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Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the degeneration of motor neurons for which effective therapies are lacking. One of the most explored areas of research in ALS is the discovery and validation of biomarkers that can be applied to clinical practice and incorporated into the development of innovative therapies. The study of biomarkers requires an adequate theoretical and operational framework, highlighting the "fit-for-purpose" concept and distinguishing different types of biomarkers based on common terminology. In this review, we aim to discuss the current status of fluid-based prognostic and predictive biomarkers in ALS, with particular emphasis on those that are the most promising ones for clinical trial design and routine clinical practice. Neurofilaments in cerebrospinal fluid and blood are the main prognostic and pharmacodynamic biomarkers. Furthermore, several candidates exist covering various pathological aspects of the disease, such as immune, metabolic and muscle damage markers. Urine has been studied less often and should be explored for its possible advantages. New advances in the knowledge of cryptic exons introduce the possibility of discovering new biomarkers. Collaborative efforts, prospective studies and standardized procedures are needed to validate candidate biomarkers. A combined biomarkers panel can provide a more detailed disease status.

Background: Low-dose interleukin-2 (ld-IL-2) enhances regulatory T-cell (Treg) function in auto-inflammatory conditions. Neuroinflammation being a pathogenic feature of amyotrophic lateral sclerosis (ALS), we evaluated the pharmacodynamics and safety of ld-IL-2 in ALS subjects., Methods: We performed a single centre, parallel three-arm, randomised, double-blind, placebo-controlled study. Eligibility criteria included age < 75 years, disease duration < 5 years, riluzole treatment > 3 months, and a slow vital capacity ≥ 70% of normal. Patients were randomised (1:1:1) to aldesleukin 2 MIU, 1 MIU, or placebo once daily for 5 days every 4 weeks for 3 cycles. Primary outcome was change from baseline in Treg percentage of CD4 + T cells (%Tregs) following a first cycle. Secondary laboratory outcomes included: %Treg and Treg number following repeated cycles, and plasma CCL2 and neurofilament light chain protein (NFL) concentrations as surrogate markers of efficacy. Safety outcomes included motor-function (ALSFRS-R), slow vital capacity (SVC), and adverse event reports. This trial is registered with ClinicalTrials.gov, NCT02059759., Findings: All randomised patients (12 per group), recruited from October 2015 to December 2015, were alive at the end of follow-up and included in the intent-to-treat (ITT) analysis. No drug-related serious adverse event was observed. Non-serious adverse events occurred more frequently with the 1 and 2 MIU IL-2 doses compared to placebo, including injection site reactions and flu-like symptoms. Primary outcome analysis showed a significant increase (p < 0·0001) in %Tregs in the 2 MIU and 1 MIU arms (mean [SD]: 2 MIU: +6·2% [2·2]; 1 MIU: +3·9% [1·2]) as compared to placebo (mean [SD]: -0·49% [1·3]). Effect sizes (ES) were large in treated groups: 2 MIU ES=3·7 (IC95%: 2·3-4·9) and 1 MIU ES=3·5 (IC95%: 2·1-4·6). Secondary outcomes showed a significant increase in %Tregs following repeated cycles (p < 0·0001) as compared to placebo, and a dose-dependent decrease in plasma CCL2 (p = 0·0049). There were no significant differences amongst the three groups on plasma NFL levels., Interpretation: Ld-IL-2 is well tolerated and immunologically effective in subjects with ALS. These results warrant further investigation into their eventual therapeutic impact on slowing ALS disease progression., Funding: The French Health Ministry (PHRC-I-14-056), EU H2020 (grant #633413), and the Association pour la Recherche sur la SLA (ARSLA)., Competing Interests: Declaration of Competing Interest Drs. Camu, Mickunas, Payan, Juntas Morales, Pageot, Masseguin, Suehs, De Vos, Saker, Andreasson and Veyrune have nothing to disclose. Dr. Bensimon reports grants from French Health Ministry (PHRC-I), ARSLA and EU HORIZON 2020, during the conduct of the study; in addition, Dr. Bensimon has a patent (WO 2012123381 A1) with royalties paid to Assistance Publique Hopitaux de Paris (APHP), Institut National de la Sante et de la Recherche Medicale INSERM, and Sorbonne Universite. Drs. Bensimon, Tree, Leigh, Locati, Garlanda, Shaw, Kirby, Malaspina have a patent (B75649EPD40021) pending. Dr. Malaspina reports grants from EU HORIZON 2020, grants from MND Association UK, grants and other from Barts and the London Charity, and from UCB Pharma SPRL, during the conduct of the study; and from F. Hoffmann-La Roche outside the submitted work. Dr. Zetterberg reports personal fees from Samumed, Roche Diagnostics, Denali, CogRx and Wave, outside the submitted work. Dr. Kirby reports grants from The Nimes University Hospital Center (CHU Nimes) and grants from EU HORIZON 2020, during the conduct of the study. Dr. Shaw reports grants from EU HORIZON 2020, Sheffield component and MIROCALS (633413), outside the submitted work. Dr. Al-Chalabi reports involvement as Chief Investigator for LEVALS clinical trial and European CI for REFALS clinical trial for OrionPharma, as well as consultancy from Mitsubishi Tanabe Pharma, consultancy and involvement in debating panel for Cytokinetics Inc, consultancy from Chronos Therapeutics, GSK, Lilly, and from Biogen Idec, outside the submitted work., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Motor Unit Number Index (MUNIX) is a quantitative neurophysiological method that reflects loss of motor neurons in Amyotrophic Lateral Sclerosis (ALS) in longitudinal studies. It has been utilized in one natural history ALS study and one drug trial (Biogen USA) after training and qualification of raters., Methods: Prior to testing patients, evaluators had to submit test-retest data of 4 healthy volunteers. Twenty-seven centres with 36 raters measured MUNIX in 4 sets of 6 different muscles twice. Coefficient of variation of all measurements had to be <20% to pass the qualification process. MUNIX COV of the first attempt, number of repeated measurements and muscle specific COV were evaluated., Results: COV varied considerably between raters. Mean COV of all raters at the first measurements was 12.9% ± 13.5 (median 8.7%). Need of repetitions ranged from 0 to 43 (mean 10.7 ± 9.1, median 8). Biceps and first dorsal interosseus muscles showed highest repetition rates. MUNIX variability correlated considerably with variability of compound muscle action potential., Conclusion: MUNIX revealed generally good reliability, but was rater dependent and ongoing support for raters was needed., Significance: MUNIX can be implemented in large clinical trials as an outcome measure after training and a qualification process., (Copyright © 2018 International Federation of Clinical Neurophysiology. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is one of the most severe motor neuron (MN) disorders in adults. Phenotype of ALS patients is highly variable and may be influenced by modulators of energy metabolism. Recent works have implicated the liver X receptors α and β (LXRs), either in the propagation process of ALS or in the maintenance of MN survival. LXRs are nuclear receptors activated by oxysterols, modulating cholesterol levels, a suspected modulator of ALS severity. In a cohort of 438 ALS patients and 330 healthy controls, the influence of LXR genes on ALS risk and phenotype was studied using single nucleotide polymorphisms (SNPs). The two LXRα SNPs rs2279238 and rs7120118 were shown to be associated with age at onset in ALS patients. Consistently, homozygotes were twice more correlated than were heterozygotes to delayed onset. The onset was thus delayed by 3.9 years for rs2279238 C/T carriers and 7.8 years for T/T carriers. Similar results were obtained for rs7120118 (+2.1 years and +6.7 years for T/C and C/C genotypes, respectively). The LXRβ SNP rs2695121 was also shown to be associated with a 30% increase of ALS duration (p = 0.0055, FDR = 0.044). The tested genotypes were not associated with ALS risk. These findings add further evidence to the suspected implication of LXR genes in the disease process of ALS and might open new perspectives in ALS therapeutics.

We report the third case of amyotrophic lateral sclerosis related to p.E121G Superoxide dismutase-1 (SOD1) mutation. Besides a sporadic presentation and a slow progressive course, as described in the 2 previously cases, our patient presented with prominent sensory and cerebellar signs. This case report strengthens that p.E121G should be considered as a causal mutation. Slowly upper and lower motor neuron degeneration, even with non-motor clinical features, should prompt a sequencing of SOD1.

Background/aims: To describe the use of peripherally inserted central catheter (PICC), in amyotrophic lateral sclerosis (ALS) at a later stage., Methods: Twenty-five ALS patients in the later stages of the disease underwent PICC insertion followed by parenteral nutrition (PN). For all of them, gastrostomy was non-feasible. Patients were followed until death and monitored for complications., Results: PICC insertion was successful in all patients. Three months after insertion, the mean body weight increased by 4.5% (p = 0.0057). PICC could be maintained until death in all but 1 patient. The mean delay between insertion and death was 4.5 months, but PN was administered for more than 1 year in 2 patients. Complications were noted in 6 patients: sepsis (n = 4), venous thrombosis (n = 1), and upper limb oedema (n = 1), none of them resulting in death., Conclusion: PICC insertion for PN at a later stage of ALS, in patients for whom gastrostomy is non-feasible, appears to be a useful option compared to the central venous catheter., (© 2016 S. Karger AG, Basel.)

Introduction: Amyotrophic lateral sclerosis (ALS) is the most common motor neurone disease. It occurs in two forms: (1) familial cases, for which several genes have been identified and (2) sporadic cases, for which various hypotheses have been formulated. Notably, the β-N-methylamino-L-alanine (L-BMAA) toxin has been postulated to be involved in the occurrence of sporadic ALS. The objective of the French BMAALS programme is to study the putative link between L-BMAA and ALS., Methods and Analysis: The programme covers the period from 1 January 2003 to 31 December 2011. Using multiple sources of ascertainment, all the incident ALS cases diagnosed during this period in the area under study (10 counties spread over three French regions) were collected. First, the standardised incidence ratio will be calculated for each municipality under concern. Then, by applying spatial clustering techniques, overincidence and underincidence zones of ALS will be sought. A case-control study, in the subpopulation living in the identified areas, will gather information about patients' occupations, leisure activities and lifestyle habits in order to assess potential risk factors to which they are or have been exposed. Specimens of drinking water, food and biological material (brain tissue) will be examined to assess the presence of L-BMAA in the environment and tissues of ALS cases and controls., Ethics and Dissemination: The study has been reviewed and approved by the French ethical committee of the CPP SOOM IV (Comité de Protection des Personnes Sud-Ouest & Outre-Mer IV). The results will be published in peer-reviewed journals and presented at national and international conferences., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

ALS is likely to be a disorder of multifactorial origin. Among all the factors that may increase the risk of ALS, environmental ones are being studied for many years, but in the recent years, several advances have pointed to a new interest in their potential involvement in the disease process, especially for the cyanotoxin BMAA. Food containing BMAA has been found on Guam, a well-known focus of ALS/parkinsonism/dementia and high levels of BMAA have been identified into the brain of these patients. The BMAA cyanotoxin is potentially ubiquitous and have also been found into the food of patients who died from ALS both in Europe and USA. BMAA can be wrongly integrated into the protein structure during mRNA traduction, competing with serine. This may induce abnormal protein folding and a subsequent cell death. Heavy metals, such as lead or mercury may be directly toxic for neuronal cells. Several works have suggested an increased risk of ALS in individuals chronically exposed to these metals. Exposure to pesticides has been suggested to be linked to an increased risk of developing ALS. The mechanism of their toxicity is likely to be mediated by paraoxonases. These proteins are in charge of detoxifying the organism from toxins, and particularly organophosphates. To date, there are insufficient scientific data to suggest that exposure to electromagnetic fields may increase the risk of having ALS. We are particularly missing longitudinal cohorts to demonstrate that risk., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is an incurable paralytic disorder primarily typified by the selective and progressive degeneration of motoneurons in the brain and spinal cord. ALS causes muscle wasting and atrophy, resulting eventually in respiratory failure and death within 3-5 years of diagnosis. Vitamin D is a potent secosteroid hormone with diverse biological functions that include protection against neuronal damage. The detrimental consequences of vitamin D dietary deficiency have been documented in other neurodegenerative diseases. However, the protective effect of vitamin D on motoneuron and the influence of its levels on disease course remains elusive. Here we found that the biologically active form of vitamin D significantly potentiated the effect of neurotrophic factors and prevented motoneurons from a Fas-induced death, while electrophysiological properties of motoneurons were not affected. In ALS patients, we report that a severe vitamin D deficiency accelerates by 4 times the rate of decline and were associated with a marked shorter life expectancy. Our findings support a neuroprotective function of vitamin D on motoneurons and propose vitamin D as a reliable prognostic factor of ALS., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. Prognosis is highly variable, ranging from few months to more than 30 years. 25OH vitamin D (25OH VD) blood levels have been associated with worse prognosis of ALS, but these results remain in dispute. We addressed this controversy with a prospective study and multivariate analysis to study the influence of known clinical prognostic factors of the disease and 25OH VD levels on Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) severity score (ALS-SS), as defined by the monthly rate of decline of ALSFRS-R score, to identify the factors most closely linked to the risk of worsening of the disease. Results: This prospective cohort of ALS patients recruited 127 individuals, and 105 of them met inclusion criteria. Mean age of onset was 62.2 ± 12.1 years, 32% of subjects had bulbar onset, and gender ratio was 1.44 (male/female). Mean 25OH VD level was 26.8 ± 10.8 ng/ml and was similar between males and females. Patients with 25OH VD levels <15 ng/ml had significantly higher ALS-SS at inclusion (ALS-SSi) than those with normal levels (>30 ng/ml), p = 0.011. The study of ALS-SS as calculated at the end of follow-up (ALS-SSe) was not found correlated to initial 25OH VD levels (r = −0.19; p = 0.084). Univariate analysis showed that ALS-SSe correlated with 25OH VD levels, ALS duration at inclusion, slow vital capacity (SVC) at inclusion, and SVC loss. Multivariate model showed that 25OH VD levels were independently associated with ALS-SSe: r = −0.0125, p = 0.033. Log rank test with Kaplan–Meier curves did not show significant differences of survival between the groups defined by 25OH VD levels: <15, >15 and <30, and > 30 ng/ml, p = 0.88. Conclusions: This prospective study in ALS patients confirmed previous retrospective results: ALS-SSi is significantly higher in patients with severe VD deficiency. For the first time, multivariate analysis showed that 25OH VD level was an independent prognostic factor correlated to ALS-SSe, suggesting that discrepancies between previous works could be due to confounders. It would be important that the present work be replicated in larger samples to confirm the present findings. [ABSTRACT FROM AUTHOR]

Background: In familial amyotrophic lateral sclerosis (ALS) cases, the presence of an abnormal C9ORF72 repeat expansion (C9RE) is the most frequent genetic cause identified. Various clinical phenotypes have been described in relation to the presence of C9RE, including psychiatric disorders or Huntington-like symptoms. In a subset of sporadic ALS, C9RE has also been described. In the present study, all index cases with ALS and C9RE identified in our center and their clinical profile, as well as neurological and psychiatric characteristics of identified family members, were described. Clinical characteristics of ALS patients were compared to 999 patients with sporadic ALS (SALS) from our database. Results: From the 70 index cases with ALS identified, a total of 200 individuals were studied, 118 with ALS, 32 with fronto-temporal lobe degeneration (FTD), 37 with ALS/FTD, and 13 with psychiatric disorders. A familial history was present in 57 of the index cases (81%). In ALS and ALS/FTD cases with C9RE, the age of onset (AoO) was earlier than that in SALS cases, p < 0.0001 and p = 0.008, respectively. Sporadic cases with C9REALS (n = 13) had an earlier AoO compared to familial C9REALS ones, p < 0.0001. Within families, there was an earlier AoO in index cases and their siblings compared to their parental generation (p < 0.01). There was also a significant intrafamilial correlation for bulbar onset of ALS. The parental generation had significant female predominance compared to index cases and their siblings (sex ratio 0.47 vs. 1.4, p = 0.004), and this predominance was also present when considering parent–child pairs. In the group with psychiatric disorders, suicide was prominent (n = 9) and mean age was 54 years. Conclusion: Although our sample size is rather limited, the earlier AoO in index cases and their siblings compared to the parental generation may suggest an anticipation. Reasons for predominance of female transmission are unclear, but the hypothesis that gender influences transmission of the genetic trait or C9RE size variation may be taken into account. Intrafamilial correlation suggests that genetic aspects underlie the occurrence of bulbar onset in ALS patients. Studies on larger samples are warranted to confirm those results. [ABSTRACT FROM AUTHOR]

Objective: Recently, the ASC-1 complex has been identified as a mechanistic link between amyotrophic lateral sclerosis and spinal muscular atrophy (SMA), and 3 mutations of the ASC-1 gene TRIP4 have been associated with SMA or congenital myopathy. Our goal was to define ASC-1 neuromuscular function and the phenotypical spectrum associated with TRIP4 mutations.Methods: Clinical, molecular, histological, and magnetic resonance imaging studies were made in 5 families with 7 novel TRIP4 mutations. Fluorescence activated cell sorting and Western blot were performed in patient-derived fibroblasts and muscles and in Trip4 knocked-down C2C12 cells.Results: All mutations caused ASC-1 protein depletion. The clinical phenotype was purely myopathic, ranging from lethal neonatal to mild ambulatory adult patients. It included early onset axial and proximal weakness, scoliosis, rigid spine, dysmorphic facies, cutaneous involvement, respiratory failure, and in the older cases, dilated cardiomyopathy. Muscle biopsies showed multiminicores, nemaline rods, cytoplasmic bodies, caps, central nuclei, rimmed fibers, and/or mild endomysial fibrosis. ASC-1 depletion in C2C12 and in patient-derived fibroblasts and muscles caused accelerated proliferation, altered expression of cell cycle proteins, and/or shortening of the G0/G1 cell cycle phase leading to cell size reduction.Interpretation: Our results expand the phenotypical and molecular spectrum of TRIP4-associated disease to include mild adult forms with or without cardiomyopathy, associate ASC-1 depletion with isolated primary muscle involvement, and establish TRIP4 as a causative gene for several congenital muscle diseases, including nemaline, core, centronuclear, and cytoplasmic-body myopathies. They also identify ASC-1 as a novel cell cycle regulator with a key role in cell proliferation, and underline transcriptional coregulation defects as a novel pathophysiological mechanism. ANN NEUROL 2020;87:217-232. [ABSTRACT FROM AUTHOR]

La sclérose latérale amyotrophique (SLA) est une maladie neuromusculaire de pronostic sévère, entraînant des troubles qui favorisent la survenue d'une dénutrition. Celle-ci est un facteur indépendant de survie dans cette maladie. Cependant, le tube digestif est le plus souvent fonctionnel. Pour des raisons de difficultés de mise en place d'une nutrition entérale, ou de refus des patients, la nutrition parentérale (NP) a été proposée dans certains cas. L'objectif de l'étude était de faire le point sur les données de la littérature concernant la NP lors de la SLA. Les divers articles de la littérature étaient analysés dans le cadre d'un atelier thématique interprofessionnel et d'une revue détaillée. Seulement trois articles sur ce sujet étaient retrouvés, tous d'origine française. Ils étaient mono ou multicentriques, représentaient 161 patients, et un seul article était en partie prospectif. Les patients étaient sélectionnés sur les indications usuelles de la NP ou la présence d'une capacité vitale < 50 %, ou l'association d'une démence frontotemporale. Les abords veineux centraux étaient des sites d'injection ou des cathéters insérés par voie périphérique (PICC lines). La surveillance était médico-diététique. Il s'agissait de patients dont l'évolution avait été longue, et leur durée de vie sous NP était très brève. La prévalence des infections liées à la NP était dans la fourchette des valeurs usuelles, et celle des thromboses était plus élevée. La qualité de vie des patients n'était pas précisée. La NP lors de la SLA est possible chez des patients en fin d'évolution. La technique devrait être réservée aux contre-indications de la nutrition entérale, mais une discussion au cas par cas est nécessaire. L'étude présente a permis de faire des propositions de recommandations pratiques. Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease with a severe prognosis, leading to disorders that promote the occurrence of undernutrition. This is an independent factor of survival in this disease. However, the digestive tract is most often functional. For reasons of difficulty in setting up enteral nutrition, or refusal of patients, parenteral nutrition (PN) has been proposed in some cases. The objective of the study was to review literature data regarding PN during ALS. The various articles in the literature were analyzed in the framework of an interprofessional thematic workshop and a detailed review. There were only three articles on this subject, all of French origin, mono or multicentric, and representing 161 patients. Only one article was in part prospective. Patients were selected on the usual indications of PN or the presence of a vital capacity < 50%, or the combination of frontotemporal dementia. Infusions were performed using injection sites or peripherally inserted central catheters (PICC lines). The supervision was medico-dietary. These were patients whose evolution had been long, and their life under PN was very short. The prevalence of PN-related infections was in the range of usual values, and that of thromboses was higher. The quality of life of patients was not specified. PN in ALS is possible in late-stage patients. The technique should be reserved for contraindications of enteral nutrition, but a case-by-case discussion is needed. The present study made proposals for practical recommendations. [ABSTRACT FROM AUTHOR]