent neural networks. Unimodal and multimodal random forest classifiers were built to classify ALS. Out-of-sample prediction errors were assessed via five-fold cross-validation. Unimodal classifiers achieved a classification accuracy of 56.35-61.66%. Multimodal classifiers outperformed unimodal classifiers achieving accuracies of 62.85-66.82%. Evaluating the ranking of individual features' importance scores across all classifiers revealed that rsFC features were most dominant in classification. While univariate analyses revealed reduced rsFC in ALS patients, functional features more generally indicated deficits in information integration across resting state brain networks in ALS. The present work undermines that combining brain structure and function provides an additional benefit to diagnostic classification, as indicated by multimodal classifiers, while emphasizing the importance of capturing both linear and nonlinear functional brain properties to identify discriminative biomarkers of ALS.
Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Brain; Connectome; Deep Learning; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Nerve Net
PubMed: 34655259
DOI: 10.1002/hbm.25679