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IMPORTANCEThere is growing interest in the role of nutrition in the pathogenesis and progression of amyotrophic lateral sclerosis (ALS).OBJECTIVE To evaluate the associations between nutrients, individually and in groups, and ALS function and respiratory function at diagnosis. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional baseline analysis of the Amyotrophic Lateral Sclerosis Multicenter Cohort Study of Oxidative Stress study was conducted from March 14, 2008, to February 27, 2013, at 16 ALS clinics throughout the United States among 302 patients with ALS symptom duration of 18 months or less.EXPOSURES Nutrient intake, measured using a modified Block Food Frequency Questionnaire (FFQ).MAIN OUTCOMES AND MEASURES Amyotrophic lateral sclerosis function, measured using the ALS Functional Rating Scale-Revised (ALSFRS-R), and respiratory function, measured using percentage of predicted forced vital capacity (FVC).RESULTS Baseline data were available on 302 patients with ALS (median age, 63.2 years [interquartile range, 55.5-68.0 years]; 178 men and 124 women). Regression analysis of nutrients found that higher intakes of antioxidants and carotenes from vegetables were associated with higher ALSFRS-R scores or percentage FVC. Empirically weighted indices using the weighted quantile sum regression method of "good" micronutrients and "good" food groups were positively associated with ALSFRS-R scores (β [SE], 2.7 [0.69] and 2.9 [0.9], respectively) and percentage FVC (β [SE], 12.1 [2.8] and 11.5 [3.4], respectively) (all P < .001). Positive and significant associations with ALSFRS-R scores (β [SE], 1.5 [0.61]; P = .02) and percentage FVC (β [SE], 5.2 [2.2]; P = .02) for selected vitamins were found in exploratory analyses.CONCLUSIONS AND RELEVANCE Antioxidants, carotenes, fruits, and vegetables were associated with higher ALS function at baseline by regression of nutrient indices and weighted quantile sum regression analysis. We also demonstrated the usefulness of the weighted quantile sum regression method in the evaluation of diet. Those responsible for nutritional care of the patient with ALS should consider promoting fruit and vegetable intake since they are high in antioxidants and carotenes.

BackgroundThe objective of this study was to investigate cellular bioenergetics in primary skin fibroblasts derived from patients with amyotrophic lateral sclerosis (ALS) and to determine if they can be used as classifiers for patient stratification.MethodsWe assembled a collection of unprecedented size of fibroblasts from patients with sporadic ALS (sALS, n = 171), primary lateral sclerosis (PLS, n = 34), ALS/PLS with C9orf72 mutations (n = 13), and healthy controls (n = 91). In search for novel ALS classifiers, we performed extensive studies of fibroblast bioenergetics, including mitochondrial membrane potential, respiration, glycolysis, and ATP content. Next, we developed a machine learning approach to determine whether fibroblast bioenergetic features could be used to stratify patients.ResultsCompared to controls, sALS and PLS fibroblasts had higher average mitochondrial membrane potential, respiration, and glycolysis, suggesting that they were in a hypermetabolic state. Only membrane potential was elevated in C9Orf72 lines. ATP steady state levels did not correlate with respiration and glycolysis in sALS and PLS lines. Based on bioenergetic profiles, a support vector machine (SVM) was trained to classify sALS and PLS with 99% specificity and 70% sensitivity.ConclusionssALS, PLS, and C9Orf72 fibroblasts share hypermetabolic features, while presenting differences of bioenergetics. The absence of correlation between energy metabolism activation and ATP levels in sALS and PLS fibroblasts suggests that in these cells hypermetabolism is a mechanism to adapt to energy dissipation. Results from SVM support the use of metabolic characteristics of ALS fibroblasts and multivariate analysis to develop classifiers for patient stratification.Electronic supplementary materialThe online version of this article (10.1186/s13024-017-0217-5) contains supplementary material, which is available to authorized users.

Objective:To understand phenotypic and molecular characteristics of patients with clinically “definite” primary lateral sclerosis (PLS) in a prospective study.Methods:Six sites enrolled 41 patients who had pure upper motor neuron dysfunction, bulbar symptoms, a normal EMG done within 12 months of enrollment, and onset of symptoms ≥5 years before enrollment. For phenotypic analyses, 27 demographic, clinical, and cognitive variables were analyzed using the k-means clustering method. For molecular studies, 34 available DNA samples were tested for the C9ORF72 mutation, and exome sequencing was performed to exclude other neurologic diseases with known genetic cause.Results:K-means clustering using the 25 patients with complete datasets suggested that patients with PLS can be classified into 2 groups based on clinical variables, namely dysphagia, objective bulbar signs, and urinary urgency. Secondary analyses performed in all 41 patients and including only variables with complete data corroborated the results from the primary analysis. We found no evidence that neurocognitive variables are important in classifying patients with PLS. Molecular studies identified C9ORF72 expansion in one patient. Well-characterized pathogenic mutations were identified in SPG7, DCTN1, and PARK2. Most cases showed no known relevant mutations.Conclusions:Cluster analyses based on clinical variables indicated at least 2 subgroups of clinically definite PLS. Molecular analyses further identified 4 cases with mutations associated with amyotrophic lateral sclerosis, Parkinson disease, and possibly hereditary spastic paraplegia. Phenotypic and molecular characterization is the first step in investigating biological clues toward the definition of PLS. Further studies with larger numbers of patients are essential.

This investigation revealed high levels of cognitive and behavioral impairment in patients with ALS within 18 months of symptom onset, comparable to prior investigations. This investigation illustrates the successful use and scientific value of adding a cognitive-behavioral screening tool in studies of motor neuron diseases, to provide neurologists with an efficient method to measure these common deficits and to understand how they relate to key clinical variables, when extensive neuropsychological examinations are unavailable. These tools, developed specifically for patients with motor impairment, may be particularly useful in patient populations with multiple sclerosis and Parkinson disease, who are known to have comorbid cognitive decline.

Objective In a multicenter study of newly diagnosed ALS patients without a reported family history of ALS, we are prospectively investigating whether markers of oxidative stress (OS) are associated with disease progression. Methods An extensive structured telephone interview ascertained environmental, lifestyle, dietary and psychological risk factors associated with OS. Detailed assessments were performed at baseline and at 3 to 6 month intervals during the ensuing 30 months. Our biorepository includes DNA, plasma, urine, and skin. Results 355 patients were recruited. Subjects were enrolled over a 36 month-period at 16 sites. To meet the target number of subjects, the recruitment period was prolonged and additional sites were included. Demographic and disease characteristics were similar between 477 eligible/non-enrolled and enrolled patients, with the only difference being type of health insurance among enrolled patients. Sites were divided into 3 groups by the number of enrolled subjects. Comparing these 3 groups, the Columbia site had fewer “definite ALS” diagnoses. Conclusion This is the first prospective, interdisciplinary, in-depth, multicenter epidemiological investigation of OS related to ALS progression and was accomplished by an aggressive recruitment process. The baseline demographic and disease features of the study sample are now fully characterized.

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.

Objective To determine prevalence of depressive disorders and wish to die at the baseline visit of a longitudinal multi-site study of patients with ALS. Methods Structured telephone interviews were conducted with patients diagnosed in past 18 months at 16 U.S. ALS centers. Demographic, medical, psychiatric and other psychological measures were administered. Results Of 329 patients assessed, mean ALSFRS-R score was 36.6; 88% (289/329) had no depressive disorder, 7% (24/329)had minor depression, and 5% (16/329)had current major depressive disorder (DSM-IV criteria). Demographic, financial and employment factors were unrelated to depression, as were duration of ALS symptoms and respiratory status, although depressed patients had lower scores on the total ALSFRS-R ( p = .004) and gross motor function (p<.001). Depressed patients reported less pleasure, greater suffering, weariness and anxiety, more stress, were less hopeful, felt less control over illness management, reported lower quality of life, more often had thoughts about ending their lives and hastening death (all p<.001). Of the 62 patients (19% of the sample) who expressed a wish to die, only 37% (23/62) were clinically depressed. Conclusions Depressive disorders are not only to be expected of ALS patients. Wish to die is not always expressed in the context of depression and does not necessarily represent psychopathology as such.