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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.

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 x 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. Refereed/Peer-reviewed

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.

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 is currently incurable despite intense research and numerous unsuccessful clinical trials. Although considered as a pure motor neuron disease, increasing evidence indicates that the sole protection of motor neurons by a single target drug is not sufficient to improve the pathological phenotype. We therefore evaluated the therapeutic potential of the multi-target drug, trimetazidine, in SOD1G93A mice. Experimental approach: Trimetazidine is an anti-ischemic drug used for the treatment of coronary artery disease. As a metabolic modulator, Trimetazidine improves glucose metabolism. Furthermore, Trimetazidine enhances mitochondrial metabolism and promotes nerve regeneration, exerting an anti-inflammatory and antioxidant effect. Here, we orally treated SOD1G93A mice with Trimetazidine, solubilized in drinking water at a dose of 20 mg/kg, 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 nerve and 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 dismantlement 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. Keywords: Amyotrophic Lateral Sclerosis; Hypermetabolism; Mitochondria; Neurodegeneration; SOD1G93A mice; Trimetazidine.

Objective: To investigate changes in immune markers and frequencies throughout disease progression in patients with amyotrophic lateral sclerosis (ALS). Methods: In this longitudinal study, serial blood samples were collected from 21 patients with ALS over a time period of up to 16 months. Flow cytometry was used to quantitate CD14, HLA-DR, and CD16 marker expression on monocyte subpopulations and neutrophils, as well as their cell population frequencies. A Generalized Estimating Equation model was used to assess the association between changes in these immune parameters and disease duration and the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Results: CD14 expression on monocyte subpopulations increased with both disease duration and a decrease in ALSFRS-R score in patients with ALS. HLA-DR expression on monocyte subpopulations also increased with disease severity and/or duration. The expression of CD16 did not change relative to disease duration or ALSFRS-R. Finally, patients had a reduction in non-classical monocytes and an increase in the classical to non-classical monocyte ratio throughout disease duration. Conclusion: The progressive immunological changes observed in this study provide further support that monocytes are implicated in ALS pathology. Monocytic CD14 and HLA-DR surface proteins may serve as a therapeutic target or criteria for the recruitment of patients with ALS into clinical trials for immunomodulatory therapies.

Introduction: The gut microbiota has important roles in maintaining human health. The microbiota and its metabolic byproducts could play a role in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Areas covered: The authors evaluate the methods of assessing the gut microbiota, and also review how the gut microbiota affects the various physiological functions of the gut. The authors then consider how gut dysbiosis could theoretically affect the pathogenesis of ALS. They present the current evidence regarding the composition of the gut microbiota in ALS and in rodent models of ALS. Finally, the authors review therapies that could improve gut dysbiosis in the context of ALS. Expert opinion: Currently reported studies suggest some instances of gut dysbiosis in ALS patients and mouse models; however, these studies are limited, and more information with well-controlled larger datasets is required to make a definitive judgment about the role of the gut microbiota in ALS pathogenesis. Overall this is an emerging field that is worthy of further investigation. The authors advocate for larger studies using modern metagenomic techniques to address the current knowledge gaps.

To establish the utility of venous creatinine as a biomarker to monitor loss of fat-free mass in patients with amyotrophic lateral sclerosis (ALS).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).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).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.

International audience; 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.

Background People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease. Results We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson’s disease (and none with Alzheimer’s disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights. Conclusions We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.

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.

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.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability of around 50%. DNA methylation patterns can serve as biomarkers 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 (EWAS) meta-analysis in 10,462 samples (7,344 ALS patients and 3,118 controls), representing the largest case-control study of DNA methylation for any disease to date. 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 show that DNA-methylation-based proxies for HDL-cholesterol, BMI, white blood cell (WBC) proportions and alcohol intake were independently associated with ALS. Integration of these results with our latest GWAS showed that cholesterol biosynthesis was causally related to ALS. Finally, we found that DNA methylation levels at several DMPs and blood cell proportion estimates derived from DNA methylation data, are associated with survival rate in patients, and could represent indicators of underlying disease processes.

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.

International audience; Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults. While it is primarily characterized by the death of upper and lower motor neurons, there is a significant metabolic component involved in the progression of the disease. Two-thirds of ALS patients have metabolic alterations that are associated with the severity of symptoms. In ALS, as in other neurodegenerative diseases, the metabolism of glycosphingolipids, a class of complex lipids, is strongly dysregulated. We therefore assume that this pathway constitutes an interesting avenue for therapeutic approaches. We have shown that the glucosylceramide degrading enzyme, glucocerebrosidase (GBA) 2 is abnormally increased in the spinal cord of the SOD1G86R mouse model of ALS. Ambroxol, a chaperone molecule that inhibits GBA2, has been shown to have beneficial effects by slowing the development of the disease in SOD1G86R mice. Currently used in clinical trials for Parkinson's and Gaucher disease, ambroxol could be considered as a promising therapeutic treatment for ALS.

Summary 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., Graphical Abstract, Highlights • Cross-ethnic meta-analysis finds an association between the ACSL5-ZDHHC6 locus and ALS • The ACSL5-ZDHHC6 association is replicated in an independent Australian cohort • ACSL5-ZDHHC6 lead SNP is in ACSL5 and is an eQTL of ZDHHC6 in brain tissues • ACSL5 SNPs might have an effect on fat-free mass in ALS patients, Using meta-analysis of European and Chinese ALS GWAS data, Iacoangeli et al. find an association between ACSL5-ZDHHC6 and ALS risk, with replication in an Australian cohort. They identify B4GALNT1, G2E3-SCFD1, and TRIP11-ATXN3 using a gene-based analysis. They also find a suggestive association between ACSL5 SNPs and lower fat-free mass in patients.

Amyotrophic lateral sclerosis is characterized by the degeneration of upper and lower motor neurons, yet an increasing number of studies in both mouse models and patients with amyotrophic lateral sclerosis suggest that altered metabolic homeostasis is also a feature of disease. Pre-clinical and clinical studies have shown that modulation of energy balance can be beneficial in amyotrophic lateral sclerosis. However, the capacity to target specific metabolic pathways or mechanisms requires detailed understanding of metabolic dysregulation in amyotrophic lateral sclerosis. Here, using the superoxide dismutase 1, glycine to alanine substitution at amino acid 93 (SOD1G93A) mouse model of amyotrophic lateral sclerosis, we demonstrate that an increase in whole-body metabolism occurs at a time when glycolytic muscle exhibits an increased dependence on fatty acid oxidation. Using myotubes derived from muscle of amyotrophic lateral sclerosis patients, we also show that increased dependence on fatty acid oxidation is associated with increased whole-body energy expenditure. In the present study, increased fatty acid oxidation was associated with slower disease progression. However, within the patient cohort, there was considerable heterogeneity in whole-body metabolism and fuel oxidation profiles. Thus, future studies that decipher specific metabolic changes at an individual patient level are essential for the development of treatments that aim to target metabolic pathways in amyotrophic lateral sclerosis., In superoxide dismutase 1, glycine to alanine substitution at amino acid 93 (SOD1G93A) mice, increased whole-body metabolism occurs alongside fat depletion and increased fatty acid oxidation in glycolytic muscle. Myotubes from patients with amyotrophic lateral sclerosis have increased fatty acid oxidation, and this is associated with increased whole-body energy expenditure. Increased fatty acid oxidation may sustain energy supply to slow disease., Graphical Abstract Graphical Abstract

International audience; 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.

Lipids play an important role in the central nervous system (CNS). They contribute to the structural integrity and physical characteristics of cell and organelle membranes, act as bioactive signalling molecules, and are utilised as fuel sources for mitochondrial metabolism. The intricate homeostatic mechanisms underpinning lipid handling and metabolism across two major CNS cell types; neurons and astrocytes, are integral for cellular health and maintenance. Here, we explore the various roles of lipids in these two cell types. Given that changes in lipid metabolism have been identified in a number of neurodegenerative diseases, we also discuss changes in lipid handling and utilisation in the context of amyotrophic lateral sclerosis (ALS), in order to identify key cellular processes affected by the disease, and inform future areas of research.

Amyotrophic lateral sclerosis (ALS) is an insidious disease. Diagnosis is made following observation of functional deficits that occur due to the death of upper and lower motor neurons. Pathological hallmarks of corticospinal tract involvement are almost always present, whereas upper motor neuron involvement could be subclinical.1 This complex clinicopathological phenotype is now recognised within a wide spectrum of disease that may include extramotor features such as cognitive and behavioural impairments.1 While median survival is currently 3 years following symptom onset, survival could become much longer. Superimposed on this elaborate canvas of presentation and progression is a range of factors thought to impact survival. Van Mantgem and colleagues …

Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons, yet an increasing number of studies in both mouse models and patients with ALS suggest that altered metabolic homeostasis is a feature of disease. Pre-clinical and clinical studies have shown that modulation of energy balance can be beneficial in ALS. However, our capacity to target specific metabolic pathways or mechanisms requires detailed understanding of metabolic dysregulation in ALS. Here, using the SOD1G93Amouse model of ALS, we demonstrate that an increase in whole-body metabolism occurs at a time when glycolytic muscle exhibits an increased dependence on fatty acid oxidation. Using myotubes derived from muscle of ALS patients, we also show that increased dependence on fatty acid oxidation is associated with increased whole-body energy expenditure. In the present study, increased fatty acid oxidation was associated with slower disease progression. However, we observed considerable heterogeneity in whole-body metabolism and fuel oxidation profiles across our patient cohort. Thus, future studies that decipher specific metabolic changes at an individual patient level are essential for the development of treatments that aim to target metabolic pathways in ALS.

Summary Patients with ALS show, in addition to the loss of motor neurons in the spinal cord, brainstem, and cerebral cortex, an abnormal depletion of energy stores alongside hypermetabolism. In this study, we show that bioenergetic defects and muscle remodeling occur in skeletal muscle of the SOD1G93A mouse model of ALS mice prior to disease onset and before the activation of muscle denervation markers, respectively. These changes in muscle physiology were followed by an increase in energy expenditure unrelated to physical activity. Finally, chronic treatment of SOD1G93A mice with Ranolazine, an FDA-approved inhibitor of fatty acid β-oxidation, led to a decrease in energy expenditure in symptomatic SOD1G93A mice, and this occurred in parallel with a robust, albeit temporary, recovery of the pathological phenotype., Graphical Abstract, Highlights • Metabolic switch use occurs early in the skeletal muscle of SOD1G93A mice • Mitochondrial impairment precedes locomotor deficits and evokes catabolic pathways • Sarcolipin upregulation in presymptomatic SOD1G93A mice precedes hypermetabolism • Pharmacological modulation of hypermetabolism improves locomotor performance, Drugs; Molecular Neuroscience; Cellular Neuroscience

Natural killer (NK) cells play critical roles in protection against hematological malignancies but can acquire a dysfunctional state, which limits antitumor immunity. However, the underlying reasons for this impaired NK cell function remain to be uncovered. We found that NK cells in aggressive B-cell lymphoma underwent substantial transcriptional reprogramming associated with increased lipid metabolism, including elevated expression of the transcriptional regulator peroxisome activator receptor-γ (PPAR-γ). Exposure to fatty acids in the lymphoma environment potently suppressed NK cell effector response and cellular metabolism. NK cells from both diffuse large B-cell lymphoma patients and Eµ-myc B-cell lymphoma-bearing mice displayed reduced interferon-γ (IFN-γ) production. Activation of PPAR-γ partially restored mitochondrial membrane potential and IFN-γ production. Overall, our data indicate that increased lipid metabolism, while impairing their function, is a functional adaptation of NK cells to the fatty-acid rich lymphoma environment.

We conducted DNA methylation association analyses using Illumina 450K data from whole blood for an Australian amyotrophic lateral sclerosis (ALS) case–control cohort (782 cases and 613 controls). Analyses used mixed linear models as implemented in the OSCA software. We found a significantly higher proportion of neutrophils in cases compared to controls which replicated in an independent cohort from the Netherlands (1159 cases and 637 controls). The OSCA MOMENT linear mixed model has been shown in simulations to best account for confounders. When combined in a methylation profile score, the 25 most-associated probes identified by MOMENT significantly classified case–control status in the Netherlands sample (area under the curve, AUC = 0.65, CI95% = [0.62–0.68], p = 8.3 × 10−22). The maximum AUC achieved was 0.69 (CI95% = [0.66–0.71], p = 4.3 × 10−34) when cell-type proportion was included in the predictor.

Immunity has emerged as a key player in neurodegenerative diseases such as amyotrophic lateral sclerosis, with recent studies documenting aberrant immune changes in patients and animal models. A challenging aspect of amyotrophic lateral sclerosis research is the heterogeneous nature of the disease. In this study, we investigate the associations between peripheral blood myeloid cell populations and clinical features characteristic of amyotrophic lateral sclerosis. Peripheral blood leukocytes from 23 healthy controls and 48 patients with amyotrophic lateral sclerosis were analysed to measure myeloid cell alterations. The proportion of monocytes (classical, intermediates and non-classical subpopulations) and neutrophils, as well as the expression of select surface markers, were quantitated using flow cytometry. Given the heterogeneous nature of amyotrophic lateral sclerosis, multivariable linear analyses were performed to investigate associations between patients’ myeloid profile and clinical features, such as the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, bulbar subscore of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale over disease duration and respiratory function. We demonstrate a shift in monocyte subpopulations in patients with amyotrophic lateral sclerosis, with the ratio of classical to non-classical monocytes increased compared with healthy controls. In line with this, patients with greater disease severity, as determined by a lower Revised Amyotrophic Lateral Sclerosis Functional Rating Scale score, had reduced non-classical monocytes. Interestingly, patients with greater bulbar involvement had a reduction in the proportions of classical, intermediate and non-classical monocyte populations. We also revealed several notable associations between myeloid marker expression and clinical features in amyotrophic lateral sclerosis. CD16 expression on neutrophils was increased in patients with greater disease severity and a faster rate of disease progression, whereas HLA-DR expression on all monocyte populations was elevated in patients with greater respiratory impairment. This study demonstrates that patients with amyotrophic lateral sclerosis with distinct clinical features have differential myeloid cell signatures. Identified cell populations and markers may be candidates for targeted mechanistic studies and immunomodulation therapies in amyotrophic lateral sclerosis., Monocyte and neutrophil frequencies and their expression markers were associated with bulbar symptoms, disease severity, rate of disease progression and respiratory impairment in patients with amyotrophic lateral sclerosis. Our study reveals that aberrant peripheral immunity is related to amyotrophic lateral sclerosis patient phenotype and supports the need for tailored therapies to modify the immune profile., Graphical Abstract

Amyotrophic lateral sclerosis (ALS) is a complex late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies have identified eleven risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Current association analysis data alone cannot determine the most plausible risk gene in this locus. Here, we undertake a comprehensive suite of studies to provide objective evidence to support or reject the relevance of these two genes. We use bioinformatic integration of genetic association data with omics reference data sets, in-vitro and in-vivo approaches to narrow down the likely candidate. TNIP1 and GPX3 are implicated in-silico (rs10463311 is an eQTL for these two genes). In-vivo expression analyses in ALS cases identify that GPX3 expression decreases with increased disability and rate of progression. Validation in-vivo, indicate GPX3 loss-of-function causes motor deficits in zebrafish embryos. Taken together, these results support GPX3 as being the ALS risk gene in this locus which has implications for understanding disease mechanisms and targeted therapeutic approaches.

The pathology of amyotrophic lateral sclerosis (ALS) is associated with impaired RNA processing and miRNA dysregulation. Here we investigate the regulation of the members of the miRNA biogenesis pathways and total miRNA levels at different stages of the disease. Muscle, brain and spinal cord tissue were obtained from pre-symptomatic, symptomatic and end-stage SOD1G93A mice. miRNA and transcript levels were measured by qPCR. As the diseases progresses, several genes involved in miRNA biogenesis as well as the miRNA/total RNA ratio increased in the tibialis anterior muscle, but not in the soleus or in neural tissue. We propose that a dysregulation in the miRNA/total RNA ratio in the tibialis anterior muscle from SOD1G93A mice reflects a pathological increase in miRNA biogenesis machinery. Alterations in the miRNA/total RNA ratio influence the levels of reference ncRNAs and may therefore potentially compromise the accuracy of commonly used miRNA normalization strategies. This article is protected by copyright. All rights reserved.

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 (r2 = 0.62 r = 0.79 p r2 = 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.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease defined by the presence of upper and lower motor neuron dysfunction. Clinical presentation and disease progression are variable between patients with ALS, with psychosocial, neuropsychological, nutritional and genetic factors all related to ALS outcome. We present a detailed characterisation of a patient with familial ALS with a novel TBK1 mutation with coexistent brain atrophy, behavioural changes and metabolic dysfunction. This male patient was first seen at age 62 years with a 3-month history of gait unsteadiness, weakness of the right arm and emotional lability. There was a history of depression. His father had died of ALS at age 67 years. At first assessment, there was weakness of the right upper limb, ALS Functional Rating Scale-Revised (ALSFRS-R) was 39 and his weight was 72 kg. After 6 months, there was onset of dysphagia. He had tongue fasciculations, brisk jaw jerk, weakness, wasting, brisk reflexes and fasciculations of upper and lower limbs. The ALSFRS-R was 34 and weight had further declined to 65 kg. Three months later, he had deteriorated further with severe weakness, nausea, anorexia and depression. ALSFRS-R was 25 and weight was 54 kg. His respiratory function declined from FVC of 4.57 L to 1.05 L over 6 months. He died ~16 months after the onset of symptoms. The patient participated in a series of neuropsychological, imaging and metabolic studies of unselected consenting patients with ALS enrolled from our clinic.1 Neuropsychological assessment results for this patient are presented in online supplementary table 1. Comparison of his individual results with those of other patients with ALS is presented in online supplementary tables 2 to 4. Genetic assessment was done by massively parallel sequencing using a custom-designed neuromuscular gene capture panel that tests for 66 genes known to be associated …

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

Besides loss of motor neurons in spinal cord, brainstem and cerebral cortex, patients with ALS show an abnormal depletion of energy stores and a parallel hypermetabolism in spite of simultaneous progression of skeletal muscle atrophy. Our results highlighted bioenergetic defects in skeletal muscle of ALS mice long before the disease onset that lead to deep modifications of muscle physiology. Muscle remodelling occurs in SOD1G93A mice before the activation of muscle denervation markers and this is followed by an increase of energy expenditure unrelated to physical activity. To this regard our attention has been focused on the identification of precocious biomarkers closely related to hypermetabolism, a phenomenon that possesses prognostic and diagnostic relevance. Finally, chronic Ranolazine treatment, a FDA-approved inhibitor of fatty acid b-oxidation, decreases energy expenditure in symptomatic SOD1G93A mice and this correlates with a robust, albeit temporary, recovery of pathological phenotype.

Metabolic dysfunction in skeletal muscle contributes to the aetiology and development of muscle diseases and metabolic diseases. As such, assessment of skeletal muscle cellular bioenergetics provides a powerful means to understand the role of skeletal muscle metabolism in disease and to identify possible therapeutic targets. Here, we developed a method that allows for the real-time assessment of cellular respiration in intact skeletal muscle fibre bundles obtained from the extensor digitorum longus (EDL) muscle of adult mice. Using this method, we assessed the contribution of ATP turnover and proton leak to basal mitochondrial oxygen consumption rate (OCR). Our data demonstrate that the mitochondria in EDL fibres are loosely coupled. Moreover, in the presence of carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), we show that palmitate exposure induced comparable peak OCR and higher total OCR in EDL fibre bundles when compared to pyruvate exposure, suggesting that fatty acids might be a more sustainable fuel source for skeletal muscle when mitochondria are driven to maximal respiration. Application of this method to EDL fibre bundles obtained from chronic high-fat diet fed mice revealed lower basal OCR and enhanced mitochondrial oxidation capacity in the presence of FCCP when compared to the chow-diet fed control mice. By using a 96-well microplate format, our method provides a flexible and efficient platform to investigate mitochondrial parameters of intact skeletal muscle fibres obtained from adult mice.

Studying rats fed high cholesterol diet and a pancreatic β-cell line (Min6), we aimed to determine the mechanisms by which quercetin protects against cholesterol-induced pancreatic β-cell dysfunction and impairments in glycemic control. Quercetin prevented the increase in total plasma cholesterol, but only partially prevented the high cholesterol diet-induced alterations in lipid profile. Quercetin prevented cholesterol-induced decreases in pancreatic ATP levels and mitochondrial bioenergetic dysfunction in Min6 cells, including decreases in mitochondrial membrane potentials and coupling efficiency in the mitochondrial respiration (basal and maximal oxygen consumption rate (OCR), ATP-linked OCR and reserve capacity). Quercetin protected against cholesterol-induced apoptosis of Min6 cells by inhibiting caspase-3 and -9 activation and cytochrome c release. Quercetin prevented the cholesterol-induced decrease in antioxidant defence enzymes from pancreas (cytosolic and mitochondrial homogenates) and Min6 cells and the cholesterol-induced increase of cellular and mitochondrial oxidative status and lipid peroxidation. Quercetin counteracted the cholesterol-induced activation of the NFκB pathway in the pancreas and Min6 cells, normalizing the expression of pro-inflammatory cytokines. Quercetin inhibited the cholesterol-induced decrease in sirtuin 1 expression in the pancreas and pancreatic β-cells. Taken together, the anti-apoptotic, antioxidant and anti-inflammatory properties of quercetin, and its ability to protect and improve mitochondrial bioenergetic function are likely to contribute to its protective action against cholesterol-induced pancreatic β-cell dysfunction, thereby preserving glucose-stimulated insulin secretion (GSIS) and glycemic control. Specifically, the improvement of ATP-linked OCR and the reserve capacity are important mechanisms for protection of quercetin. In addition, the inhibition of the NFκB pathway is an important mechanism for the protection of quercetin against cytokine mediated cholesterol-induced glycemic control impairment. In summary, our data highlight cellular, molecular and bioenergetic mechanisms underlying quercetin's protective effects on β-cells in vitro and in vivo, and provide a scientifically tested foundation upon which quercetin can be developed as a nutraceutical to preserve β-cell function., Graphical abstract fx1, Highlights • Quercetin prevents the impairment in glycemic control induced by cholesterol. • Quercetin prevents cholesterol-impaired insulin secretion in pancreatic β-cells. • Quercetin improves mitochondrial bioenergetics impaired by cholesterol. • Quercetin prevents the decrease in SIRT1 expression induced by cholesterol. • Quercetin prevents NF-kB activation and prevents cholesterol-induced inflammation.

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.

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.

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.

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the loss of upper cortical and lower motor neurons. ALS causes death within 2–5years of diagnosis. Diet and body mass index influence the clinical course of disease, however there is limited information about the expression of metabolic proteins and fat-derived cytokines (adipokines) in ALS. In healthy controls and subjects with ALS, we have measured levels of proteins and adipokines that influence metabolism. We find altered levels of active ghrelin, gastric inhibitory peptide (GIP), pancreatic polypeptide (PP), lipocalin-2, plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6) and 8 (IL-8), and tumor necrosis factor alpha (TNFα) in the plasma of ALS patients relative to controls. We also observe a positive correlation between the expression of plasma nerve growth factor (NGF) relative to disease duration, and an inverse correlation between plasma glucagon and the ALS functional rating scale-revised (ALSFRS-R). Further studies are required to determine whether altered expression of metabolic proteins and adipokines contribute to motor neuron vulnerability and how these factors act to modify the course of disease.

ObjectiveTo determine the prevalence of hypermetabolism, relative to body composition, in amyotrophic lateral sclerosis (ALS) and its relationship with clinical features of disease and survival.MethodsFifty-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.ResultsHypermetabolism was more prevalent in patients with ALS than controls (41% vs 12%, adjusted OR=5.4; pConclusions and relevanceHypermetabolic 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.

Growth hormone (GH) secretory patterns emerge following birth, and changes in patterning occur throughout life. These secretory patterns are coupled to growth, reproduction and metabolism. Comparing human and animal studies, this review will highlight ultradian patterning of GH release and the mechanisms that contribute to this. Discussions will focus on the emergence in variations in the number and frequency of GH secretory events, and the amounts of GH released (peak and basal). Animal studies have contributed significantly to our understanding of the processes that regulate GH release. However, translation of knowledge from animal models to benefit our understanding of human physiology is sometimes limited. To overcome these limitations, it is critical that we reconcile the cause and consequences of differences in GH release between humans and model organisms. In doing so, we can embrace emerging technologies that will rapidly advance our knowledge of endogenous process that control GH release.

Weight loss is an effective intervention for diminishing disease burden in obese older adults. Pharmacological interventions that reduce food intake and thereby promote weight loss may offer effective strategies to reduce age-related disease. We previously reported that 17α-estradiol (17α-E2) administration elicits beneficial effects on metabolism and inflammation in old male mice. These observations were associated with reduced calorie intake. Here, we demonstrate that 17α-E2 acts through pro-opiomelanocortin (Pomc) expression in the arcuate nucleus (ARC) to reduce food intake and body mass in mouse models of obesity. These results confirm that 17α-E2 modulates appetite through selective interactions within hypothalamic anorexigenic pathways. Interestingly, some peripheral markers of metabolic homeostasis were also improved in animals with near complete loss of ARC Pomc transcription. This suggests that 17α-E2 might have central and peripheral actions that can beneficially affect metabolism cooperatively or independently. Fil: Steyn, Frederik J.. University of Queensland Centre for Clinical Research; Australia. Royal Brisbane & Women’s Hospital; Australia. Wesley Medical Research; Australia Fil: Ngo, Shyuan T.. University of Queensland Centre for Clinical Research; Australia. Royal Brisbane & Women’s Hospital; Australia. Wesley Medical Research; Australia. University of Queensland; Australia Fil: Chen, Vicky Ping. Mayo Clinic; Estados Unidos Fil: Bailey Downs, Lora C.. University of Oklahoma Health Sciences Center; Estados Unidos Fil: Xie, Teresa Y.. University of Queensland; Australia Fil: Ghadami, Martin. University of Queensland; Australia Fil: Brimijoin, Stephen. Mayo Clinic; Estados Unidos Fil: Freeman, Willard M.. University of Oklahoma Health Sciences Center; Estados Unidos Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. University of Michigan Medical School; Estados Unidos Fil: Low, Malcolm J.. University of Michigan Medical School; Estados Unidos Fil: Stout, Michael B.. University of Oklahoma. Health Sciences Center; Estados Unidos

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.

Background: Hypermetabolism, defined as an increase in measured resting energy expenditure (mREE) relative to predicted REE (pREE), is recognised as an important feature of amyotrophic lateral sclerosis (ALS). Previous predictions of REE in ALS have not accounted for differences in fat free mass (FFM). This study aimed to investigate the effect of accounting for FFM on pREE in ALS patients and a matched control population. Methodology and findings: Body composition and pREE data were obtained from 50 ALS and 50 age- and sex-matched healthy control participants. We contrast conventional models for predicting REE that rely on anthropometric measures, age, and sex, with models that predict REE relative to FFM. Given that a significantly lower FFM was observed in ALS, models that consider FFM predicted significantly lower REE in ALS participants when compared to controls. Using Bland-Altman analysis, we demonstrate a prediction bias between models that do not account for FFM between the ALS and control populations. We also demonstrate greater agreement in predictions between control and ALS populations when correcting for FFM. Conclusions/significance: Future studies should correct for reductions in FFM when predicting REE in ALS.

Autoimmune diseases are a range of diseases in which the immune response to self-antigens results in damage or dysfunction of tissues. Autoimmune diseases can be systemic or can affect specific organs or body systems. For most autoimmune diseases there is a clear sex difference in prevalence, whereby females are generally more frequently affected than males. In this review, we consider gender differences in systemic and organ-specific autoimmune diseases, and we summarize human data that outlines the prevalence of common autoimmune diseases specific to adult males and females in countries commonly surveyed. We discuss possible mechanisms for sex specific differences including gender differences in immune response and organ vulnerability, reproductive capacity including pregnancy, sex hormones, genetic predisposition, parental inheritance, and epigenetics. Evidence demonstrates that gender has a significant influence on the development of autoimmune disease. Thus, considerations of gender should be at the forefront of all studies that attempt to define mechanisms that underpin autoimmune disease.

Amyotrophic lateral sclerosis (ALS) is an adult onset, neurodegenerative disease that is characterized by the loss of upper (corticospinal) and lower motor neurons. ALS is a multifactorial disease whereby a combination of genetic and environmental factors may contribute to disease pathogenesis. While the majority of studies indicate that the underlying causes for ALS pathology may be due to multiple defects at the cellular level, factors that have recently been identified to be associated with survival could lead to the development of beneficial interventions. In ALS, a higher pre-morbid body mass index (BMI) and the maintenance of BMI and nutritional state is associated with improved outcome. This review will focus on the associations between body composition and adiposity relative to disease duration and risk, and will discuss current evidence that supports the benefits of improving energy balance, and the maintenance of body mass through nutritional intervention in ALS.

GH deficiency is thought to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, therapy with GH and/or IGF-I has not shown benefit. To gain a better understanding of the role of GH secretion in ALS pathogenesis, we assessed endogenous GH secretion in wild-type and hSOD1G93A mice throughout the course of ALS disease. Male wild-type and hSOD1G93A mice were studied at the presymptomatic, onset, and end stages of disease. To assess the pathological features of disease, we measured motor neuron number and neuromuscular innervation. We report that GH secretion profile varies at different stages of disease progression in hSOD1G93A mice; compared with age-matched controls, GH secretion is unchanged prior to the onset of disease symptoms, elevated at the onset of disease symptoms, and reduced at the end stage of disease. In hSOD1G93A mice at the onset of disease, GH secretion is positively correlated with the percentage of neuromuscular innervation but not with motor neuron number. Moreover, this occurs in parallel with an elevation in the expression of muscle IGF-I relative to controls. Our data imply that increased GH secretion at symptom onset may be an endogenous endocrine response to increase the local production of muscle IGF-I to stimulate reinnervation of muscle, but that in the latter stages of disease this response no longer occurs.

Pathological changes associated with obesity are thought to contribute to GH deficiency. However, recent observations suggest that impaired GH secretion relative to excess calorie consumption contributes to progressive weight gain and thus may contribute to the development of obesity. To clarify this association between adiposity and GH secretion, we investigated the relationship between pulsatile GH secretion and body weight; epididymal fat mass; and circulating levels of leptin, insulin, non-esterified free fatty acids (NEFAs), and glucose. Data were obtained from male mice maintained on a standard or high-fat diet. We confirm the suppression of pulsatile GH secretion following dietary-induced weight gain. Correlation analyses reveal an inverse relationship between measures of pulsatile GH secretion, body weight, and epididymal fat mass. Moreover, we demonstrate an inverse relationship between measures of pulsatile GH secretion and circulating levels of leptin and insulin. The secretion of GH did not change relative to circulating levels of NEFAs or glucose. We conclude that impaired pulsatile GH secretion in the mouse occurs alongside progressive weight gain and thus precedes the development of obesity. Moreover, data illustrate key interactions between GH secretion and circulating levels of insulin and reflect the potential physiological role of GH in modulation of insulin-induced lipogenesis throughout positive energy balance.

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-43Q331K 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.

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.