Article

Patients with elevated triglyceride and cholesterol serum levels have a prolonged survival in Amyotrophic Lateral Sclerosis

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Abstract

Weight loss is a common phenomenon and an independent prognostic factor in amyotrophic lateral sclerosis (ALS). Several potential causal mechanisms, including intrinsic hypermetabolism and deficient food intake, have been discussed. We investigated the influence of fasting serum glucose, cholesterol, and triglyceride levels at time of diagnosis on survival in ALS. Serum cholesterol (LDL, HDL, and LDL/HDL ratio), triglycerides, and glucose were investigated in 488 patients (age of onset = 57.6 ± 12.6 years) in relation to survival and revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALS-FRS) data. High serum levels of both fasting cholesterol and triglycerides had a significantly positive effect on survival (p < 0.05). We found a median prolonged life expectancy by 14 months for patients with serum triglyceride levels above the median of 1.47 mmol/l. The results suggest that the lipid metabolism and the nutritional status of ALS patients are important prognostic factors. These parameters should be thoroughly monitored during the clinical management of these patients. In case of progressive loss of body weight, a diet rich in lipids and calories should be considered. However, the final decision whether a lipid-rich diet should be recommended to ALS patients can only be based on a double-blind placebo-controlled interventional trial. Our results further imply that lipid-lowering drugs, e.g., statins, should be applied carefully in ALS patients although individual risk considerations must be made.

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... Cholesterol is attracting significant attention as a predictive factor for prognosis and a pathomechanistic mediator in ALS. There are reports indicating that high triglycerides (TG) [10][11][12] and high low-density lipoprotein cholesterol (LDL) [13][14][15] are favorable prognostic markers based on univariate analyses, while others argue against this relationship 11,12 . The relevance of high-density lipoprotein cholesterol (HDL) is also controversial. ...
... Furthermore, the combination of the BMM index and presence of either high HDL in both sexes or low LDL in female patients (namely LLRA) improved the prognostic predictive value (Fig. 5). Several studies have argued against the correlation between HDL and survival in ALS [10][11][12]16,17,29 . One possible explanation for the discrepancy between these reports and ours is the timing of blood sampling after the clinical onset. ...
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The prognostic predictive value of lipid profiling in amyotrophic lateral sclerosis (ALS) remains unclear. Here, we aimed to clarify the value of the levels of serum lipids, including high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG), for predicting the prognosis in ALS. This was a single-center retrospective study of 78 patients with ALS. The serum lipid profiles at the first hospital visit after symptom onset were analyzed to determine the correlations of lipids with survival and physical parameters, including nutritional, respiratory, and metabolic conditions. The cutoff level for high HDL was defined as the third quartile, while that of low LDL and TG, as the first quartile. Hypermetabolism was defined as the ratio of resting energy expenditure to lean soft tissue mass ≥ 38 kcal/kg. High HDL was an independent factor for poor prognosis in all patients (hazards ratio [HR]: 9.87, p < 0.001) in the Cox proportional hazard model, including %vital capacity and the monthly decline rate in body mass index and the Revised Amyotrophic Lateral Functional Rating Scale score from symptom onset to diagnosis. Low LDL was a factor for poor prognosis (HR: 6.59, p = 0.017) only in women. Moreover, subgroup analyses with log-rank tests revealed that the prognostic predictive value of high HDL was evident only in the presence of hypermetabolism (p = 0.005). High HDL predicts poor prognosis in all patients, whereas low LDL, only in women. Hypermetabolism and high HDL synergistically augment the negative effect on prognosis.
... Moreover, the relationships between the lipids and survival of ALS have not been explored clearly. Some studies reported that hyperlipidemia was an independent predictor of survival of ALS (4,9). ...
... Ahmed et al. reported that a higher TC level was correlated with 3.25 times improved survival in ALS-FTD patients (7). Some studies hold the idea that hyperlipidemia is a significant prognostic factor for the survival of patients with ALS (4,9), but other studies demonstrated that the prognosis of ALS was not influenced by the lipid profile (5,17,21,28,29), and these findings were in accordance with our current study. However, our results should be interpreted with care because only four studies from Europe up to our standard were included in the final analysis, and many confounding factors, including areas and ethnic variations, the use of lipid-lowering drugs, and the period of delay diagnosis, among others, should not be neglected. ...
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Background: Studies have investigated the lipid profile in amyotrophic lateral sclerosis (ALS), including the levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), and higher low-density lipoprotein (LDL), and the associations with mortality of ALS, but the results were inconsistent. Therefore, we conducted this meta-analysis to systematically answer this unsolved question. Methods: We searched all the related studies that probed into the association between serum lipid levels and ALS based on PubMed, EMBASE, and Cochrane library from January 1990 to July 2020. The quality of the included studies was evaluated by using the Newcastle-Ottawa Scale (NOS). All the statistical analyses of this meta-analysis were performed using the Stata version 12.0 software. Results: Fourteen studies with a total of 3,291 ALS patients and 3,367 controls were included. Among them, 10 studies compared the lipid profile between ALS patients and controls. The results indicated that compared with controls, ALS patients from both Europe and Asia had lower levels of TG and HDL, but the levels of TC and LDL were higher in ALS patients from Europe. However, after systemic analyses, the altered TC level was significant only in Asian ALS patients; the differences of other lipids were not significant. Concerning the effect of lipid profile on mortality of ALS, analyses of four cohort studies showed that the levels of all lipids were not associated with overall mortality in ALS. Conclusion: The results of the present study showed that Asian ALS patients had lower TC levels than controls, and the levels of all lipids were not associated with mortality of ALS.
... As discussed above, the elevations of TGs may be protective in ALS. 66 Again, these results agree with previous reports showing faster rates of functional decline and lower survival rates in ALS with hypermetabolism, 67 suggesting that decreased concentrations of specific TGs could be markers of hypermetabolism in humans. The relationship of hypermetabolism with faster progressions has been confirmed in ALS experimental models, such as SOD1G93A transgenic mice, where glycolysis, b-oxidation, and mitochondrial metabolism are altered in the spinal cord before disease onset. ...
Article
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Since amyotrophic lateral sclerosis cases exhibit significant heterogeneity, we aim to investigate the association of lipid composition of plasma and cerebrospinal fluid with amyotrophic lateral sclerosis diagnosis, its progression, and clinical characteristics. Lipidome analyses would help to stratify patients on a molecular basis. For this reason, we have analyzed the lipid composition of paired plasma and cerebrospinal fluid samples from amyotrophic lateral sclerosis cases and age-matched non-amyotrophic lateral sclerosis individuals (controls) by comprehensive liquid chromatography coupled to mass spectrometry. The concentrations of neurofilament light chain –an index of neuronal damage- were also quantified in cerebrospinal fluid samples and plasma. Amyotrophic lateral sclerosis vs. control comparison in a moderate stringency mode showed that plasma from cases contains more differential lipids (n = 122 for raw p < 0.05;n=27 for p < 0.01) than cerebrospinal fluid (n = 17 for raw p < 0.05; n = 4 for p < 0.01), with almost no overlapping differential species, mainly characterized by an increased content of triacylglyceride species in plasma and decreased in cerebrospinal fluid. Of note, false discovery rate correction indicated that one of the cerebrospinal fluid lipids (monoacylglycerol 18:0) had high statistic robustness (false discovery rate-p<0.01). Plasma lipidomes also varied significantly with the main involvement at onset (bulbar, spinal, or respiratory). Notably, faster progression cases showed particular lipidome fingerprints featured by decreased triacylclycerides and specific phospholipids in plasma., with 11 lipids with false discovery rate-p<0.1 (n = 56 lipids in plasma for raw p < 0.01). Lipid species associated with progression rate clustered in a relatively low number of metabolic pathways, mainly triacylglyceride metabolism and glycerophospholipid and sphingolipid biosynthesis. A specific triacylglyceride (68:12) correlated with neurofilament content (r = 0.8, p < 0.008). Thus, the present findings suggest that systemic hypermetabolism –potentially sustained by increased triacylglyceride content- and central nervous system alterations of specific lipid pathways could be associated as modifiers of disease progression. Further, these results confirm biochemical lipid heterogeneity in amyotrophic lateral sclerosis with different presentations and progression, suggesting the use of specific lipid species as potential disease classifiers.
... Accordingly, this has urged clinical trials aiming to restore the energy balance with diets rich in fats [12,13], relatively successful, although more extensive studies and larger cohorts are needed to draw more definitive conclusions. Lipid alterations have been observed in blood and cerebrospinal fluid (CSF) of ALS patients and in a symptomatic mouse model of ALS overexpressing mutant human Cu/Zn-superoxide dismutase gene (SOD1 G93A ) [14], correlating with disease prognosis [15]. The neuronal tissues also show alterations in lipid metabolism, especially in the spinal cord tissues of SOD1 G93A rats [16] and mice, as well as in post mortem spinal cord tissue of ALS patients [17]. ...
Article
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Amyotrophic lateral sclerosis (ALS) is a multifactorial and complex fatal degenerative disorder. A number of pathological mechanisms that lead to motor neuron death have been identified, although there are many unknowns in the disease aetiology of ALS. Alterations in lipid metabolism are well documented in the progression of ALS, both at the systemic level and in the spinal cord of mouse models and ALS patients. The origin of these lipid alterations remains unclear. This study aims to identify early lipid metabolic pathways altered before systemic metabolic symptoms in the spinal cord of mouse models of ALS. To do this, we performed a transcriptomic analysis of the spinal cord of SOD1G93A mice at an early disease stage, followed by a robust transcriptomic meta-analysis using publicly available RNA-seq data from the spinal cord of SOD1 mice at early and late symptomatic disease stages. The meta-analyses identified few lipid metabolic pathways dysregulated early that were exacerbated at symptomatic stages; mainly cholesterol biosynthesis, ceramide catabolism, and eicosanoid synthesis pathways. We present an insight into the pathological mechanisms in ALS, confirming that lipid metabolic alterations are transcriptionally dysregulated and are central to ALS aetiology, opening new options for the treatment of these devastating conditions.
... Our results, showing a favourable vascular profile in a subpopulation of male ALS patients, i.e., a reduced prevalence of hypertension in men, also noted by Armon et al., [37], and a possible positive association between hypertension and bulbar-onset ALS in women, suggests that combining different ALS phenotypes when analysing risk factors in ALS should be avoided. A favourable lipid profile has been described in ALS, probably related to lower premorbid weight [23], but hyperlipidemia has been associated with a longer survival [54]. However, studies on lipid levels in ALS [55] and of diabetes, hypertension and cardiovascular events are inconsistent in ALS. ...
Article
Background The role of cardiovascular risk factors in amyotrophic lateral sclerosis (ALS) is controversial. A favourable profile has been found in ALS patients, but previous studies have not specifically considered the profile in different disease phenotypes. Methods Demographic data, smoking habits, lifetime exercise, and medical history including diabetes mellitus, arterial hypertension, hypercholesterolemia, hypertriglyceridemia, stroke, and cardiac events, were analysed in ALS patients and in controls with other neurological disorders, utilising a standardized questionnaire applied by the same neurologist. In ALS patients the results were analysed according to their different phenotypes. Univariate analyses and multinomial logistic models were applied to estimate the odds ratios (ORs) and confidence intervals (CIs) for covariates, to test potential modifiers and their effects. Results 500 consecutively assessed adult ALS patients (mean age 65.6, 47% women, and 136 bulbar-onset) and 327 age and gender-matched controls were studied. Patients with spinal-onset ALS took more exercise (p = 0.012), reported less hypertension (p = 0.002) and had fewer cardiac events (p = 0.012). Multinomial regression analysis showed that men without hypertension have a higher risk of having spinal-onset ALS (p < 0.001) while female with hypertension have a higher risk of having bulbar-onset ALS (p = 0.033). Conclusions Risk-factors in ALS can be influenced by gender and phenotype. This study suggests that men with spinal ALS are healthier, exercise more and have lower rate of hypertension, but females with bulbar-onset ALS are more prone to hypertension. The complex interplay between exercise, diet and comorbidities with ALS phenotype requires further investigation.
... Serum levels of various lipids were suggested to be potentially informative of disease progression of ALS, albeit with contrasting results [239][240][241]. This could be due to the different population groups included in each study and heterogeneity among patients. ...
Article
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Building evidence reveals the importance of maintaining lipid homeostasis for the health and function of neurons, and upper motor neurons (UMNs) are no exception. UMNs are critically important for the initiation and modulation of voluntary movement as they are responsible for conveying cerebral cortex’ input to spinal cord targets. To maintain their unique cytoarchitecture with a prominent apical dendrite and a very long axon, UMNs require a stable cell membrane, a lipid bilayer. Lipids can act as building blocks for many biomolecules, and they also contribute to the production of energy. Therefore, UMNs require sustained control over the production, utilization and homeostasis of lipids. Perturbations of lipid homeostasis lead to UMN vulnerability and progressive degeneration in diseases such as hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS). Here, we discuss the importance of lipids, especially for UMNs.
... There is an ongoing debate as to the prevalence and causes of hyperlipidaemia in ALS, and whether or not hyperlipidaemia has a role in promoting or protecting against neurodegeneration [225]. These divergent views are reflected in studies showing a survival benefit of up to 14 months in those with hyperlipidaemia [224,226], whilst others report no such benefit [227]. Higher rates of impaired glucose tolerance and insulin resistance are also reported, possibly resulting from reduced ability to store glucose due to reduced muscle mass [228]. ...
Article
Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease typically presenting with bulbar or limb weakness. There is increasing evidence that amyotrophic lateral sclerosis is a multisystem disease with early and frequent impacts on cognition, behaviour, sleep, pain and fatigue. Dysfunction of normal physiological and metabolic processes also appears common. Evidence from pre-symptomatic studies and large epidemiological cohorts examining risk factors for the future development of amyotrophic lateral sclerosis have reported a high prevalence of changes in behaviour and mental health before the emergence of motor weakness. This suggests that changes beyond the motor system are underway at an early stage with dysfunction across brain networks regulating a variety of cognitive, behavioural and other homeostatic processes. The full impact of non-motor dysfunction continues to be established but there is now sufficient evidence that the presence of non-motor symptoms impacts overall survival in amyotrophic lateral sclerosis, and with up to 80% reporting non-motor symptoms, there is an urgent need to develop more robust therapeutic approaches. This review provides a contemporary overview of the pathobiology of non-motor dysfunction, offering readers a practical approach with regard to assessment and management. We review the current evidence for pharmacological and non-pharmacological treatment of non-motor dysfunction in amyotrophic lateral sclerosis and highlight the need to further integrate non-motor dysfunction as an important outcome measure for future clinical trial design.
... If so, understanding this may allow for better personalised prognostic estimates, a more holistic approach to care, and refinement of pragmatic analyses of real-world disease cohorts and inclusive clinical trials. Previous studies investigating the impact of specific comorbidities on MND survival have yielded conflicting results, ranging from negative [1,3] to neutral [2,7,8] and beneficial effects [9,10]. Discordant results may have arisen due to differences between study populations, classification of comorbidities, or complexity in the impact of different patterns of individual comorbidities and multimorbidity. ...
Article
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Objectives To determine the prevalence of multimorbidity in people with motor neuron disease (MND) and to identify whether specific patterns of multimorbidity impact survival beyond age alone. Methods We performed a retrospective analysis of the Scottish national MND register 01/01/2015-29/10/2019. People with amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy or progressive bulbar palsy were included. We fitted latent class regression models incorporating comorbidities (class indicators), age, sex and bulbar onset (covariates), and survival (distal outcome) with multimorbidity as a hypothesised latent variable. We also investigated the association between the Charlson Comorbidity Index and survival in Cox regression and compared its discrimination and calibration to age alone. Results 937 people with MND were identified (median age 67, 60.2% male); 64.8% (515) had two or more comorbidities. We identified a subpopulation with high prevalence of cardiovascular disease but, when accounting for the relationship between age and individual comorbidities, there was no difference in survival. Both Charlson Comorbidity Index (hazard ratio [HR] per unit increase 1.11 95%CI 1.07, 1.15; P<0.0001) and age (HR per year increase 1.04 95% CI 1.03, 1.05; P < 0.0001) were significantly associated with survival but discrimination was higher for age compared to Charlson Comorbidity Index (C-index 0.63 vs 0.59). Conclusions Multimorbidity is common in MND necessitating holistic inter-disciplinary management but age is the dominant predictor of prognosis in people with MND. Excluding people with MND and multimorbidity from trial participation may do little to homogenise the cohort in terms of survival potential and could harm generalisability.
... Epidemiological surveys have revealed that ALS patients display increased catabolism [2,3] and that a lower body-mass index (BMI) constitutes a risk factor for ALS [4]. Furthermore, reduced levels of metabolic rate proxies such as plasma lipids and body fat content are predictors of survival in ALS patients [5][6][7], that is, weight loss is strongly correlated with shorter survival [8]. The increased catabolism may be a result of intrinsic hypermetabolism, as demonstrated in both ALS patients (in about 50-60% of cases [9][10][11][12][13]) and mutant SOD1 ALS mice [14][15][16]. ...
Article
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Background Increased catabolism has recently been recognized as a clinical manifestation of amyotrophic lateral sclerosis (ALS). The hypothalamic systems have been shown to be involved in the metabolic dysfunction in ALS, but the exact extent of hypothalamic circuit alterations in ALS is yet to be determined. Here we explored the integrity of large-scale cortico-hypothalamic circuits involved in energy homeostasis in murine models and in ALS patients. Methods The rAAV2-based large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik software suites were used to identify and quantify projections from the forebrain to the lateral hypothalamus in the SOD1(G93A) ALS mouse model (hypermetabolic) and the Fus ΔNLS ALS mouse model (normo-metabolic). 3 T diffusion tensor imaging (DTI)-magnetic resonance imaging (MRI) was performed on 83 ALS and 65 control cases to investigate cortical projections to the lateral hypothalamus (LHA) in ALS. Results Symptomatic SOD1(G93A) mice displayed an expansion of projections from agranular insula, ventrolateral orbitofrontal and secondary motor cortex to the LHA. These findings were reproduced in an independent cohort by using a different analytic approach. In contrast, in the Fus ΔNLS ALS mouse model hypothalamic inputs from insula and orbitofrontal cortex were maintained while the projections from motor cortex were lost. The DTI-MRI data confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients. Conclusion This study provides converging murine and human data demonstrating the selective structural disruption of hypothalamic inputs in ALS as a promising factor contributing to the origin of the hypermetabolic phenotype.
... The fasciculation potential (FP) has been included in Awaji criteria as a hallmark of ALS muscular albumin, creatinine levels, and lymphocyte count as markers for ALS, indicating muscle waste and inflammation respectively . Other markers potentially related to a better ALS outcome have been proposed: LDL/HDL levels, which are elevated in ALS plasma and represent a general unexplained hypermetabolism (Dorst et al., 2011;L. Dupuis et al., 2008); serum uric acid levels, which are decreased among ALS patients, further demonstrating the possible role of oxidative stress in the induction and propagation of the disease (Keizman et al., 2009); serum ferritin levels which are elevated in ALS patients and could reflect perturbation in iron metabolism (Qureshi, Brown, Rogers, & Cudkowicz, 2008); concentrations of certain amino acids, which are decreased in ALS (Ilżecka, Stelmasiak, Solski, Wawrzycki, & Szpetnar, 2003); levels of serum proinflammatory cytokines, such as IL-6, which are increased in ALS (Ono, Hu, Shimizu, Imai, & Nakagawa, 2001). ...
Thesis
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder caused by progressive degeneration of upper and lower motor neurons (MNs), with a very rapid clinical course. It leads to muscle weakness and atrophy progressing to paralysis, with respiratory failure being the major cause of death within years following clinical diagnosis. Two major genes mutated in ALS patients are the RNA-binding protein FUS (FUSed in sarcoma), implicated in RNA metabolism, and coiled-coil-helix-coiled-coil-helix domain 10 (CHCHD10), which plays a role in mitochondria stability. Both these genes have been investigated through different model systems, from small invertebrate models to patient biopsies. However, the major phenotypic features obtained in these models are complex and often controversial. The objective of this work is to provide new insights on the implication of these genes in ALS through the use of new models.To investigate the pathogenic mechanisms induced by FUS and CHCHD10, we generated and characterized two novel stable non-sense mutant zebrafish models for the orthologues of these genes and highlighted several ALS phenotypic features. We demonstrated, for the FUS model but not for CHCHD10, reduced lifespan, locomotor disabilities, aberrant motor axons, disorganized neuromuscular junction (NMJ), muscle and mitochondrial alteration, as well as molecular changes. These findings indicate that loss of fus expression is responsible for the occurrence of distal pathological signs at the NMJ, thus supporting a “dying-back” neuronopathy, in which early disease hallmarks start at the level of the NMJ and progress towards MN cell bodies.
... Whether hypolipidemia is also a preclinical feature in human ALS patients is difficult to assess, since diagnostic certainty is only reached in a progressed stage of the disease [84]. Elevated serum cholesterol and apolipoprotein E levels were shown to prolong survival and delay disease progression in ALS patients in most studies [92,155,156], while statin treatment was associated with worsened outcomes [157]. Interestingly, recent studies have shown that statins can modulate autophagy [158,159] where it was reported that the cytotoxic effect of simvastatin in NSC34 cells expressing mutant SOD1 G93A was mediated by the accumulation of autophagic vacuoles with elevated levels of LC3 II/I and P62, leading to impaired autophagic flux [160]. ...
Article
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Amyotrophic lateral sclerosis (ALS) patients show a myriad of energetic abnormalities, such as weight loss, hypermetabolism, and dyslipidaemia. Evidence suggests that these indices correlate with and ultimately affect the duration of survival. This review aims to discuss ALS metabolic abnormalities in the context of autophagy, the primordial system acting at the cellular level for energy production during nutrient deficiency. As the primary pathway of protein degradation in eukaryotic cells, the fundamental role of cellular autophagy is the adaptation to metabolic demands. Therefore, autophagy is tightly coupled to cellular metabolism. We review evidence that the delicate balance between autophagy and metabolism is aberrant in ALS, giving rise to intracellular and systemic pathophysiology observations. Understanding the metabolism autophagy crosstalk can lead to the identification of novel therapeutic targets for ALS.
... These metabolic changes, which confer a high risk for cardiovascular disorders, seem to be protective in ALS cases. For instance , hyperlipidemia, diabetes and higher BMI spell out seem to delay ALS onset in human patients 28,51 and in animal models 52 . Our data shows that, although ALS and PLS patients, show increases in TGs containing C16 and C18, these are only significant and discriminant in PLS plasma (TG 50:3/16:1, TG 52:3/18:1, TG 52:4/18:1). ...
Article
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Motor neuron disorders (MND) include a group of pathologies that affect upper and/or lower motor neurons. Among them, amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle weakness, with fatal outcomes only in a few years after diagnosis. On the other hand, primary lateral sclerosis (PLS), a more benign form of MND that only affects upper motor neurons, results in life-long progressive motor dysfunction. Although the outcomes are quite different, ALS and PLS present with similar symptoms at disease onset, to the degree that both disorders could be considered part of a continuum. These similarities and the lack of reliable biomarkers often result in delays in accurate diagnosis and/or treatment. In the nervous system, lipids exert a wide variety of functions, including roles in cell structure, synaptic transmission, and multiple metabolic processes. Thus, the study of the absolute and relative concentrations of a subset of lipids in human pathology can shed light into these cellular processes and unravel alterations in one or more pathways. In here, we report the lipid composition of longitudinal plasma samples from ALS and PLS patients initially, and after 2 years following enrollment in a clinical study. Our analysis revealed common aspects of these pathologies suggesting that, from the lipidomics point of view, PLS and ALS behave as part of a continuum of motor neuron disorders.
... Concerning survival, patients with ALS who had high LDL/HDL ratios lived longer than those with a low LDL/HDL ratio [48]. Several other studies reported that ALS patients with dyslipidemia or higher cholesterol levels were more likely to have a longer survival rate than those with no lipid abnormalities [48,50,[56][57][58][59]76,77]. However, others found no association between plasma lipid levels and ALS survival [51,54,78], although a decrease in LDL/HDL ratio has been reported to be associated with a high rate of respiratory impairment [49]. ...
Article
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Amyotrophic Lateral Sclerosis (ALS) is a devastating progressive neurodegenerative disease that affects motor neurons, leading to a relentless paralysis of skeletal muscles and eventual respiratory failure. Although a small percentage of patients may have a longer survival time (up to 10 years), in most cases, the median survival time is from 20 to 48 months. The pathogenesis and risk factors for ALS are still unclear: among the various aspects taken into consideration, metabolic abnormalities and nutritional factors have been the focus of recent interests. Although there are no consistent findings regarding prior type-2 diabetes, hypercholesterolemia and ALS incidence, abnormalities in lipid and glucose metabolism may be linked to disease progression, leading to a relatively longer survival (probably as a result of counteract malnutrition and cachexia in the advanced stages of the disease). Among potential dietary risk factors, a higher risk of ALS has been associated with an increased intake of glutamate, while the consumption of antioxidant and anti-inflammatory compounds, such as vitamin E, n-3 polyunsaturated fatty acids, and carotenoids, has been related to lower incidence. Poor nutritional status and weight loss in ALS resulting from poor oral intake, progressive muscle atrophy, and the potential hypermetabolic state have been associated with rapid disease progression. It seems important to routinely perform a nutritional assessment of ALS patients at the earliest referral: weight maintenance (if adequate) or gain (if underweight) is suggested from the scientific literature; evidence of improved diet quality (in terms of nutrients and limits for pro-inflammatory dietary factors) and glucose and lipid control is yet to be confirmed, but it is advised. Further research is warranted to better understand the role of nutrition and the underlying metabolic abnormalities in ALS, and their contribution to the pathogenic mechanisms leading to ALS initiation and progression.
... Studies have shown that ALS patients have a higher probability of dyslipidemia compared with the general population. Two studies from the United Kingdom and Germany found that the prevalence of hypercholesterolemia and hypertriglyceridemia in ALS patients was signi cantly increased [18][19] . Some researchers believe that hyperlipidemia is a protective factor for ALS. ...
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Objective The present study was to investigate the significance of creatinine, uric acid, creatine kinase, total cholesterol, triglyceride, HCY (Homocysteine), and cystatin C in neurological function and progression rate of amyotrophic lateral sclerosis. Methods According to the diagnostic criteria of EI-Escorial (2000), 103 patients with ALS were enrolled. All patients were given corresponding serological tests at the initial diagnosis. The Revised ALS Functional Rating Scale (ALSFRS-R) and Disease Progression Rate (DPR) were evaluated. The detected indexes in blood tests included creatinine, uric acid, creatine kinase, total cholesterol, triglycerides, homocysteine, and cystatin C. All data were input into the computer, and the data analysis was performed by SPSS22.0 statistical software. Results 1. There were significant differences in creatinine, uric acid, creatine kinase, total cholesterol, HCY and cystatin C between the two groups ( P <0.05). The levels of uric acid and creatinine of ALS group were lower than those of the control group, and the levels of creatine kinase, total cholesterol, triglyceride, HCY and cystatin C were higher than that in the control group. 2. The results from correlation analysis demonstrated that there was a significant correlation between ALSFRS-R and creatinine ( P <0.01), the correlation coefficient was 0.567 (positive correlation); There was also a significant correlation between DPR and creatinine ( P <0.01), and the correlation coefficient was -0.808 (negative correlation). The correlations of DPR with triglyceride and total cholesterol were significantly negative correlated ( P <0.05), with -0.201 and -0.210 of correlation coefficients, respectively. The remaining indexes did not show any correlation with ALSFRS-R and DPR. Conclusions 1. Uric acid and creatinine of ALS patients were lower than that in healthy people. Creatine kinase, triglyceride, total cholesterol, HCY, and cystatin C in ALS patients were higher than those in health controls. There were significant metabolic abnormalities in ALS patients. 2. Creatinine level is an independent risk factor affecting ALSFRS-R. The creatinine and total cholesterol levels are also the independent risk factors affecting DPR. Creatinine and total cholesterol levels could be used as reliable indicators to evaluate the ALSFRS-R and DPR of ALS patients.
... Second, our cohort had a relatively lean body type, so the results might not be applicable to other populations. Median BMI was 20.3 kg/m 2 in our cohort, which is lower than that of ALS patients in Europe and North America (23.7-27.1 kg/m 2 ) [36,[45][46][47][48][49][50][51] and even low compared with that reported in other Asian populations (21-22 kg/m 2 ) [52,53]. ...
Article
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Background/aims: Nutritional status is a factor affecting prognosis in patients with amyotrophic lateral sclerosis (ALS). Here, we aimed to clarify the factors associated with hypermetabolism and the prognosticators of ALS. Methods: Forty-two inpatients (22 men, 20 women) diagnosed with ALS according to the revised El-Escorial criteria were investigated. The following data were retrospectively analyzed: anthropometric measurements, blood biochemistry, disease severity, basal energy expenditure (BEE), resting energy expenditure (REE) measured by indirect calorimetry, spirometry, and bioelectrical impedance analysis. Single and multiple regression analysis was performed to examine factors affecting REE and metabolic changes (defined as the ratio of REE to fat-free mass [FFM]). The Kaplan-Meier method was used to examine factors associated with the occurrence of cumulative events (death or tracheostomy). Results: Among the 42 inpatients, REE was significantly higher than BEE, indicating hypermetabolism in ALS. Multiple regression analysis revealed that REE/FFM is strongly associated with the skeletal muscle index (-3.746 to -1.532, p < 0.0001) and percent forced vital capacity (%FVC) (-0.172 to -0.021, p = 0.013). Moreover, both the skeletal muscle index and %FVC were significant prognosticators associated with the occurrence of cumulative events. Conclusions: Energy metabolism was elevated in ALS, and respiratory status and muscle mass were associated with the hypermetabolism and poor prognosis. Adequate nutritional support may improve outcomes in ALS by preventing deterioration of respiratory status and reduction in muscle mass.
... Furthermore, cholesterol ester (CE) accumulation is observed in whole spinal cord tissue homogenates of sporadic ALS patients and in rodent models of ALS (Cutler et al., 2002;Chaves-Filho et al., 2019), and total cholesterol levels are elevated in the CSF of ALS patients (Abdel-Khalik et al., 2017). And last, dyslipidemia and altered apolipoprotein metabolism in blood are risk factors for ALS, and are also prognostic indicators of disease progression in ALS patients (Dupuis et al., 2008;Dorst et al., 2011;Mariosa et al., 2017;Chen et al., 2018). Although it is evident that lipid cacostasis manifests during ALS, it is still unclear whether it occurs in the region of the spinal cord where MNs degenerate, specifically the ventral gray matter (GM), and if so, what causes it. ...
Article
Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease characterized by motor neuron (MN) death. Lipid dysregulation manifests during disease; however, it is unclear whether lipid homeostasis is adversely affected in the in the spinal cord gray matter (GM), and if so, whether it is because of an aberrant increase in lipid synthesis. Moreover, it is unknown whether lipid dysregulation contributes to MN death. Here, we show that cholesterol ester (CE) and triacylglycerol levels are elevated several-fold in the spinal cord GM of male sporadic ALS patients. Interestingly, HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, was reduced in the spinal cord GM of ALS patients. Increased cytosolic phospholipase A2 activity and lyso-phosphatidylcholine (Lyso-PC) levels in ALS patients suggest that CE accumulation was driven by acyl group transfer from PC to cholesterol. Notably, Lyso-PC, a byproduct of CE synthesis, was toxic to human MNs in vitro Elevations in CE, triacylglycerol, and Lyso-PC were also found in the spinal cord of SOD1G93A mice, a model of ALS. Similar to ALS patients, a compensatory downregulation of cholesterol synthesis occurred in the spinal cord of SOD1G93A mice; levels of sterol regulatory element binding protein 2, a transcriptional regulator of cholesterol synthesis, progressively declined. Remarkably, overexpressing sterol regulatory element binding protein 2 in the spinal cord of normal mice to model CE accumulation led to ALS-like lipid pathology, MN death, astrogliosis, paralysis, and reduced survival. Thus, spinal cord lipid dysregulation in ALS likely contributes to neurodegeneration and developing therapies to restore lipid homeostasis may lead to a treatment for ALS.SIGNIFICANCE STATEMENT Neurons that control muscular function progressively degenerate in patients with amyotrophic lateral sclerosis (ALS). Lipid dysregulation is a feature of ALS; however, it is unclear whether disrupted lipid homeostasis (i.e., lipid cacostasis) occurs proximal to degenerating neurons in the spinal cord, what causes it, and whether it contributes to neurodegeneration. Here we show that lipid cacostasis occurs in the spinal cord gray matter of ALS patients. Lipid accumulation was not associated with an aberrant increase in synthesis or reduced hydrolysis, as enzymatic and transcriptional regulators of lipid synthesis were downregulated during disease. Last, we demonstrated that genetic induction of lipid cacostasis in the CNS of normal mice was associated with ALS-like lipid pathology, astrogliosis, neurodegeneration, and clinical features of ALS.
... Unlike the association of higher LDL and apoB and lower HDL and apoA1 with a higher risk of ALS in the presymptomatic literature, higher levels of total and LDL cholesterol as well as triglycerides (and in some cases lower HDL) are associated with less rapid disability progression and better respiratory function and survival. [36][37][38][39] Whether this is a protective effect of lipids or a proxy for other factors portending poor prognosis such as lower BMI is not resolved. 6 However, this highlights the need to distinguish the symptomatic and presymptomatic phases of ALS as much as possible. ...
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Background Premorbid body mass index, physical activity, diabetes and cardiovascular disease have been associated with an altered risk of developing amyotrophic lateral sclerosis (ALS). There is evidence of shared genetic risk between ALS and lipid metabolism. A very large prospective longitudinal population cohort permits the study of a range of metabolic parameters and the risk of subsequent diagnosis of ALS. Methods The risk of subsequent ALS diagnosis in those enrolled prospectively to the UK Biobank (n=502 409) was examined in relation to baseline levels of blood high and low density lipoprotein (HDL, LDL), total cholesterol, total cholesterol:HDL ratio, apolipoproteins A1 and B (apoA1, apoB), triglycerides, glycated haemoglobin A1c (HbA1c) and creatinine, plus self-reported exercise and body mass index. Results Controlling for age and sex, higher HDL (HR 0.84, 95% CI 0.73 to 0.96, p=0.010) and apoA1 (HR 0.83, 95% CI 0.72 to 0.94, p=0.005) were associated with a reduced risk of ALS. Higher total cholesterol:HDL was associated with an increased risk of ALS (HR 1.17, 95% CI 1.05 to 1.31, p=0.006). In models incorporating multiple metabolic markers, higher LDL or apoB was associated with an increased risk of ALS, in addition to a lower risk with higher HDL or apoA. Coronary artery disease, cerebrovascular disease and increasing age were also associated with an increased risk of ALS. Conclusions The association of HDL, apoA1 and LDL levels with risk of ALS contributes to an increasing body of evidence that the premorbid metabolic landscape may play a role in pathogenesis. Understanding the molecular basis for these changes will inform presymptomatic biomarker development and therapeutic targeting.
... Several clinical prognostic factors have been identified for ALS, including age, site of onset, functional and respiratory status, cognitive function, noninvasive ventilation, some genetic mutations [26], and clinical phenotypes [27]. In addition, there are some biological markers proposed as related to the ALS outcome, including dyslipidemia [28,29], uric acid [30,31], creatinine, albumin [4], and granulocyte count [32]. However, it is still unclear whether the WM network parameters have predictive value for the ALS baseline progression rate. ...
Article
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Objective There is increasing evidence that amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease impacting large-scale brain networks. However, it is still unclear which structural networks are associated with the disease and whether the network connectomics are associated with disease progression. This study was aimed to characterize the network abnormalities in ALS and to identify the network-based biomarkers that predict the ALS baseline progression rate. Methods Magnetic resonance imaging was performed on 73 patients with sporadic ALS and 100 healthy participants to acquire diffusion-weighted magnetic resonance images and construct white matter (WM) networks using tractography methods. The global and regional network properties were compared between ALS and healthy subjects. The single-subject WM network matrices of patients were used to predict the ALS baseline progression rate using machine learning algorithms. Results Compared with the healthy participants, the patients with ALS showed significantly decreased clustering coefficient C p ( P = 0.0034, t = 2.98), normalized clustering coefficient γ ( P = 0.039, t = 2.08), and small‐worldness σ ( P = 0.038, t = 2.10) at the global network level. The patients also showed decreased regional centralities in motor and non-motor systems including the frontal, temporal and subcortical regions. Using the single-subject structural connection matrix, our classification model could distinguish patients with fast versus slow progression rate with an average accuracy of 85%. Conclusion Disruption of the WM structural networks in ALS is indicated by weaker small-worldness and disturbances in regions outside of the motor systems, extending the classical pathophysiological understanding of ALS as a motor disorder. The individual WM structural network matrices of ALS patients are potential neuroimaging biomarkers for the baseline disease progression in clinical practice.
... Cholesterol, in particular, may play a pivotal role in disease. Dyslipidemia and altered apolipoprotein metabolism in blood are risk factors for ALS and are also prognostic indicators of disease progression in ALS patients [13][14][15][16] . Furthermore, cholesterol esters (CEs) accumulate several fold in the spinal cords of ALS patients 17,18 and in rodent models of ALS 17-19 , and total cholesterol levels are elevated in the CSF of ALS patients 20 . ...
Article
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Aberrant cholesterol homeostasis is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease that is due to motor neuron (MN) death. Cellular toxicity from excess cholesterol is averted when it is enzymatically oxidized to oxysterols and bile acids (BAs) to promote its removal. In contrast, the auto oxidation of excess cholesterol is often detrimental to cellular survival. Although oxidized metabolites of cholesterol are altered in the blood and CSF of ALS patients, it is unknown if increased cholesterol oxidation occurs in the SC during ALS, and if exposure to oxidized cholesterol metabolites affects human MN viability. Here, we show that in the SOD1 G93A mouse model of ALS that several oxysterols, BAs and auto oxidized sterols are increased in the lumbar SC, plasma, and feces during disease. Similar changes in cholesterol oxidation were found in the cervical SC of sporadic ALS patients. Notably, auto-oxidized sterols, but not oxysterols and BAs, were toxic to iPSC derived human MNs. Thus, increased cholesterol oxidation is a manifestation of ALS and non-regulated sterol oxidation likely contributes to MN death. Developing therapeutic approaches to restore cholesterol homeostasis in the SC may lead to a treatment for ALS.
... In addition, patients with type 2 diabetes tend to be older at ALS onset, which was also confirmed in the ALS Registry Swabia. 29 Therefore, it had been speculated whether diabetes as a disease with metabolic disturbances is a protective factor in ALS. [37][38][39] Among the strengths of our study are the large sample size with virtually complete follow-up of the ALS cases, the wellcharacterized study sample, and the comprehensive assessment of PA history. ...
Article
Background and Objectives Whether physical activity (PA) is a risk factor for amyotrophic lateral sclerosis (ALS) is controversial since data on life-long PA are rare. The main objective of this study is to provide insight in PA as a potential risk factor for ALS, reporting data on cumulative PA, leisure time PA and occupational PA. This study also aims at gathering evidence on the role of PA as a prognostic factor in disease course. Methods Lifetime PA values collected by questionnaires addressing work and leisure time were quantified into metabolic equivalents (MET). A population-based case-control study embedded in the ALS Registry Swabia served to calculate odds ratio (OR) of ALS by PA in different time intervals and prognosis. Results In ALS cases (393 cases, 791 age- and sex-matched controls), we observed reduced total PA at interview and up to 5 years before interview compared to controls. Total PA was not associated with ALS risk 5-55 years before interview. Heavy occupational work intensity was associated with increased ALS risk (OR=1.97, 95%-CI (1.34, 2.89)). Total PA levels were associated with survival in a nonlinear manner: inactive patients and highest activity levels (25 METh/week) revealed the worst survival time of 15.4/19.3 months, respectively. Best median survival with 29.8 months was seen at 10.5 METh/week after adjusting for other prognostic factors. Discussion Lifetime combined PA sharply decreased several years before disease onset compared to controls. The risk of developing ALS was not associated with former total PA levels 5-55 years before interview in contrast to occupational PA, probably reflecting work associated exposures. We found a strong nonlinear association of current and pre-diagnostic PA level and survival in ALS cases with the best survival with moderate PA. PA intensity may be a disease modifying factor with an unfavourable outcome in sedentary and hyperactive behaviour. Classification of evidence This study provides Class III evidence that physical activity was not associated with the development of ALS.
... It is interesting to note that changes in the metabolome as well as alterations in energy metabolism, such as an increase in resting energy expenditure, often precede the development of motor symptoms in ALS and correlates to disease progression. For instance, a lipid-specific metabolic abnormality is present at the pre-symptomatic stage of ALS animal models while increased serum levels of total cholesterol, LDL, LDL/HDL ratio, and triglycerides were associated with longer survival and slower disease progression in ALS patients and animal models (Dorst et al., 2011;De Aguilar, 2019;Germeys et al., 2019). However, the relationship between lipid levels and ALS is still rather controversial and poorly understood, and some followup observational studies of ALS did not observe any association between dyslipidemia and the incidence of ALS (Zufiría et al., 2016;De Aguilar, 2019;Zeng and Zhou, 2019). ...
Article
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Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disorder, caused by the degeneration of upper and lower motor neurons for which there is no truly effective cure. The lack of successful treatments can be well explained by the complex and heterogeneous nature of ALS, with patients displaying widely distinct clinical features and progression patterns, and distinct molecular mechanisms underlying the phenotypic heterogeneity. Thus, stratifying ALS patients into consistent and clinically relevant subgroups can be of great value for the development of new precision diagnostics and targeted therapeutics for ALS patients. In the last years, the use and integration of high-throughput “omics” approaches have dramatically changed our thinking about ALS, improving our understanding of the complex molecular architecture of ALS, distinguishing distinct patient subtypes and providing a rational foundation for the discovery of biomarkers and new individualized treatments. In this review, we discuss the most significant contributions of omics technologies in unraveling the biological heterogeneity of ALS, highlighting how these approaches are revealing diagnostic, prognostic and therapeutic targets for future personalized interventions.
... Supporting this hypothesis, analysis from genome-wide association studies revealed that polygenic risk score for hyperlipidaemia was linked to a higher risk of ALS [323,324]. Nonetheless, a good prognostic role of elevated serum triglycerides and cholesterol was observed across several studies [325][326][327], suggesting that these alterations may represent a compensatory mechanism to the ongoing neuromuscular damage. Indeed, motor neurons from SOD1 G93A mice show defective bioenergetics from the embryonic stage onwards due to early mitochondrial dysfunction and activate a metabolic reprogramming favoring FA β-oxidation and ketone bodies formation over glucose catabolism [328]. ...
Article
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Increasing evidence gives support for the idea that extra‐-neuronal factors may affect brain physiology and its predisposition to neurodegenerative diseases. Epidemiological and experimental studies show that nutrition and metabolic disorders such as obesity and type 2 diabetes increase the risk of Alzheimer’s and Parkinson’s diseases after midlife, while the relationship with amyotrophic lateral sclerosis is uncertain, but suggests a protective effect of features of metabolic syndrome. The microbiota has recently emerged as a novel factor engaging strong interactions with neurons and glia, deeply affecting their function and behavior in these diseases. In particular, recent evidence suggested that gut microbes are involved in the seeding of prion‐-like proteins and their spreading to the central nervous system. Here, we present a comprehensive review of the impact of metabolism, diet and microbiota in neurodegeneration, by affecting simultaneously several aspects of health regarding energy metabolism, immune system and neuronal function. Advancing technologies may allow researchers in the future to improve investigations in these fields, allowing the buildup of population‐-based preventive interventions and development of targeted therapeutics to halt progressive neurologic disability.
... Higher-than-expected levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG) and low/high-density lipoprotein cholesterol ratio (LDL-C/HDL-C) have been reported among patients with ALS by many although not all studies. [1][2][3][4][5][6] In a recent observational study, we found that patients with ALS had increased levels of LDL-C and apolipoprotein B up to 20 years before diagnosis. 7 Whether or not there is a genetic contribution to the noted dyslipidemia in ALS is unknown, and it is also unclear whether dyslipidemia plays a causal role in ALS. ...
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Dyslipidemia is common among patients with amyotrophic lateral sclerosis (ALS). We aimed to test the association and causality between blood lipids and ALS, using polygenic analyses on the summary results of genome-wide association studies. Polygenic risk scores (PRS) based on low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) risk alleles were significantly associated with a higher risk of ALS. Using single nucleotide polymorphisms (SNPs) specifically associated with LDL-C and TC as the instrumental variables, statistically significant causal effects of LDL-C and TC on ALS risk were identified in Mendelian randomization analysis. No significant association was noted between PRS based on triglycerides or high-density lipoprotein cholesterol risk alleles and ALS, and the PRS based on ALS risk alleles were not associated with any studied lipids. This study supports that high levels of LDL-C and TC are risk factors for ALS, and it also suggests a causal relationship of LDL-C and TC to ALS.
... 27,28 The role of hyperlipidaemia and statins is controversial at present. [29][30][31] Nutritional factors associated with reduced survival in MND are weight loss, malnutrition and severe dysphagia. 32 Progressive weight loss is associated with worsening motor symptoms and reduced survival. ...
Article
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Background: For patients with motor neuron disease (MND), the final 12 months of life can be a tumultuous period, with rapid and significant losses in function and independence, regular contact with the health system and carer stress. Objective: The aim of this article is to provide an outline of the challenges encountered during the last 12 months of life and the role of the specialised multidisciplinary team in managing the challenges that may arise. Discussion: While MND remains rare overall, it is likely that most general practitioners (GPs) will encounter at least one patient with MND during their career. An understanding of the complexity of this group of diseases, including management in the terminal phase, is important given the GP is a valuable member of the multidisciplinary team.
... Together with sterols, fatty acid and acylglycerol dysregulation have contributed greatly to the dyslipidaemia observed in ALS patients. When using non-omics techniques for the analysis of plasma samples of ALS patients, an increase in total fatty acids is observed, without changes in the TG levels [53,74,75]. In a meta-analysis using blood lipid data from over 400 ALS patients in China [55], there was a tendency of a better prognosis in patients with higher TG levels in their blood (a median prolonged life expectancy of 5.8 months for patients with serum TG levels above the median of 127.5 mg/dL). ...
Article
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There is an increasing interest in the study of the relation between alterations in systemic lipid metabolism and neurodegenerative disorders, in particular in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). In ALS these alterations are well described and evident not only with the progression of the disease but also years before diagnosis. Still, there are some discrepancies in findings relating to the causal nature of lipid metabolic alterations, partly due to the great clinical heterogeneity in ALS. ALS presentation is within a disorder spectrum with Frontotemporal Dementia (FTD), and many patients present mixed forms of ALS and FTD, thus increasing the variability. Lipid metabolic and other systemic metabolic alterations have not been well studied in FTD, or in ALS–FTD mixed forms, as has been in pure ALS. With the recent development in lipidomics and the integration with other -omics platforms, there is now emerging data that not only facilitates the identification of biomarkers but also enables understanding of the underlying pathological mechanisms. Here, we reviewed the recent literature to compile lipid metabolic alterations in ALS, FTD, and intermediate mixed forms, with a view to appraising key commonalities or differences within the spectrum.
... In patients with ALS, a host of metabolic alterations have been observed, such as poor glucose handling, hyperlipidaemia, and hypo/hypermetabolism [133][134][135][136][137][138][139]. Further to this, a number of studies have implicated alterations in lipid metabolism in disease pathogenesis [140,141]. The ALS-linked genes TARDBP and C9ORF72 have also been shown to play significant roles in lipid metabolism. ...
Article
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.
... Toward this end, attention has been focused on potential biological components as biomarkers, which may enable not only a reliable diagnosis but also a predictable follow-up and efficacy assessments of therapeutic interventions [23]. In the last decades, several ALS-related biological biomarkers have been recorded [24][25][26][27][28][29][30][31][32][33], some of which are from blood [34][35][36][37][38]. Interestingly, biomarkers from blood samples are receiving increased attention and have even contributed to the evaluation of oxidative stress in ALS patients treated with riluzole (Rilutec®) [39]. ...
Article
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Amyotrophic lateral sclerosis (ALS) is a multifactorial and progressive neurodegenerative disease of unknown etiology. Due to ALS’s unpredictable onset and progression rate, the search for biomarkers that allow the detection and tracking of its development and therapeutic efficacy would be of significant medical value. Considering that alterations of energy supply are one of ALS’s main hallmarks and that a correlation has been established between gene expression in human brain tissue and peripheral blood mononuclear cells (PBMCs), the present work investigates whether changes in mitochondrial function could be used to monitor ALS. To achieve this goal, PBMCs from ALS patients and control subjects were used; blood sampling is a quite non-invasive method and is cost-effective. Different parameters were evaluated, namely cytosolic calcium levels, mitochondrial membrane potential, oxidative stress, and metabolic compounds levels, as well as mitochondrial dynamics and degradation. Altogether, we observed lower mitochondrial calcium uptake/retention, mitochondria depolarization, and redox homeostasis deregulation, in addition to a decrease in critical metabolic genes, a diminishment in mitochondrial biogenesis, and an augmentation in mitochondrial fission and autophagy-related gene expression. All of these changes can contribute to the decreased ATP and pyruvate levels observed in ALS PBMCs. Our data indicate that PBMCs from ALS patients show a significant mitochondrial dysfunction, resembling several findings from ALS’ neural cells/models, which could be exploited as a powerful tool in ALS research. Our findings can also guide future studies on new pharmacological interventions for ALS since assessments of brain samples are challenging and represent a relevant limited strategy. Graphical abstract
... The causes of hyperlipidaemia, which could further affect energy metabolism, also remain controversial [55]. Along with increased apoE levels [97] and type 2 diabetes [85,118], hyperlipidaemia has in fact been shown to be protective in ALS [51,54]. Nevertheless, the link between energy metabolism and ALS pathogenesis remains unclear despite animal studies providing a number of suggestions [55] with therapeutic promise [119]. ...
Article
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Abstract Despite the considerable progress made towards understanding ALS pathophysiology, several key features of ALS remain unexplained, from its aetiology to its epidemiological aspects. The glymphatic system, which has recently been recognised as a major clearance pathway for the brain, has received considerable attention in several neurological conditions, particularly Alzheimer’s disease. Its significance in ALS has, however, been little addressed. This perspective article therefore aims to assess the possibility of CSF contribution in ALS by considering various lines of evidence, including the abnormal composition of ALS-CSF, its toxicity and the evidence for impaired CSF dynamics in ALS patients. We also describe a potential role for CSF circulation in determining disease spread as well as the importance of CSF dynamics in ALS neurotherapeutics. We propose that a CSF model could potentially offer additional avenues to explore currently unexplained features of ALS, ultimately leading to new treatment options for people with ALS.
... ALS patients often encounter a loss of weight or a decreased body mass index (BMI) and body fat along with disease progression [10,11]. Dyslipidemia is also a quite common characteristic of ALS patients, and higher levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), total triglycerides (TG), and LDL-C/high-density lipoprotein cholesterol (HDL-C) ratio have been shown to be more prevalent in ALS patients than in controls, although subsequent results are not consistent [12][13][14]. The polygenic risk scores based on LDL-C and TC risk alleles are also shown to be associated with ALS risk [15]. ...
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Background: Epidemiological and clinical studies have suggested comorbidity between amyotrophic lateral sclerosis (ALS) and obesity-related traits. However, little is known about their shared genetic architecture. Objective: To examine whether there exist genetic enrichment between ALS and eleven obesity-related traits, including body mass index (BMI), waist hip ratio, body fat percentage (BFP), birth weight, triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), type 2 diabetes (T2D), fasting glucose, fasting insulin, and identify shared loci among them. Methods: Using the conditional false discovery rate (FDR) statistical framework, we analyzed genome wide association summary statistics for ALS (n=80610) and obesity-related traits, and further conducted functional enrichment analysis. Results: Robust genetic enrichment was observed for ALS conditional on BMI, BFP, HDL-C, LDL-C and T2D, but minimal enrichment on the other traits. 9 shared genetic loci with conjunctional FDR < 0.05 was identified, among which 6 were replicated in a second ALS cohort, including rs3849942 (C9orf72), rs170663 (G2E3), rs8018993 (SCFD1), rs978220 (ATXN3), rs62333164 (CLCN3) and rs12603276 (GGNBP2). We further identified GGNBP2 as a novel potential ALS risk gene, by integrating cis-expression quantitative trait loci analysis in human brain tissue and summary-data-based Mendelian randomization analysis. Functional analysis indicated the shared risk genes were involved in pathways membrane trafficking and vesicle-mediated transport. Conclusions: Our findings demonstrate selective genetic overlap between ALS and obesity-related traits, and identified new shared risk loci, including novel potential ALS risk gene GGNBP2. These results provide better understanding for the pleiotropy of ALS and have implications for future therapeutic trials.
... 57 Similar findings have been reported in ALS patients without FTD, and while the exact mechanism is yet unclear, effects on survival may be mediated through alterations in muscle and lipid metabolism. 58 Other biomarkers identified through lipidomics, such as cardiolipin, acylcarnitine, lysophosphatidylcholine, and acrolein, have been shown to be significantly altered in FTD, with consequent effects on mitochondrial dysfunction, increased inflammatory activity, and oxidative stress, although the direct impact on survival has not been elucidated. 59 Further analyses of survival in FTLD combining assessment of metabolic changes such as eating behaviour, BMI, lipid profiles, and other biomarker levels with central neuropathophysiological and neuroendocrinological changes will enable better understanding between these factors and potentially lead to disease-modifying therapies. ...
Article
After decades of research, large-scale clinical trials in patients diagnosed with frontotemporal lobar degeneration (FTLD) are now underway across multiple centres worldwide. As such, refining the determinants of survival in FTLD represents a timely and important challenge. Specifically, disease outcome measures need greater clarity of definition to enable accurate tracking of therapeutic interventions in both clinical and research settings. Multiple factors potentially determine survival, including the clinical phenotype at presentation; radiological patterns of atrophy including markers on both structural and functional imaging; metabolic factors including eating behaviour and lipid metabolism; biomarkers including both serum and cerebrospinal fluid markers of underlying pathology; as well as genetic factors, including both dominantly inherited genes, but also genetic modifiers. The present review synthesises the effect of these factors on disease survival across the syndromes of frontotemporal dementia, with comparison to amyotrophic lateral sclerosis, progressive supranuclear palsy and corticobasal syndrome. A pathway is presented that outlines the utility of these varied survival factors for future clinical trials and drug development. Given the complexity of the FTLD spectrum, it seems unlikely that any single factor may predict overall survival in individual patients, further suggesting that a precision medicine approach will need to be developed in predicting disease survival in FTLD, to enhance drug target development and future clinical trial methodologies.
Article
Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disorder leading to quadriplegia and aphagia. While swallowing difficulties and increased energy demand lead to malnutrition, increased lipid concentration may correlate with survival and respiratory functions. Objective: To analyze the frequency and type of dyslipidemias in a large population of clinically characterized ALS patients (PALS). Methods: The retrospective study included clinical and laboratory data of 650 consecutive PALS fulfilling the El Escorial criteria and 365 age- and gender-matched hospital controls. Results: 65% of PALS suffered from dyslipidemia independently of concomitant metabolic diseases. The most frequent lipid disorder was hypercholesterolemia (35% PALS, 25% controls), followed by mixed dyslipidemia (24.6%, 14%), with rare cases of hypertriglyceridemia and atherogenic dyslipidemia. Triacylglycerols (TAG) and LDL/HDL correlated with BMI, while LDL/HDL and total cholesterol (TCh) with disease duration. Among PALS with concomitant metabolic diseases, TCh correlated with disease duration and ALSFRS-R, while TAG with respiratory functions (FVC) in patients without metabolic diseases. The highest median concentration of TCh, LDL and LDL/HDL was found in classic ALS and PMA and the lowest in PBP. Conclusion: Dyslipidemia occurs more frequently in PALS compared to controls and independently of concomitant metabolic diseases. Similar to the general population, the most frequent lipid disturbance is hypercholesterolemia, followed by mixed dyslipidemia. Although particular lipid parameters correlate with BMI and disease duration, they do not show strong correlations with disease progression rate. There is a need of randomized control trials assessing the risk and benefits of the use of lipid lowering agents in ALS.
Article
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by selective degeneration of motor neurons of the motor cortex, brain stem and brain stem. Mutations in genes coding for SOD1, C9ORF72, TDP-43, FUS and others are associated with ALS and result in abnormal processing and transport of RNA as well as changes in the dynamics of cytoskeleton. In addition, a sharp change in the metabolism of various lipid classes, including phospholipids, fatty acids, sphingolipids, etc., was detected. This review describes changes in lipid content and activity of enzymes involved in their metabolism in ALS animal models as well as in patients. Changes in the metabolism of fatty acids, phospholipids, cholesterol and its derivatives are reviewed in detail. The prospects of searching for new drugs among modulators of lipid metabolism enzymes are discussed.
Chapter
Bei der amyotrophen Lateralsklerose (ALS) kombinieren sich die Läsion der Betz-Zellen des motorischen Kortex und der Pyramidenbahn (des ersten Motoneurons), sowie der motorischen Vorderhornzellen (des zweiten Motoneurons). Dieses Degenerationsmuster erkannte der Erstbeschreiber der ALS, der französische Neurologe Jean-Martin Charcot, als pathognomonisch und stellte die bei seinen pathologisch-anatomischen Untersuchungen der ALS erhobenen Befunde zeichnerisch dar. Heute ist bekannt, dass die ALS dem Konzept einer Multisystemdegeneration unterzuordnen ist, die systematisch in neuroanatomisch definierten Stadien primär das zentrale Nervensystem erfasst. Die Ursachen der Erkrankungen der Motoneurone sind weitgehend unbekannt, und das Verständnis ihrer genetischen Grundlagen, der Pathogenese und die Entwicklung von Behandlungsansätzen stehen erst am Anfang.
Article
There is currently no diagnostic or prognostic biomarker available in clinical practice for Amyotrophic Lateral Sclerosis (ALS). The objective of this study was to monitor a combination of various inflammatory markers, lipids, and apolipoprotein alterations in ALS patients at the time of diagnosis, to assess their role as early diagnostic or prognostic biomarker candidates. C-reactive protein, orosomucoid, prealbumin, calprotectin, lipids and apoliproteins were determined in the blood of all subjects (25 ALS patients, 23 controls) as routinely performed in our laboratory. Inflammatory mediators were evaluated by a bead-based multiplex assay. A two-step approach was used for each analytical strategy: univariate analysis followed by multivariate analysis. Eight features were significantly different between ALS patients and controls, sometimes with important fold changes. The supervised Partial least Squares Discriminant Analysis separated ALS and controls with great accuracy (94 %) and the permutation test was significant (p < 0.01), ensuring the robustness of the model. The prediction model leads to a mean sensitivity and specificity of 90 (+/- 10) and 78 (+/- 10) %, respectively, with a mean predictive positive value and negative predictive value of 80 (+/- 8.9) and 89 (+/- 11.8) %, respectively. However, the models did not discriminate subgroups of ALS patients based on ALS characteristics. This study highlights the usefulness of evaluating a combination of multiple pathways rather than focusing on a single target. These promising results suggest the need for the longitudinal monitoring of these candidates to determine their role in disease evolution.
Article
Epidemiological and clinical studies have suggested comorbidities between amyotrophic lateral sclerosis (ALS) and obesity-related traits. However, little is known about their shared genetic architecture. To examine whether genetic enrichment exists between ALS and obesity-related traits and to identify shared risk loci, we analyzed summary statistics from genome-wide association studies using the conditional false discovery rate statistical framework, and further conducted functional enrichment analysis. Robust genetic enrichment was observed for ALS conditional on body mass index, body fat percentage, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and type 2 diabetes. Nine shared genetic loci were identified, among which 6 were replicated in a second ALS cohort, including C9orf72, G2E3, SCFD1, ATXN3, CLCN3 and GGNBP2. We further identified GGNBP2 as a novel ALS risk gene, by integrating summary data-based Mendelian randomization analysis. Functional enrichment analysis indicated that the shared risk genes were involved in two pathways, namely membrane trafficking and vesicle-mediated transport. These results provide a better understanding for the pleiotropy of ALS and have implications for future therapeutic trials.
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Dyslipidemia is correlated with the prognosis of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder characterized pathologically by TAR DNA binding protein (TDP-43) inclusions. We investigated molecular mechanisms of lipid metabolism regulated by TDP-43 in ALS. Expression microarray and RNA deep sequencing (RNA-Seq) were performed using cell lines expressing doxycycline-inductive TDP-43. Gene expression and transcriptome profiling identified 434 significantly altered genes under high levels of TDP-43 (Tukey’s test, P < 0.05) including sterol regulatory element-binding protein 2 (SREBP2), a master regulator of cholesterol homeostasis and its downstream genes. TDP-43 overexpression impaired SREBP2 transcriptional activity, leading to inhibition of cholesterol biosynthesis via the nutrient- and growth factor-responsive kinase mTOR Complex I (mTORC1). The amount of cholesterol was significantly decreased in motor neuronal cultures derived from ALS-patient induced pluripotent stem cells (iPSCs) as well as in the spinal fluids of ALS patients and in the spinal cord of ALS model mice. Impairment of cholesterol synthesis is caused by an increase in toxic function of TDP-43 in ALS.
Chapter
Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disorder. While initially pathophysiology was thought to be restricted to motor deficits, it is increasingly recognized that patients develop prominent changes in weight and eating behavior that result from and mediate the underlying neurodegenerative process. These changes include alterations in metabolism, lipid levels, and insulin resistance. Emerging research suggests that these alterations may be mediated through changes in the hypothalamic function, with atrophy of the hypothalamus shown in both ALS patients and also presymptomatic genetic at-risk patients. This chapter reviews the evidence for hypothalamic involvement in ALS, including melanocortin pathways and potential treatment targets.
Article
Amyotrophic lateral sclerosis (ALS), the most common adult‐onset motor neuron disease, is characterized by the selective degeneration of motor neurons leading to paralysis and eventual death. Multiple pathogenic mechanisms, including systemic dysmetabolism, have been proposed to contribute to ALS. Among them, dyslipidemia, i.e., abnormal level of cholesterol and other lipids in the circulation and central nervous system (CNS), have been reported in ALS patients, but without a consensus. Cholesterol is a constituent of cellular membranes and a precursor of steroid hormones, oxysterols and bile acids. Consequently, optimal cholesterol levels are essential for health. Due to the blood‐brain barrier (BBB), cholesterol cannot move between the CNS and the rest of the body. As such, cholesterol metabolism in the CNS is proposed to operate autonomously. Despite its importance, it remains elusive how cholesterol dyshomeostasis may contribute to ALS. In this review, we aim to describe the current state of cholesterol metabolism research in ALS, identify unresolved issues, and provide potential directions.
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Background The survival time of amyotrophic lateral sclerosis (ALS) is greatly variable and protective or risk effects of the potential survival predictors are controversial. Thus, we aim to undertake a comprehensive meta-analysis of studies investigating non-genetic prognostic and survival factors in patients with ALS. Methods A search of relevant literature from PubMed, Embase, Cochrane library and other citations from 1st January 1966 to 1st December 020 was conducted. Random-effects models were conducted to pool the multivariable or adjusted hazard ratios (HR) by Stata MP 16.0. PROSPERO registration number: CRD42021256923. Findings A total of 5717 reports were identified, with 115 studies meeting pre-designed inclusion criteria involving 55,169 ALS patients. Five dimensions, including demographic, environmental or lifestyle, clinical manifestations, biochemical index, therapeutic factors or comorbidities were investigated. Twenty-five prediction factors, including twenty non-intervenable and five intervenable factors, were associated with ALS survival. Among them, NFL (HR:3.70, 6.80, in serum and CSF, respectively), FTD (HR:2.98), ALSFRS-R change (HR:2.37), respiratory subtype (HR:2.20), executive dysfunction (HR:2.10) and age of onset (HR:1.03) were superior predictors for poor prognosis, but pLMN or pUMN (HR:0.32), baseline ALSFRS-R score (HR:0.95), duration (HR:0.96), diagnostic delay (HR:0.97) were superior predictors for a good prognosis. Our results did not support the involvement of gender, education level, diabetes, hypertension, NIV, gastrostomy, and statins in ALS survival. Interpretation Our study provided a comprehensive and quantitative index for assessing the prognosis for ALS patients, and the identified non-intervenable or intervenable factors will facilitate the development of treatment strategies for ALS. Funding This study was supported by the National Natural Science Fund of China (Grant No. 81971188), the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (Grant No. 2019HXFH046), and the Science and Technology Bureau Fund of Sichuan Province (No. 2019YFS0216).
Thesis
L’altération de l’état nutritionnel lors de la Sclérose latérale amyotrophique (SLA) est liée à une diminution des prises alimentaires et/ou une augmentation de la dépense énergétique de repos (DER). L’hypermétabolisme (HM), défini par un pourcentage de variation de DER (ΔDER) supérieur à +10% entre la DER mesurée en calorimétrie indirecte et la DER calculée par équations prédictives, est décrit dans 50 à 60% des cas de SLA. Si l’HM n’est pas compensé par l’alimentation, il expose le patient au risque de dénutrition, facteur de mauvais pronostic. Le dépistage de l’HM apparait donc comme essentiel pour repérer les situations les plus à risque de dénutrition et proposer des mesures adaptatives. Cependant, l’existence de l’HM n’est pas consensuelle, et il persiste de nombreuses questions quant à la notion de modification de la DER lors de la SLA.Une première étude retrouvait, chez 315 patients souffrants de SLA, une DER mesurée systématiquement supérieure à la DER calculée par 12 équations prédictives (p<0,0001). Selon l’équation testée, l’HM concernait 35,2% à 76,3% des patients, et 14,6% à 53,3% des cas présentaient une ΔDER > +20%. Les patients avec une ΔDER > +20% selon les équations de Harris et Bénédict de 1919 et leurs versions révisées de 1984 avaient un risque de décès majoré, respectivement de 42% (p=0,01) et 38% (p=0,02). Avec ce même seuil de ΔDER selon la formule de Mifflin, l’évolution fonctionnelle (p=0,02) et respiratoire (p=0,003) étaient plus délétères et la survie plus altérée (p=0,003).Dans une seconde étude, le niveau métabolique était clairement plus élevé chez 287 patients souffrants de SLA en comparaison à celui de 78 témoins sains (1500 versus 1230 kcal/jour, p<0,0001). L’HM, concernant 55% des patients contre seulement 13,3% des témoins (p<0,0001), était fortement, positivement et significativement associé à la maladie (ORajusté=9,5 [4,5-20,1], p<0,0001). Même en cas de ΔDER inférieure au seuil de +10%, la DER était plus élevée chez les patients comparativement aux témoins (p=0,0008).Une troisième étude testait l’exactitude de la DER calculée par 11 équations prédictives, par rapport à DER obtenue en calorimétrie indirecte chez 315 patients. La concordance des formules était modérée (coefficient de corrélation intra-classe [CCI] variant de 0,60 à 0,71), le pourcentage de bonnes prédictions faible (27,3% à 57,5% des cas) et la sous-estimation fréquente (31,7% à 71,4% des cas). Les équations existantes n’étant pas adaptées à la SLA, une formule spécifique était créée et testée : la concordance entre la DER mesurée et celle obtenue par cette formule était très bonne (CCI = 0,85), le pourcentage de bonnes prédictions était amélioré (65%) et la sous-estimation de la DER nettement diminuée (17,5%). Dans une quatrième étude menée sur la même cohorte, 55,2% des patients présentaient un HM et 23,3% un HM sévère (ΔDER > +20%). Comparativement aux sujets sans HM, les patients avec un HM sévère avaient une proportion de masse grasse au diagnostic plus faible (29,7% versus 32,1%, p=0,005) et une tendance au déclin fonctionnel plus rapide lors du suivi (p=0,07). En analyse univariée, l’HM sévère avait tendance à majorer le risque de décès comparativement à l’absence d’HM (Hazard ratio =1,33 [0,99-1,79], p=0,055). Au total, les études montrent que la DER est réellement augmentée lors de la SLA. Ces modifications concernent tous les patients. L’HM affecte plus de la moitié des patients et pourrait être un marqueur de la maladie. Il existe désormais une formule prédictive de la DER applicable dans la SLA, qui représente un recours à la calorimétrie indirecte. L’HM, surtout lorsqu’il est sévère, modifie la composition corporelle au diagnostic et semble être un facteur de mauvais pronostic pour l’évolution fonctionnelle, respiratoire et la survie. L’ensemble renforce l’importance de l’évaluation métabolique, pour adapter les besoins énergétiques et dépister les situations les plus à risque d’évolution délétère.
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Background: Patients with amyotrophic lateral sclerosis (ALS) suffer from dysphagia that increases the risk for aspiration, pneumonia and weight loss. Pharyngeal electrical stimulation (PES) is a therapeutic technique that applies electric stimuli to the patient's pharynx in order to improve swallowing based on the principle of cortical plasticity and reorganization. Previous studies have demonstrated positive effects in patients with various neurological diseases. Objective: This study was initiated to investigate the effect of PES on swallowing function in patients with ALS. Methods: In all, 20 ALS patients with severe dysphagia [characterized by a Penetration Aspiration Scale (PAS) of at least 4 in thin liquid] were randomized to receive either PES for 10 min at 3 consecutive days in addition to Standard Logopaedic Therapy (SLT) or SLT alone. Swallowing function was evaluated by Fiberoptic Endoscopic Evaluation of Swallowing (FEES) at five timepoints: at baseline, 1 day, 4 days, 3 weeks and 3 months after treatment. Primary endpoint was the severity of penetrations or aspirations as classified by PAS. Secondary endpoints were adverse events, dysphagia-related quality of life, Swallowing Quality of Life (SWAL-QOL), Dysphagia Severity Rating Scale (DSRS), residues, leaking, ALS Functional Rating Scale Revised (ALSFRS-R), and the performance in Clinical Evaluation of Swallowing (CES). The trial is registered under the name of 'Pharyngeal Electrical Stimulation in Amyotrophic Lateral Sclerosis' with ClinialTrials.gov, number NCT03481348 (https://clinicaltrials.gov/ct2/show/NCT03481348). Results: Both groups combined showed a significant improvement (p = 0.003) of median Total-PAS from 3.6 [interquartile range (IQR) = 2.9-5.0] at baseline to 2.3 (IQR = 1.8-4.0) 1 day after treatment. During subsequent study visits, PAS increased again but remained below baseline. PES and control group did not differ significantly 1 day after intervention (p = 0.32). Similar effects were found in the majority of secondary endpoints. Interpretation: The findings suggest that PES may not provide an additional positive effect on swallowing function in ALS. SLT seems to yield at least short-term positive effects on swallowing function and swallowing-specific life quality in ALS.Registration: ClinialTrials.gov: NCT03481348.
Article
Objective: The aim of the present study was to determine the prevalence of the ACSL A/G single nucleotide polymorphism among athletes and patients with amyotrophic lateral sclerosis (ALS). ALS is a progressive neurodegenerative disorder of motor neurons that leads to paralysis and death usually within 3-5 years from onset. Previous epidemiological studies reported a higher risk of ALS among soccer players. The ACSL (long-chain-fatty-acid-CoA ligase 1) gene codes the long-chain fatty-acid-coenzyme A ligase family that plays a key role in lipid biosynthesis and fatty acid oxidation. The ACSL A/G polymorphism is associated with endurance trainability. Methods: One hundred and seventy-eight ALS patients, 172 athletes (60 soccer players, 112 middle- and long-distance runners), and 111 nonathletic controls participated in the study. Genomic DNA was extracted from blood or buccal cells according to the salting-out procedure. Genotypes were determined using the TaqMan allelic discrimination assay. Results: The prevalence of the ACSL AA genotype was significantly higher among soccer players (35.0%) and ALS patients (39.3%) compared to runners (16.1%) and controls (18.0%). However, ALS GG carriers had a higher mortality rate. Conclusion: We postulate that soccer players and ALS patients carry a common genetic predisposition that is related to impaired fatty acid utilization. Moreover, while the A allele might be associated with a genetic predisposition toward ALS, especially among soccer players, the G allele might be associated with disease severity. Further research is needed in order to explore the role of the ACSL rs6552828 polymorphism in ALS.
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Dyslipidemia is considered an essential component of the pathological process of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease. Although TAR DNA Binding Protein 43 kDa (TDP-43) links both familial and sporadic forms of ALS and cytoplasmic aggregates are a hallmark of most cases of ALS, the molecular mechanism and the in vivo relation of ALS dyslipidemia with TDP-43 have been unclear. To analyze the dyslipidemia-related gene expression by TDP-43, we performed expression microarray and RNA deep sequencing (RNA-Seq) using cell lines expressing high levels of TDP-43 and identified 434 significantly altered genes including sterol regulatory element-binding protein 2 (SREBP2), a master regulator of cholesterol homeostasis and its downstream genes. Elevated TDP-43 impaired SREBP2 transcriptional activity, leading to inhibition of cholesterol biosynthesis. The amount of cholesterol was significantly decreased in the spinal cords of TDP-43-overexpressed ALS model mice and in the cerebrospinal fluids of ALS patients. These results suggested that TDP-43 could play an essential role in cholesterol biosynthesis in relation to ALS dyslipidemia.
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Objective: To investigate the association between the use of common medications on hypertension, hyperlipidemia, diabetes, and the risk of amyotrophic lateral sclerosis (ALS). Methods: PubMed, EMBASE, OVID, and Web of Science were searched systematically until December 2021 for studies quantitatively investigating the effect of medications on hypertension, hyperlipidemia, and diabetes on the risk of ALS. We conducted a fixed-effects model or random-effects meta-analysis to calculate the summary ORs (odds ratios) and 95%CIs (confidence intervals). Results: Regular intake of angiotensin-converting enzyme inhibitors (ACEIs) (OR: 0.81, 95%CI: 0.74, 0.89), beta-blockers (OR: 0.82, 95%CI: 0.76, 0.90), calcium-channel blockers (CCBs) (OR: 0.85, 95%CI: 0.79, 0.93), or diuretics (OR: 0.87, 95%CI: 0.81, 0.93) was inversely associated with the incidence of ALS. There was no significant association between statin use and risk of ALS (OR: 0.92, 95%CI: 0.83, 1.03). Metformin (OR: 0.83, 95%CI: 0.75, 0.93) and sulfonylureas (OR: 0.79, 95%CI:0.71, 0.89) use could significantly reduce the risk of ALS. Conclusion: Regular use of anti-hypertensive drugs and anti-diabetes including ACEIs, beta-blockers, CCBs, diuretics, metformin, and sulfonylureas could protect against the incidence of ALS. No significant association between anti-hyperlipidemia drug use and risk of ALS was revealed. Regular medications for hypertension, hyperlipidemia, and diabetes should be recommended regardless of the diagnosis of ALS.
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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that primarily affects motor neurons and causes muscle atrophy, paralysis, and death. While a great deal of progress has been made in deciphering the underlying pathogenic mechanisms, no effective treatments for the disease are currently available. This is mainly due to the high degree of complexity and heterogeneity that characterizes the disease. Over the last few decades of research, alterations to bioenergetic and metabolic homeostasis have emerged as a common denominator across many different forms of ALS. These alterations are found at the cellular level (e.g., mitochondrial dysfunction and impaired expression of monocarboxylate transporters) and at the systemic level (e.g., low BMI and hypermetabolism) and tend to be associated with survival or disease outcomes in patients. Furthermore, an increasing amount of preclinical evidence and some promising clinical evidence suggests that targeting energy metabolism could be an effective therapeutic strategy. This review examines the evidence both for and against these ALS-associated metabolic alterations and highlights potential avenues for therapeutic intervention.
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Objective Amyotrophic lateral sclerosis (ALS) pathogenesis is still unclear, its course is considerably variable, and prognosis is hard to determine. Despite much research, there is still a lack of easily accessible markers predicting prognosis. We investigated routine blood parameters in ALS patients regarding correlations with disease severity, progression rate, and survival. Additionally, we analyzed disease and patients' characteristics relating to baseline blood parameter levels. Methods We analyzed creatine kinase (CK), albumin (ALB), creatinine (CREA), total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG) levels around time of diagnosis in 1,084 ALS patients. We carried out linear regression analyses including disease and patients' characteristics with each blood parameter to detect correlations with them. Linear regression models were performed for ALSFRS-R at study entry, its retrospectively defined rate of decay and prospectively collected progression rate. Different survival analysis methods were used to examine associations between blood parameters and survival. Results We found higher CK ( p -value 0.001), ALB ( p -value <0.001), CREA ( p -value <0.001), and HDL levels ( p -value 0.044) at time of diagnosis being associated with better functional status according to ALSFRS-R scores at study entry. Additionally, higher CREA levels were associated with lower risk of death ( p -value 0.003). Conclusions Our results indicate potential of CK, ALB, CREA, and HDL as disease severity or progression markers, and may also provide clues to ALS pathogenesis. However, these values are highly dependent on other variables, and further careful, longitudinal analyses will be necessary to prove the relevance of our findings.
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Astrocytes are the most abundant glial cell in the central nervous system and are involved in multiple processes including metabolic homeostasis, blood brain barrier regulation and neuronal crosstalk. Astrocytes are the main storage point of glycogen in the brain and it is well established that astrocyte uptake of glutamate and release of lactate prevents neuronal excitability and supports neuronal metabolic function. However, the role of lipid metabolism in astrocytes in relation to neuronal support has been until recently, unclear. Lipids play a fundamental role in astrocyte function, including energy generation, membrane fluidity and cell to cell signaling. There is now emerging evidence that astrocyte storage of lipids in droplets has a crucial physiological and protective role in the central nervous system. This pathway links β-oxidation in astrocytes to inflammation, signalling, oxidative stress and mitochondrial energy generation in neurons. Disruption in lipid metabolism, structure and signalling in astrocytes can lead to pathogenic mechanisms associated with a range of neurological disorders.
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Our objective was to test the hypothesis that changes in body mass index (BMI) are associated with changes in the clinical course of ALS. We examined the relationships between BMI at first clinical visit and changes in BMI up to a two-year follow-up, and multiple clinical variables related to ALS: age of onset, rate of progression of motor symptoms, and survival. Baseline BMI was classified according to the World Health Organization (WHO) criteria. Changes in BMI were classified as a loss of >1 unit, no change, or a gain of >1 unit. Our results showed that baseline BMI was not associated with age of onset, rate of progression or survival. In contrast, a loss of BMI >1 over two years was associated with significantly shorter survival and a faster rate of progression. In a multiple regression model, these results were independent of gender, site of onset, history of diabetes mellitus and apolipoprotein (ApoE) genotype. In summary, a change in BMI after ALS diagnosis was significantly associated with rate of progression and survival. This raises the possibility that early changes in BMI may identify patients likely to have a more malignant course of the disease. However, further research is needed to clarify the relationship between BMI and ALS.
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Our objectives were to analyse carbohydrate metabolism in a series of ALS patients and to examine potential association with parameters of lipid metabolism and clinical features. Glucose tolerance was assessed by the oral glucose tolerance test in 21 non-diabetic ALS patients and compared with 21 age- and sex-matched normal subjects. Lipids and lactate/pyruvate ratio, levels of pro-inflammatory cytokines (tumour necrosis factor-alpha and interleukin-6) and adipocytokines (leptin and adiponectin) were also measured in ALS patients. Mann-Whitney U-tests analysed continuous data and Fisher's exact tests assessed categorical data. Blood glucose determined 120 min after the glucose bolus was significantly higher in patients with ALS (7.41 mmol/l+/-1.68) compared to controls (6.05+/-1.44, p=0.006). ALS patients with impaired glucose tolerance (IGT) according to WHO criteria (n=7, 33%) were more likely to have elevated free fatty acids (FFA) levels compared to patients with normal glucose tolerance (0.77 nmol/l+/-0.30 vs. 0.57+/-0.19, p=0.04). IGT was not associated with disease duration or severity. In conclusion, patients with ALS show abnormal glucose tolerance that could be associated with increased FFA levels, a key determinant of insulin resistance. The origin of glucose homeostasis abnormalities in ALS may be multifactorial and deserves further investigation.
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Eight patients with classical motor neurone disease, and eight control patients with neurological disease and matched for degree of wasting, were studied. Both groups had abnormal glucose tolerance, but the patients with motor neurone disease had a significantly lower insulin response both to oral glucose loading and to intravenous tolbutamide. These results suggest that in patients with motor neurone disease there is an impaired synthesis or release of insulin due to islet cell damage. Blood pyruvate and lactate, and cerebrospinal fluid pyruvate, lactate, and citrate, did not differ significantly from the control group. Blood citrate levels were significantly higher in patients with motor neurone disease compared with the controls. Triglyceride levels were raised in patients with motor neurone disease compared to the control patients. This may be secondary to the increased citrate levels.
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To evaluate the occurrence of malnutrition in patients with ALS, to assess the relation of malnutrition to the neurologic deficit, and to determine the impact of nutritional status on patient survival. Although ALS may be associated with significant malnutrition, the relative impact on patient survival has not yet been well established. In a prospective 7-month study of 55 ALS patients in a referral neurology practice, nutritional status was assessed by calculating body mass index. Neurologic evaluation includes four functional scores and identifies the form of disease onset. Slow vital capacity (VC) was also measured. Occurrence of malnutrition in patients studied was 16.4%. Survival (using the Kaplan-Meier method) was worse for malnourished patients (p < 0.0001), with a 7.7-fold increased risk of death. Using multivariate analysis, only reduced VC (p < 0.0001) and malnutrition (p < 0.01) were found to have significant independent prognostic value. The degree of malnutrition is independent of neurologic scores and of forms of ALS onset. Nutritional surveillance of ALS patients is very important, both in bulbar-onset and spinal-onset patients.
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Amyotrophic lateral sclerosis (ALS) is a severe disease characterized by neurogenic amyotrophy and degeneration of upper and lower motor neurons. Although ALS patients usually experience reductions in fat-free mass (FFM), hypermetabolism via an undetermined source has also been reported. The objective was to clarify the metabolic level of ALS patients. We measured the resting energy expenditure (REE) of 62 patients (32 men and 30 women) with ALS and investigated the factors correlated with metabolic level. Nutritional evaluation included bioelectrical impedance analysis, indirect calorimetry, and calculation of the body mass index. Neurologic assessment included an evaluation of peripheral and central neurologic deficit. Forced vital capacity was measured and smoking status was noted. A complete blood cell count was made and thyroid hormone and C-reactive protein concentrations were measured. Patients were hypermetabolic, by an average of approximately 10% more than in a reference healthy population. FFM, age, and the neutrophil count were significantly associated with REE. The only variable that contributed to the prediction of REE, REE/Z100 kHz (bioimpedance at 100 kHz), REE adjusted for FFM, or the ratio of measured REE to calculated REE was the neutrophil count, which explained only a small percentage of variance in the multiple regression analysis. Hypermetabolism was not associated with a reduction in respiratory function, tobacco use, hyperthyroidism, spasticity and fasciculation intensities, or infection. Our study corroborates the surprising finding that ALS patients are hypermetabolic. FFM, age, sex, manual muscular testing, the modified Norris limb score, weight, and an increase in circulating neutrophil counts correlated with the hypermetabolic state. Other factors may play a role in pathophysiologic processes that involve mitochondrial energy production or even sympathoadrenergic activation.
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Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by selective loss of motor neurons and progressive muscle wasting. Growing evidence indicates that mitochondrial dysfunction, not only occurring in motor neurons but also in skeletal muscle, may play a crucial role in the pathogenesis. In this regard, the life expectancy of the ALS G93A mouse line is extended by creatine, an intracellular energy shuttle that ameliorates muscle function. Moreover, a population of patients with sporadic ALS exhibits a generalized hypermetabolic state of as yet unknown origin. Altogether, these findings led us to explore whether alterations in energy homeostasis may contribute to the disease process. Here, we show important variations in a number of metabolic indicators in transgenic ALS mice, which in all shows a metabolic deficit. These alterations were accompanied early in the asymptomatic phase of the disease by reduced adipose tissue accumulation, increased energy expenditure, and concomitant skeletal muscle hypermetabolism. Compensating this energetic imbalance with a highly energetic diet extended mean survival by 20%. In conclusion, we suggest that hypermetabolism, mainly of muscular origin, may represent by itself an additional driven force involved in increasing motor neuron vulnerability.
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AimThe purpose of this study was to estimate the order of magnitude of the metabolic syndrome (MetS) prevalence in Germany despite a lack of sufficient fasting participants in representative national studies. Subjects and methodsThis analysis was based on 6,666 participants of the National Health Examination Survey (NHIES) 1998 aged 18–79, using the criteria of the National Cholesterol Education Program (NCEP), hemoglobin A1c (HbA1c), non-fasting triglycerides and fasting time. ResultsAmong 6,666 participants, 26.3% were fasting for at least 8h and an additional 60.4% could be classified according to the NCEP criteria based on their waist circumference, HDL cholesterol and blood pressure alone (if all three parameters were above or all below the NCEP thresholds). MetS determination in the remaining 13.3% of the sample according to the NCEP criteria would have required fasting glucose and triglyceride values that were not available (inconclusive cases). The metabolic syndrome prevalence in the overall sample was therefore estimated to be at least 13.6%, if all inconclusive cases did not have the MetS, and at most 26.9%, if all inconclusive cases had the MetS. We narrowed down this range by classifying the inconclusive cases stepwise, first by adding information on HbA1c with cutoffs >6.1% and >6.0% and then by including information on non-fasting triglycerides with three different cutoffs (≥250mg/dl, ≥200mg/dl and ≥75th percentile of the population distribution stratified by fasting time). Based on these different cutoffs, the prevalence of the MetS in adults aged 18–79 in Germany was estimated to lie between 20.0 to 22.5%. Using one of the more conservative scenarios (HbA1c >6.1% and triglycerides ≥75th population percentile), the presence of the MetS was associated with living in East compared to West Germany (OR 1.4, 95% CI 1.2–1.6), with lower education (OR 1.7, 95% CI 1.4–2.0 compared to higher education) and with male sex (OR 1.5, 95% CI 1.3–1.7) in an analysis additionally adjusting for age, current daily smoking and non-HDL cholesterol. ConclusionsDespite imperfect data for prevalence estimation, a high prevalence and an uneven East-West and socioeconomic distribution of the MetS phenotype in Germany can be shown and should be used in order to improve national preventive strategies.
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Several metabolic derangements associated with diabetes mellitus type 2 (DM) have been associated with a better outcome in amyotrophic lateral sclerosis (ALS), including hyperlipidemia and obesity. Here, we tested the hypothesis that DM would have a positive effect on the motor and cognitive findings of ALS. We compared data from ALS patients with pre-morbid DM (ALS-DM; n = 175) versus without DM (ALS; n = 2196) with regard to the age of onset, rate of motor progression, survival, and neuropsychological test performance. The age of onset was later for women, Caucasians and patients with bulbar-onset ALS. However, we also found that after adjusting for gender, ethnicity and site of onset, DM was associated with a 4-year later onset of ALS (ALS = 56.3, ALS-DM = 60.3, P < 0.05). Diabetes mellitus type 2 may delay the onset of motor symptoms in ALS. These findings support other studies suggesting a relationship between the pathophysiology of ALS and metabolic derangements. Further investigations are needed to ascertain whether manipulating metabolic parameters would improve outcomes in ALS.
Article
Recently hyperlipidemia was reported to be related to a significantly better outcome in amyotrophic lateral sclerosis (ALS). To investigate this, we evaluated the status of blood lipids in a large Italian series of patients with ALS, and assessed the effect of hyperlipidemia on patients' survival. The study population included 658 patients with ALS consecutively observed in 2 Italian ALS centers between 2000 and 2006. They were compared to a series of 658 healthy subjects, matched by age and gender. The mean levels of total cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and the LDL/HDL ratio were similar in patients with ALS and controls. Total cholesterol, HDL, triglyceride, and LDL/HDL ratio levels showed a significant decrease in patients with forced vital capacity <70% compared to those with FVC >or=90%. For each level of ALS-FRS, poorer respiratory function was related to a lower LDL/HDL ratio. Univariate survival analysis did not find any significant effect of LDL/HDL ratio on survival, either when comparing patients with ratios <or=2.99 vs >2.99 or patients in the first quartile of LDL/HDL ratio (<or=1.67) vs those in the fourth quartile (>2.79). No dose-response was found for LDL/HDL ratio subdividing patients into 5 quintiles. Our findings do not support the observation that patients with amyotrophic lateral sclerosis have hyperlipidemia or that hyperlipidemia in this population is related to longer survival. However, some evidence emerged that respiratory impairment, but not a worse clinical status or a lower body mass index, is related to a decrease in blood lipids and LDL/HDL ratio.
Article
In this study, circulating concentrations of intermediary metabolites were measured in eight non-obese subjects with motor neurone disease in the basal (postabsorptive) state, and after a 75 g oral glucose challenge. Eight healthy subjects of similar age and body mass index served as controls. Basal pyruvate concentration was significantly elevated in the subjects with motor neurone disease (p less than 0.02). After oral glucose ingestion, overall levels of pyruvate (p less than 0.01) and lactate (p less than 0.05) were significantly higher in these subjects. Blood glucose concentrations fulfilled the criteria diagnostic of impaired glucose tolerance in six of the eight subjects with motor neurone disease (WHO, 1985). Cumulative insulin levels were slightly higher in these subjects and peak insulin response was delayed (120 min vs. 60 min) relative to the healthy controls. Circulating concentrations of alanine, glycerol, non-esterified fatty acids and total ketone bodies were similar between groups. These results confirm that impaired glucose tolerance is a common feature of motor neurone disease. Furthermore, our data indicate disordered regulation of both pyruvate and lactate metabolism, consistent with reports of defective skeletal muscle pyruvate oxidation in individuals with this disorder. In contrast, our results indicate that the regulation of lipolysis and ketone body metabolism is unimpaired in motor neurone disease.
Article
The levels of plasma high density lipoprotein (HDL) cholesterol and plasma triglyceride were determined in 44 patients with motor neuron disease (MND) and in 36 patients with spinocerebellar degeneration (SCD). In both groups the HDL cholesterol levels were significantly lower than those in healthy controls, whereas the plasma triglyceride levels were higher than those in the controls. Glucose levels during the oral glucose tolerance test (GTT) were significantly higher in both MND and SCD groups than in healthy controls. Immunoreactive insulin (IRI) levels during GTT were rather higher at 0 and 120 min in both MND and SCD groups than in healthy controls. Glycosylated hemoglobin levels were lower in MND than in the controls. These results indicate that both lipoprotein and carbohydrate metabolisms were impaired in MND and SCD groups. The possibility was presented that denervation might play a part in the pathogenesis of abnormalities of lipoprotein and carbohydrate metabolisms.
Article
Amyotrophic lateral sclerosis (ALS) is the most serious form of degenerative motor neuron disease in adults, characterized by upper and lower motor neuron degeneration, skeletal muscle atrophy, paralysis, and death. High prevalence of malnutrition and weight loss adversely affect quality of life. Moreover, two thirds of patients develop a hypermetabolism of unknown cause, leading to increased resting energy expenditure. Inasmuch as lipids are the major source of energy for muscles, we determined the status of lipids in a population of patients with ALS and investigated whether lipid contents may have an impact on disease progression and survival. Blood concentrations of triglycerides, cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were measured in a cohort of 369 patients with ALS and compared to a control group of 286 healthy subjects. Postmortem histologic examination was performed on liver specimens from 59 other patients with ALS and 16 patients with Parkinson disease (PD). The frequency of hyperlipidemia, as revealed by increased plasma levels of total cholesterol or LDL, was twofold higher in patients with ALS than in control subjects. As a result, steatosis of the liver was more pronounced in patients with ALS than in patients with PD. Correlation studies demonstrated that bearing an abnormally elevated LDL/HDL ratio significantly increased survival by more than 12 months. Hyperlipidemia is a significant prognostic factor for survival of patients with amyotrophic lateral sclerosis. This finding highlights the importance of nutritional intervention strategies on disease progression and claims our attention when treating these patients with lipid-lowering drugs.
El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis
  • BR Brooks
El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis
  • B R Brooks
  • R G Miller
  • M Swash
  • BR Brooks