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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Clinical heterogeneity and complex genetics pose challenges to understanding disease mechanisms and producing effective cures. To model clinical heterogeneity, we generated human induced pluripotent stem cells (iPSCs) from two sporadic ALS patients (sporadic ALS and sporadic ALS with frontotemporal dementia), two familial ALS patients (familial SOD1 mutation positive and familial C9orf72 repeat expansion positive), and four age- and sex-matched healthy controls. These iPSCs can be used to generate 2D and 3D in vitro models of ALS to investigate mechanisms of disease and screen for therapeutics., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Timothy J Tracey reports financial support was provided by Motor Neurone Disease Research Australia. Shyuan T Ngo reports financial support was provided by National Health and Medical Research Council. Shyuan T Ngo reports financial support was provided by Motor Neurone Disease Research Australia. Shyuan T Ngo reports financial support was provided by FightMND. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Arginine methylation is a protein posttranslational modification important for the development of skeletal muscle mass and function. Despite this, our understanding of the regulation of arginine methylation under settings of health and disease remains largely undefined. Here, we investigated the regulation of arginine methylation in skeletal muscles in response to exercise and hypertrophic growth, and in diseases involving metabolic dysfunction and atrophy. We report a limited regulation of arginine methylation under physiological settings that promote muscle health, such as during growth and acute exercise, nor in disease models of insulin resistance. In contrast, we saw a significant remodeling of asymmetric dimethylation in models of atrophy characterized by the loss of innervation, including in muscle biopsies from patients with myotrophic lateral sclerosis (ALS). Mass spectrometry-based quantification of the proteome and asymmetric arginine dimethylome of skeletal muscle from individuals with ALS revealed the largest compendium of protein changes with the identification of 793 regulated proteins, and novel site-specific changes in asymmetric dimethyl arginine (aDMA) of key sarcomeric and cytoskeletal proteins. Finally, we show that in vivo overexpression of PRMT1 and aDMA resulted in increased fatigue resistance and functional recovery in mice. Our study provides evidence for asymmetric dimethylation as a regulator of muscle pathophysiology and presents a valuable proteomics resource and rationale for numerous methylated and nonmethylated proteins, including PRMT1, to be pursued for therapeutic development in ALS., (© 2024 Federation of American Societies for Experimental Biology.)

Background and Objectives: Altered metabolism is observed in amyotrophic lateral sclerosis (ALS). However, without a standardized methodology to define metabolic changes, our understanding of factors contributing to and the clinical significance of altered metabolism in ALS is limited., Methods: We aimed to determine how geographic variation in metabolic rates influences estimates and accuracy of predicted resting energy expenditure (REE) in patients with ALS and controls, while validating the effectiveness of cohort-specific approaches in predicting altered metabolic rate in ALS. Participants from 3 geographically distinct sites across Australia, China, and the Netherlands underwent REE assessments, and we considered 22 unique equations for estimating REE. Analyses evaluated equation performance and the influence of demographics on metabolic status. Comparisons were made using standardized and local reference values to identify metabolic alterations., Results: 606 participants were included from Australia (patients with ALS: 140, controls: 154), the Netherlands (patients with ALS: 79, controls: 37) and China (patients with ALS: 67, controls: 129). Measured REE was variable across geographic cohorts, with fat-free mass contributing to this variation across all patients ( p = 0.002 to p < 0.001). Of the 22 predication equations assessed, the Sabounchi Structure 4 (S4) equation performed relatively well across all control cohorts. Use of prediction thresholds generated using data from Australian controls generally increased the prevalence of hypermetabolism in Chinese (55%, [43%-67%]) and Dutch (44%, [33%-55%]) cases when compared with Australian cases (30%, [22%-38%]). Adjustment of prediction thresholds to consider geographically distinct characteristics from matched control cohorts resulted in a decrease in the proportion of hypermetabolic cases in Chinese and Dutch cohorts (25%-31% vs 55% and 20%-34% vs 43%-44%, respectively), and increased prevalence of hypometabolism in Dutch cases with ALS (1% to 8%-10%)., Discussion: The identification of hypermetabolism in ALS is influenced by the formulae and demographic-specific prediction thresholds used for defining alterations in metabolic rate. A consensus approach is needed for identification of metabolic changes in ALS and will facilitate improved understanding of the cause and clinical significance of this in ALS.

Understanding the mechanisms that drive TDP-43 pathology is integral to combating amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and other neurodegenerative diseases. Here we generated a longitudinal quantitative proteomic map of the cortex from the cytoplasmic TDP-43 rNLS8 mouse model of ALS and FTLD, and developed a complementary open-access webtool, TDP-map ( https://shiny.rcc.uq.edu.au/TDP-map/ ). We identified distinct protein subsets enriched for diverse biological pathways with temporal alterations in protein abundance, including increases in protein folding factors prior to disease onset. This included increased levels of DnaJ homolog subfamily B member 5, DNAJB5, which also co-localized with TDP-43 pathology in diseased human motor cortex. DNAJB5 over-expression decreased TDP-43 aggregation in cell and cortical neuron cultures, and knockout of Dnajb5 exacerbated motor impairments caused by AAV-mediated cytoplasmic TDP-43 expression in mice. Together, these findings reveal molecular mechanisms at distinct stages of ALS and FTLD progression and suggest that protein folding factors could be protective in neurodegenerative diseases., (© 2024. The Author(s).)

Background and Purpose: Loss of appetite contributes to weight loss and faster disease progression in amyotrophic lateral sclerosis (ALS). Impairment of appetite control in ALS may include altered production or action of orexigenic (i.e., ghrelin) and anorexigenic (i.e., liver-expressed antimicrobial peptide 2 [LEAP2] and leptin) hormones. We aimed to determine if postprandial circulating ghrelin levels, LEAP2 levels, LEAP2:ghrelin molar ratio and leptin levels differ in ALS patients compared to non-neurodegenerative disease controls, and whether they are associated with disease progression and body composition., Methods: In this prospective natural history study, we assessed postprandial plasma levels of ghrelin, LEAP2 and leptin in patients with ALS (cases; n = 46) and controls (controls; n = 43). For cases, measures were compared to changes in body weight, body composition and clinical outcomes., Results: Postprandial ghrelin level was decreased by 52% in cases compared to controls (p = 0.013). LEAP2:ghrelin molar ratio was increased by 249% (p = 0.009), suggesting greater ghrelin resistance. Patients with lower LEAP2:ghrelin tended to have better functional capacity at assessment, as inferred by the ALS Functional Rating Scale-Revised (τ = -0.179, p = 0.086). Furthermore, ghrelin and LEAP2:ghrelin molar ratio correlated with diagnostic delay (ghrelin, τ = 0.223, p = 0.029; LEAP2:ghrelin, τ = -0.213, p = 0.037). Baseline ghrelin level, LEAP2 level, LEAP2:ghrelin ratio and leptin level were, however, not predictive of change in functional capacity during follow-up. Also, patients with higher postprandial ghrelin levels (hazard ratio [HR] 1.375, p = 0.048), and lower LEAP2:ghelin ratios (HR 0.828, p = 0.051) had an increased risk of earlier death., Conclusions: Reduced postprandial ghrelin levels, coupled with increased LEAP2:ghrelin molar ratios, suggests a loss of ghrelin action in patients with ALS. Given ghrelin's actions on appetite, metabolism and neuroprotection, reduced ghrelin and greater ghrelin resistance could contribute to impaired capacity to tolerate the physiological impact of disease. Comprehensive studies are needed to explain how ghrelin and LEAP2 contribute to body weight regulation and disease progression in ALS., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, has been viewed almost exclusively as a disease of upper and lower motor neurons, with muscle changes interpreted as a consequence of the progressive loss of motor neurons and neuromuscular junctions. This has led to the prevailing view that the involvement of muscle in ALS is only secondary to motor neuron loss. Skeletal muscle and motor neurons reciprocally influence their respective development and constitute a single functional unit. In ALS, multiple studies indicate that skeletal muscle dysfunction might contribute to progressive muscle weakness, as well as to the final demise of neuromuscular junctions and motor neurons. Furthermore, skeletal muscle has been shown to participate in disease pathogenesis of several monogenic diseases closely related to ALS. Here, we move the narrative towards a better appreciation of muscle as a contributor of disease in ALS. We review the various potential roles of skeletal muscle cells in ALS, from passive bystanders to active players in ALS pathophysiology. We also compare ALS to other motor neuron diseases and draw perspectives for future research and treatment., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease in which the TDP-43 protein is believed to play a central role in disease pathophysiology. Using the CRISPR-Cas9 system, we introduced the heterozygous c.1144G > A (p.A382T) missense mutation in exon 6 of the TARDBP gene into an iPSC line derived from a healthy individual. These edited iPSCs displayed normal cellular morphology, expressed major pluripotency markers, were capable of tri-lineage differentiation, and possessed a normal karyotype., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shyuan Ngo reports financial support was provided by National Health and Medical Research Council. Timothy Tracey reports financial support was provided by University of Queensland. Leanne Jiang reports financial support was provided by The University of Western Australia. Shyuan Ngo reports financial support was provided by MND and Me Foundation. Shyuan Ngo reports financial support was provided by Royal Brisbane and Women’s Hospital Foundation. Shyuan Ngo reports financial support was provided by FightMND. Shyuan Ngo reports consultancy fees from Cytokinetics., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Weight loss in patients with amyotrophic lateral sclerosis (ALS) is associated with faster disease progression and shorter survival. Decreased hypothalamic volume is proposed to contribute to weight loss due to loss of appetite and/or hypermetabolism. We aimed to investigate the relationship between hypothalamic volume and body mass index (BMI) in ALS and Alzheimer's disease (AD), and the associations of hypothalamic volume with weight loss, appetite, metabolism and survival in patients with ALS., Methods: We compared hypothalamic volumes from magnetic resonance imaging scans with BMI for patients with ALS (n = 42), patients with AD (n = 167) and non-neurodegenerative disease controls (n = 527). Hypothalamic volumes from patients with ALS were correlated with measures of appetite and metabolism, and change in anthropomorphic measures and disease outcomes., Results: Lower hypothalamic volume was associated with lower and higher BMI in ALS (quadratic association; probability of direction = 0.96). This was not observed in AD patients or controls. Hypothalamic volume was not associated with loss of appetite (p = 0.58) or hypermetabolism (p = 0.49). Patients with lower BMI and lower hypothalamic volume tended to lose weight (p = 0.08) and fat mass (p = 0.06) over the course of their disease, and presented with an increased risk of earlier death (hazard ratio [HR] 3.16, p = 0.03). Lower hypothalamic volume alone trended for greater risk of earlier death (HR 2.61, p = 0.07)., Conclusion: These observations suggest that lower hypothalamic volume in ALS contributes to positive and negative energy balance, and  is not universally associated with loss of appetite or hypermetabolism. Critically, lower hypothalamic volume with lower BMI was associated with weight loss and earlier death., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: To capture the patient's attitude toward remote monitoring of motor neuron disease (MND) in care and clinical trials, and their concerns and preferences regarding the use of digital technology., Methods: We performed an international multi-centre survey study in three MND clinics in The Netherlands, the United Kingdom, and Australia. The survey was co-developed by investigators and patients with MND, and sent to patients by e-mail or postal-mail. The main topics included: patients' attitude towards remote care, participating in decentralized clinical trials, and preferences for and concerns with digital technology use., Results: In total, 332 patients with MND participated. A majority of patients indicated they would be happy to self-monitor their health from home (69%), be remotely monitored by a multidisciplinary care team (75%), and would be willing to participate in clinical trials from home (65%). Patients considered respiratory function and muscle strength most valuable for home-monitoring. The majority of patients considered the use of at least three devices/apps (75%) once a week (61%) to be acceptable for home-monitoring. Fifteen percent of patients indicated they would not wish to perform home-measurements; reporting concerns about the burden and distress of home-monitoring, privacy and data security., Conclusion: Most patients with MND exhibited a positive attitude toward the use of digital technology in both care and clinical trial settings. A subgroup of patients reported concerns with home-monitoring, which should be addressed in order to improve widespread adoption of remote digital technology in clinical MND care., (© 2022. The Author(s).)

Amyotrophic Lateral Sclerosis (ALS) is recognised to be a complex neurodegenerative disease involving both genetic and non-genetic risk factors. The underlying causes and risk factors for the majority of cases remain unknown; however, ever-larger genetic data studies and methodologies promise an enhanced understanding. Recent analyses using published summary statistics from the largest ALS genome-wide association study (GWAS) (20,806 ALS cases and 59,804 healthy controls) identified that schizophrenia (SCZ), cognitive performance (CP) and educational attainment (EA) related traits were genetically correlated with ALS. To provide additional evidence for these correlations, we built single and multi-trait genetic predictors using GWAS summary statistics for ALS and these traits, (SCZ, CP, EA) in an independent Australian cohort (846 ALS cases and 665 healthy controls). We compared methods for generating the risk predictors and found that the combination of traits improved the prediction (Nagelkerke-R 2 ) of the case-control logistic regression. The combination of ALS, SCZ, CP, and EA, using the SBayesR predictor method gave the highest prediction (Nagelkerke-R 2 ) of 0.027 (P value = 4.6 × 10 -8 ), with the odds-ratio for estimated disease risk between the highest and lowest deciles of individuals being 3.15 (95% CI 1.96-5.05). These results support the genetic correlation between ALS, SCZ, CP and EA providing a better understanding of the complexity of ALS., (© 2021. The Author(s), under exclusive licence to European Society of Human Genetics.)

Background and Purpose: Amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles and is currently incurable. Although considered to be a pure motor neuron disease, increasing evidence indicates that the sole protection of motor neurons by a single targeted drug is not sufficient to improve the pathological phenotype. We therefore evaluated the therapeutic potential of the multi-target drug used to treatment of coronary artery disease, trimetazidine, in SOD1 G93A mice., Experimental Approach: As a metabolic modulator, trimetazidine improves glucose metabolism. Furthermore, trimetazidine enhances mitochondrial metabolism and promotes nerve regeneration, exerting an anti-inflammatory and antioxidant effect. We orally treated SOD1 G93A mice with trimetazidine, solubilized in drinking water at a dose of 20 mg kg -1 , from disease onset. We assessed the impact of trimetazidine on disease progression by studying metabolic parameters, grip strength and histological alterations in skeletal muscle, peripheral nerves and the spinal cord., Key Results: Trimetazidine administration delays motor function decline, improves muscle performance and metabolism, and significantly extends overall survival of SOD1 G93A mice (increased median survival of 16 days and 12.5 days for male and female respectively). Moreover, trimetazidine prevents the degeneration of neuromuscular junctions, attenuates motor neuron loss and reduces neuroinflammation in the spinal cord and in peripheral nerves., Conclusion and Implications: In SOD1 G93A mice, therapeutic effect of trimetazidine is underpinned by its action on mitochondrial function in skeletal muscle and spinal cord., (© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.

Objective : Hyaluronan, a glycosaminoglycan that forms a major constituent of the extracellular matrix, has been shown to be increased in the serum of patients with amyotrophic lateral sclerosis (ALS) with longer disease duration. We sought to determine whether measures of venous hyaluronan may serve as a predictive marker for disease progression in patients with ALS. Methods: Sixty-two patients with ALS, and 59 healthy control participants provided a plasma sample for the assessment of hyaluronan. Hyaluronan was compared against functional measures of disability, disease progression, and survival. Results: Hyaluronan was lower in patients with ALS when compared to healthy controls. Plasma hyaluronan was positively correlated with the change in the revised ALS functional rating scale, ΔFRS. Hyaluronan was also found to improve the prognostic power of the ΔFRS. Conclusion: Hyaluronan may serve as a predictive marker for functional decline in patients with ALS. Longitudinal studies are needed to fully explore the prognostic value of hyaluronan as a biomarker for disease progression, and to improve our understanding of components of the extracellular matrix specific to the pathophysiology of ALS.

Background: Amyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this., Methods: The Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data (N cases = 20,806, N controls = 59,804) with 'omics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray N total = 942, protein N total = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO)., Results: SMR analyses implicated both TNIP1 and GPX3 (p < 1.15 × 10 -6 ), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 × 10 -3 , adjusted R 2 = 0.042, B effect = 27.4 ± 13.3 ng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28 mm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53 mm/s, respectively, p for all < 0.0001), which were rescued with gpx3 expression, with no phenotype identified with tnip1 KD or gpx3 overexpression., Conclusions: These results support GPX3 as a lead ALS risk gene in this locus, with more data needed to confirm/reject a role for TNIP1. This has implications for understanding disease mechanisms (GPX3 acts in the same pathway as SOD1, a well-established ALS-associated gene) and identifying new therapeutic approaches. Few previous examples of in-depth investigations of risk loci in ALS exist and a similar approach could be applied to investigate future expected GWAS findings., (© 2021. The Author(s).)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons., (© 2021. The Author(s).)

Background and Purpose: To establish the utility of venous creatinine as a biomarker to monitor loss of fat-free mass in patients with amyotrophic lateral sclerosis (ALS)., Methods: In this multicenter natural history study, body composition and venous creatinine were assessed in 107 patients with ALS and 52 healthy controls. Longitudinal patterns of venous creatinine and its association with the risk of death during follow-up were determined in a cohort of patients with ALS from Australia (n = 69) and the Netherlands (n = 38)., Results: The mean levels of venous creatinine were 75.78 ± 11.15 μmol/L for controls, 70.25 ± 12.81 μmol/L for Australian patients, and 59.95 ± 14.62 μmol/L for Dutch patients with ALS. The relationship between measures of venous creatinine and fat-free mass was similar between all groups (r = 0.36, p < 0.001). Within patients, fat-free mass declined by 0.31 (95% confidence interval [CI]: 0.22-0.40) kg/month, and venous creatinine declined by 0.52 (95% CI: 0.38-0.66) μmol/L/month, with a longitudinal correlation of 0.57 (95% CI: 0.35-0.76, p < 0.001). Lower levels of venous creatinine were associated with increased risk for earlier death in patients with ALS (hazard ratio = 0.94, 95% CI: 0.90-0.98, p = 0.007)., Conclusions: Venous creatinine is decreased in ALS and declines alongside a decline in fat-free mass over the course of the disease, and may serve as a practical marker to monitor the change of fat-free mass in patients with ALS. This could inform clinical care and provide an alternative endpoint for the evaluation of therapeutic interventions that focus on slowing the loss of fat-free mass and disease progression in ALS., (© 2021 European Academy of Neurology.)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive and selective loss of motor neurons, amyotrophy and skeletal muscle paralysis usually leading to death due to respiratory failure. While generally considered an intrinsic motor neuron disease, data obtained in recent years, including our own, suggest that motor neuron protection is not sufficient to counter the disease. The dismantling of the neuromuscular junction is closely linked to chronic energy deficit found throughout the body. Metabolic (hypermetabolism and dyslipidemia) and mitochondrial alterations described in patients and murine models of ALS are associated with the development and progression of disease pathology and they appear long before motor neurons die. It is clear that these metabolic changes participate in the pathology of the disease. In this review, we summarize these changes seen throughout the course of the disease, and the subsequent impact of glucose-fatty acid oxidation imbalance on disease progression. We also highlight studies that show that correcting this loss of metabolic flexibility should now be considered a major goal for the treatment of ALS.

Disorders of sleep and wakefulness are common among neurodegenerative diseases. While amyotrophic lateral sclerosis (ALS) predominately manifests as motor symptoms, there is emerging evidence that disruptions to sleep and wakefulness also occur. This systematic review aims to report the most common disorders of sleep and wakefulness in ALS. We conducted a qualitative systematic review as per PRISMA guidelines and searched literature assessing the association between disorders of sleep and wakefulness with ALS using the PubMed and Medline database. Overall, 50-63% of patients with ALS have poor sleep quality as reported using the Pittsburgh Sleep Quality Index Questionnaire (PSQI). A higher proportion of ALS patients are categorized as poor sleepers, however there is conflicting evidence as to whether patients with ALS are more likely to exhibit excessive daytime sleepiness. Of the studies that utilized polysomnography, all reported various degrees of impairment to sleep microstructure and architecture among ALS patients. In future, longitudinal clinical studies will be essential for establishing the significance of impaired sleep in ALS. Future studies are also needed to establish whether the self-reported measures of poor sleep and impairment to sleep architecture occurs as a direct consequence of the disease, whether they are an early manifestation of the disease, and/or if they contribute to the neurodegenerative process.

Sphingolipids are complex lipids. They play a structural role in neurons, but are also involved in regulating cellular communication, and neuronal differentiation and maturation. There is increasing evidence to suggest that dysregulated metabolism of sphingolipids is linked to neurodegenerative processes in amyotrophic lateral sclerosis (ALS), Parkinson's disease and Gaucher's disease. In this review, we provide an overview of the role of sphingolipids in the development and maintenance of the nervous system. We describe the implications of altered metabolism of sphingolipids in the pathophysiology of certain neurodegenerative diseases, with a primary focus on ALS. Finally, we provide an update of potential treatments that could be used to target the metabolism of sphingolipids in neurodegenerative diseases., (Copyright © 2020. Published by Elsevier Ltd.)

Gut microbiota studies have been well-investigated for neurodegenerative diseases such as Alzheimer's and Parkinson's disease, however, fewer studies have comprehensively examined the gut microbiome in Motor Neuron Disease (MND), with none examining its impact on disease prognosis. Here, we investigate MND prognosis and the fecal microbiota, using 16S rRNA case-control data from 100 individuals with extensive medical histories and metabolic measurements. We contrast the composition and diversity of fecal microbiome signatures from 49 MND and 51 healthy controls by combining current gold-standard 16S microbiome pipelines. Using stringent quality control thresholds, we conducted qualitative assessment approaches including; direct comparison of taxa, PICRUSt2 predicted metagenomics, Shannon and Chao1-index and Firmicutes/Bacteroidetes ratio. We show that the fecal microbiome of patients with MND is not significantly different from that of healthy controls that were matched by age, sex, and BMI, however there are distinct differences in Beta-diversity in some patients with MND. Weight, BMI, and metabolic and clinical features of disease in patients with MND were not related to the composition of their fecal microbiome, however, we observe a greater risk for earlier death in patients with MND with increased richness and diversity of the microbiome, and in those with greater Firmicutes to Bacteroidetes ratio. This was independent of anthropometric, metabolic, or clinical features of disease, and warrants support for further gut microbiota studies in MND. Given the disease heterogeneity in MND, and complexity of the gut microbiota, large studies are necessary to determine the detailed role of the gut microbiota and MND prognosis.

We meta-analyze amyotrophic lateral sclerosis (ALS) genome-wide association study (GWAS) data of European and Chinese populations (84,694 individuals). We find an additional significant association between rs58854276 spanning ACSL5-ZDHHC6 with ALS (p = 8.3 × 10 -9 ), with replication in an independent Australian cohort (1,502 individuals; p = 0.037). Moreover, B4GALNT1, G2E3-SCFD1, and TRIP11-ATXN3 are identified using a gene-based analysis. ACSL5 has been associated with rapid weight loss, as has another ALS-associated gene, GPX3. Weight loss is frequent in ALS patients and is associated with shorter survival. We investigate the effect of the ACSL5 and GPX3 single-nucleotide polymorphisms (SNPs), using longitudinal body composition and weight data of 77 patients and 77 controls. In patients' fat-free mass, although not significant, we observe an effect in the expected direction (rs58854276: -2.1 ± 1.3 kg/A allele, p = 0.053; rs3828599: -1.0 ± 1.3 kg/A allele, p = 0.22). No effect was observed in controls. Our findings support the increasing interest in lipid metabolism in ALS and link the disease genetics to weight loss in patients., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective : Weight loss in amyotrophic lateral sclerosis (ALS) is associated with faster disease progression and shorter survival. It has different possible causes, including loss of appetite. Our objective is to determine the prevalence and impact of loss of appetite on change in body weight and composition in patients with ALS. Methods : We conducted a prospective case-control study, comparing demographic, clinical, appetite and prognostic features between 62 patients with ALS and 45 healthy non-neurodegenerative disease (NND) controls. To determine the impact of loss of appetite on weight throughout disease course, we conducted serial assessments at ∼three to four-month intervals. Results : Loss of appetite is more prevalent in patients with ALS than NND controls (29 vs. 11.1%, odds ratio = 3.27 (1.1-9.6); p  < 0.01). In patients with ALS, loss of appetite is associated with greater weight loss and greater loss of fat mass. Appetite scores in patients with ALS worsens as disease progresses and are correlated with worsening ALS Functional Rating Scale-Revised scores. Conclusion : We confirm that loss of appetite is prevalent in patients with ALS and is significantly associated with weight loss and loss of fat mass. Appetite worsens with disease progression. Identification and early interventions to address loss of appetite in patients with ALS may prevent or slow weight loss; this could improve disease outcome.

Objective: To determine the prevalence of hypermetabolism, relative to body composition, in amyotrophic lateral sclerosis (ALS) and its relationship with clinical features of disease and survival., Methods: Fifty-eight patients with clinically definite or probable ALS as defined by El Escorial criteria, and 58 age and sex-matched control participants underwent assessment of energy expenditure. Our primary outcome was the prevalence of hypermetabolism in cases and controls. Longitudinal changes in clinical parameters between hypermetabolic and normometabolic patients with ALS were determined for up to 12 months following metabolic assessment. Survival was monitored over a 30-month period following metabolic assessment., Results: Hypermetabolism was more prevalent in patients with ALS than controls (41% vs 12%, adjusted OR=5.4; p<0.01). Change in body weight, body mass index and fat mass (%) was similar between normometabolic and hypermetabolic patients with ALS. Mean lower motor neuron score (SD) was greater in hypermetabolic patients when compared with normometabolic patients (4 (0.3) vs 3 (0.7); p=0.04). In the 12 months following metabolic assessment, there was a greater change in Revised ALS Functional Rating Scale score in hypermetabolic patients when compared with normometabolic patients (-0.68 points/month vs -0.39 points/month; p=0.01). Hypermetabolism was inversely associated with survival. Overall, hypermetabolism increased the risk of death during follow-up to 220% (HR 3.2, 95% CI 1.1 to 9.4, p=0.03)., Conclusions and Relevance: Hypermetabolic patients with ALS have a greater level of lower motor neuron involvement, faster rate of functional decline and shorter survival. The metabolic index could be important for informing prognosis in ALS., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Anthropometric measurements including body mass index (BMI) and body adiposity index (BAI) are widely employed as indicators of fat mass (FM). Metabolic abnormalities in amyotrophic lateral sclerosis (ALS) impact disease progression, therefore assessment of FM informs care. The aim of this study was to determine whether BMI and BAI are accurate predictors of FM in ALS. Methodology and main findings: BMI, BAI and percentage FM (determined by air displacement plethysmography; FM-ADP) were measured in control (n = 35) and ALS (n = 44) participants. While BMI and BAI correlated significantly with FM-ADP, neither index provided an accurate estimate of FM. In longitudinally assessed ALS participants (n = 29; ∼six-month repeat assessment interval), although a change in BMI (r 2  = 0.62 r = 0.79 p < 0.01) and BAI (r 2  = 0.20 r = 0.44, p = 0.02) correlated with a change in FM-ADP, the anthropometric measures did not consistently reflect increases or decreases observed in FM-ADP., Conclusions/significance: Using FM-ADP as the standard, this study suggests that BMI and BAI are not accurate measures of FM in ALS. Furthermore, longitudinal assessments indicate that changes in BMI and BAI do not consistently reflect true changes of FM in ALS.

Cross-ethnic genetic studies can leverage power from differences in disease epidemiology and population-specific genetic architecture. In particular, the differences in linkage disequilibrium and allele frequency patterns across ethnic groups may increase gene-mapping resolution. Here we use cross-ethnic genetic data in sporadic amyotrophic lateral sclerosis (ALS), an adult-onset, rapidly progressing neurodegenerative disease. We report analyses of novel genome-wide association study data of 1,234 ALS cases and 2,850 controls. We find a significant association of rs10463311 spanning GPX3-TNIP1 with ALS (p = 1.3 × 10 -8 ), with replication support from two independent Australian samples (combined 576 cases and 683 controls, p = 1.7 × 10 -3 ). Both GPX3 and TNIP1 interact with other known ALS genes (SOD1 and OPTN, respectively). In addition, GGNBP2 was identified using gene-based analysis and summary statistics-based Mendelian randomization analysis, although further replication is needed to confirm this result. Our results increase our understanding of genetic aetiology of ALS.Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease. Here, Wray and colleagues identify association of the GPX3-TNIP1 locus with ALS using cross-ethnic meta-analyses.

Layer V pyramidal neurons (LVPNs) within the motor cortex integrate sensory cues and co-ordinate voluntary control of motor output. In amyotrophic lateral sclerosis (ALS) LVPNs and spinal motor neurons degenerate. The pathogenesis of neural degeneration is unknown in ALS; 10% of cases have a genetic cause, whereas 90% are sporadic, with most of the latter showing TDP-43 inclusions. Clinical and experimental evidence implicate excitotoxicity as a prime aetiological candidate. Using patch clamp and dye-filling techniques in brain slices, combined with high-resolution confocal microscopy, we report increased excitatory synaptic inputs and dendritic spine densities in early presymptomatic mice carrying a TDP-43 Q331K mutation. These findings demonstrate substantive alterations in the motor cortex neural network, long before an overt degenerative phenotype has been reported. We conclude that increased excitatory neurotransmission is a common pathophysiology amongst differing genetic cases of ALS and may be of relevance to the 95% of sporadic ALS cases that exhibit TDP-43 inclusions.

There is increasing evidence that energy metabolism is disturbed in Amyotrophic Lateral Sclerosis (ALS) patients and animal models. Treatment with triheptanoin, the triglyceride of heptanoate, is a promising approach to provide alternative fuel to improve oxidative phosphorylation and aid ATP generation. Heptanoate can be metabolized to propionyl-CoA, which after carboxylation can produce succinyl-CoA and thereby re-fill the tricarboxylic acid (TCA) cycle (anaplerosis). Here we tested the hypothesis that treatment with triheptanoin prevents motor neuron loss and delays the onset of disease symptoms in female mice overexpressing the mutant human SOD1G93A (hSOD1G93A) gene. When oral triheptanoin (35% of caloric content) was initiated at P35, motor neuron loss at 70 days of age was attenuated by 33%. In untreated hSOD1G93A mice, the loss of hind limb grip strength began at 16.7 weeks. Triheptanoin maintained hind limb grip strength for 2.8 weeks longer (p<0.01). Loss of balance on the rotarod and reduction of body weight were delayed by 13 and 11 days respectively (both p<0.01). Improved motor function occurred in parallel with alterations in the expression of genes associated with muscle metabolism. In gastrocnemius muscles, the mRNA levels of pyruvate, 2-oxoglutarate and succinate dehydrogenases and methyl-malonyl mutase were reduced by 24-33% in 10 week old hSOD1G93A mice when compared to wild-type mice, suggesting that TCA cycling in skeletal muscle may be slowed in this ALS mouse model at a stage when muscle strength is still normal. At 25 weeks of age, mRNA levels of succinate dehydrogenases, glutamic pyruvic transaminase 2 and the propionyl carboxylase β subunit were reduced by 69-84% in control, but not in triheptanoin treated hSOD1G93A animals. Taken together, our results suggest that triheptanoin slows motor neuron loss and the onset of motor symptoms in ALS mice by improving TCA cycling., Competing Interests: We have applied for a US patent regarding the treatment of ALS (Neurodegenerative disorders and methods of treatment and diagnosis thereof. US provisional patent application 2013; US 61/904,365). Sasol and Ultragenyx Pharmaceuticals Inc. donated triheptanoin. There are no additional patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurones, which leads to paralysis and death in an average of 3 years following diagnosis. The cause of ALS is unknown, but there is substantial evidence that metabolic factors, including nutritional state and body weight, affect disease progression and survival. This review provides an overview of the characteristics of metabolic dysregulation in ALS focusing on mechanisms that lead to disrupted energy supply (at a whole-body and cellular level) and altered energy expenditure. We discuss how a decrease in energy supply occurs in parallel with an increase in energy demand and leads to a state of chronic energy deficit which has a negative impact on disease outcome in ALS. We conclude by presenting potential and tested strategies to compensate for, or correct this energy imbalance, and speculate on promising areas for further research., (© 2016 S. Karger AG, Basel.)

Amyotrophic lateral sclerosis (ALS) is the most common fatal motor neuron disease in adults. Numerous studies indicate that ALS is a systemic disease that affects whole body physiology and metabolic homeostasis. Using a mouse model of the disease (SOD1(G86R)), we investigated muscle physiology and motor behavior with respect to muscle metabolic capacity. We found that at 65 days of age, an age described as asymptomatic, SOD1(G86R) mice presented with improved endurance capacity associated with an early inhibition in the capacity for glycolytic muscle to use glucose as a source of energy and a switch in fuel preference toward lipids. Indeed, in glycolytic muscles we showed progressive induction of pyruvate dehydrogenase kinase 4 expression. Phosphofructokinase 1 was inhibited, and the expression of lipid handling molecules was increased. This mechanism represents a chronic pathologic alteration in muscle metabolism that is exacerbated with disease progression. Further, inhibition of pyruvate dehydrogenase kinase 4 activity with dichloroacetate delayed symptom onset while improving mitochondrial dysfunction and ameliorating muscle denervation. In this study, we provide the first molecular basis for the particular sensitivity of glycolytic muscles to ALS pathology., (© 2015 The Authors. Published under the terms of the CC BY 4.0 license.)

Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, has been viewed almost exclusively as a disease of upper and lower motor neurons, with muscle changes interpreted as a consequence of the progressive loss of motor neurons and neuromuscular junctions. This has led to the prevailing view that the involvement of muscle in ALS is only secondary to motor neuron loss. Skeletal muscle and motor neurons reciprocally influence their respective development and constitute a single functional unit. In ALS, multiple studies indicate that skeletal muscle dysfunction might contribute to progressive muscle weakness, as well as to the final demise of neuromuscular junctions and motor neurons. Furthermore, skeletal muscle has been shown to participate in disease pathogenesis of several monogenic diseases closely related to ALS. Here, we move the narrative towards a better appreciation of muscle as a contributor of disease in ALS. We review the various potential roles of skeletal muscle cells in ALS, from passive bystanders to active players in ALS pathophysiology. We also compare ALS to other motor neuron diseases and draw perspectives for future research and treatment. [ABSTRACT FROM AUTHOR]

Background: Actigraphy has been proposed as a measure for tracking functional decline and disease progression in patients with Motor Neuron Disease (MND). There is, however, little evidence to show that wrist-based actigraphy measures correlate with functional decline, and no consensus on how best to implement actigraphy. We report on the use of wrist actigraphy to show decreased activity in patients compared to controls, and compared the utility of wrist- and hip-based actigraphy for assessing functional decline in patients with MND. Methods: In this multi-cohort, multi-centre, natural history study, wrist- and hip-based actigraphy were assessed in 139 patients with MND (wrist, n = 97; hip, n = 42) and 56 non-neurological control participants (wrist, n = 56). For patients with MND, longitudinal measures were contrasted with clinical outcomes commonly used to define functional decline. Results: Patients with MND have reduced wrist-based actigraphy scores when compared to controls (median differences: prop. active = − 0.053 [− 0.075, − 0.026], variation axis 1 = − 0.073 [− 0.112, − 0.021]). When comparing wrist- and hip-based measures, hip-based accelerometery had stronger correlations with disease progression (prop. active: τ = 0.20 vs 0.12; variation axis 1: τ = 0.33 vs 0.23), whereas baseline wrist-based accelerometery was better related with future decline in fine-motor function (τ = 0.14–0.23 vs 0.06–0.16). Conclusions: Actigraphy outcomes measured from the wrist are more variable than from the hip and present differing sensitivity to specific functional outcomes. Outcomes and analysis should be carefully constructed to maximise benefit, should wrist-worn devices be used for at-home monitoring of disease progression in patients with MND. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disorder with no cure available and limited treatment options. ALS is a highly heterogeneous disease, whereby patients present with vastly different phenotypes. Despite this heterogeneity, over 97% of patients will exhibit pathological TAR-DNA binding protein-43 (TDP-43) cytoplasmic inclusions. TDP-43 is a ubiquitously expressed RNA binding protein with the capacity to bind over 6000 RNA and DNA targets—particularly those involved in RNA, mitochondrial, and lipid metabolism. Here, we review the unique structure and function of TDP-43 and its role in affecting the aforementioned metabolic processes in ALS. Considering evidence published specifically in TDP-43-relevant in vitro, in vivo, and ex vivo models we posit that TDP-43 acts in a positive feedback loop with mRNA transcription/translation, stress granules, cytoplasmic aggregates, and mitochondrial proteins causing a relentless cycle of disease-like pathology eventuating in neuronal toxicity. Given its undeniable presence in ALS pathology, TDP-43 presents as a promising target for mechanistic disease modelling and future therapeutic investigations. [ABSTRACT FROM AUTHOR]

Background and Purpose: Amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles and is currently incurable. Although considered to be a pure motor neuron disease, increasing evidence indicates that the sole protection of motor neurons by a single targeted drug is not sufficient to improve the pathological phenotype. We therefore evaluated the therapeutic potential of the multi‐target drug used to treatment of coronary artery disease, trimetazidine, in SOD1G93A mice. Experimental Approach As a metabolic modulator, trimetazidine improves glucose metabolism. Furthermore, trimetazidine enhances mitochondrial metabolism and promotes nerve regeneration, exerting an anti‐inflammatory and antioxidant effect. We orally treated SOD1G93A mice with trimetazidine, solubilized in drinking water at a dose of 20 mg kg−1, from disease onset. We assessed the impact of trimetazidine on disease progression by studying metabolic parameters, grip strength and histological alterations in skeletal muscle, peripheral nerves and the spinal cord. Key Results: Trimetazidine administration delays motor function decline, improves muscle performance and metabolism, and significantly extends overall survival of SOD1G93A mice (increased median survival of 16 days and 12.5 days for male and female respectively). Moreover, trimetazidine prevents the degeneration of neuromuscular junctions, attenuates motor neuron loss and reduces neuroinflammation in the spinal cord and in peripheral nerves. Conclusion and Implications: In SOD1G93A mice, therapeutic effect of trimetazidine is underpinned by its action on mitochondrial function in skeletal muscle and spinal cord. [ABSTRACT FROM AUTHOR]

Ghrelin is a gut hormone best known for its role in regulating appetite and stimulating the secretion of the anabolic hormone growth hormone (GH). However, there is considerable evidence to show wider‐ranging biological actions of ghrelin that favour improvements in cellular and systemic metabolism, as well as neuroprotection. Activation of these ghrelin‐mediated pathways may alleviate pathogenic processes that are assumed to contribute to accelerated progression of disease in patients with neurodegenerative disease. Here, we provide a brief overview on the history of discoveries that led to the identification of ghrelin. Focussing on the neurodegenerative disease amyotrophic lateral sclerosis (ALS), we also present an overview of emerging evidence that suggests that ghrelin and ghrelin mimetics may serve as potential therapies for the treatment of ALS. Given that ALS is a highly heterogeneous disease, where multiple disease mechanisms contribute to variability in disease onset and rate of disease progression, we speculate that the wide‐ranging biological actions of ghrelin might offer therapeutic benefit through modulating multiple disease‐relevant processes observed in ALS. Expanding on the well‐known actions of ghrelin in regulating food intake and GH secretion, we consider the potential of ghrelin‐mediated pathways in improving body weight regulation, metabolism and the anabolic and neuroprotective actions of GH and insulin‐like growth factor‐1 (IGF‐1). This is of clinical significance because loss of body weight, impairments in systemic and cellular metabolism, and reductions in IGF‐1 are associated with faster disease progression and worse disease outcome in patients with ALS. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder primarily characterized by selective degeneration of both the upper motor neurons in the brain and lower motor neurons in the brain stem and the spinal cord. The exact mechanism for the selective death of neurons is unknown. A growing body of evidence demonstrates abnormalities in energy metabolism at the cellular and whole-body level in animal models and in people living with ALS. Many patients with ALS exhibit metabolic changes such as hypermetabolism and body weight loss. Despite these whole-body metabolic changes being observed in patients with ALS, the origin of metabolic dysregulation remains to be fully elucidated. A number of pre-clinical studies indicate that underlying bioenergetic impairments at the cellular level may contribute to metabolic dysfunctions in ALS. In particular, defects in CNS glucose transport and metabolism appear to lead to reduced mitochondrial energy generation and increased oxidative stress, which seem to contribute to disease progression in ALS. Here, we review the current knowledge and understanding regarding dysfunctions in CNS glucose metabolism in ALS focusing on metabolic impairments in glucose transport, glycolysis, pentose phosphate pathway, TCA cycle and oxidative phosphorylation. We also summarize disturbances found in glycogen metabolism and neuroglial metabolic interactions. Finally, we discuss options for future investigations into how metabolic impairments can be modified to slow disease progression in ALS. These investigations are imperative for understanding the underlying causes of metabolic dysfunction and subsequent neurodegeneration, and to also reveal new therapeutic strategies in ALS. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the deterioration of motor neurons. However, this complex disease extends beyond the boundaries of the central nervous system, with metabolic alterations being observed at the systemic and cellular level. While the number of studies that assess the role and impact of metabolic perturbations in ALS is rapidly increasing, the use of metabolism biomarkers in ALS remains largely underinvestigated. In this review, we discuss current and potential metabolism biomarkers in the context of ALS. Of those for which data does exist, there is limited insight provided by individual markers, with specificity for disease, and lack of reproducibility and efficacy in informing prognosis being the largest drawbacks. However, given the array of metabolic markers available, the potential exists for a panel of metabolism biomarkers, which may complement other current biomarkers (including neurophysiology, imaging, as well as CSF, blood and urine markers) to overturn these limitations and give rise to new diagnostic and prognostic indicators. [ABSTRACT FROM AUTHOR]

Lipids are a fundamental class of organic molecules implicated in a wide range of biological processes related to their structural diversity, and based on this can be broadly classified into five categories; fatty acids, triacylglycerols (TAGs), phospholipids, sterol lipids and sphingolipids. Different lipid classes play major roles in neuronal cell populations; they can be used as energy substrates, act as building blocks for cellular structural machinery, serve as bioactive molecules, or a combination of each. In amyotrophic lateral sclerosis (ALS), dysfunctions in lipid metabolism and function have been identified as potential drivers of pathogenesis. In particular, aberrant lipid metabolism is proposed to underlie denervation of neuromuscular junctions, mitochondrial dysfunction, excitotoxicity, impaired neuronal transport, cytoskeletal defects, inflammation and reduced neurotransmitter release. Here we review current knowledge of the roles of lipid metabolism and function in the CNS and discuss how modulating these pathways may offer novel therapeutic options for treating ALS. [ABSTRACT FROM AUTHOR]

A growing number of preclinical and human studies demonstrate a disease-modifying effect of nutritional state in amyotrophic lateral sclerosis (ALS). The management of optimal nutrition in ALS is complicated, as physiological, physical, and psychological effects of the disease need to be considered and addressed accordingly. In this regard, multidisciplinary care teams play an integral role in providing dietary guidance to ALS patients and their carers. However, with an increasing research focus on the use of dietary intervention strategies to manage disease symptoms and improve prognosis in ALS, many ALS patients are now seeking or are actively engaged in using complementary and alternative therapies that are dietary in nature. In this article, we review the aspects of appetite control, energy balance, and the physiological effects of ALS relative to their impact on overall nutrition. We then provide current insights into dietary interventions for ALS, considering the mechanisms of action of some of the common dietary interventions used in ALS, discussing their validity in the context of clinical trials. [ABSTRACT FROM AUTHOR]