Publications by authors named "Vincent Meininger"

136 Publications

Impact of a frequent nearsplice variant in amyotrophic lateral sclerosis: optimising genetic screening for gene therapy opportunities.

J Neurol Neurosurg Psychiatry 2021 Mar 30. Epub 2021 Mar 30.

Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM,Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, Île de France, France

Objective: Mutations in superoxide dismutase 1 gene (, encoding copper/zinc superoxide dismutase protein, are the second most frequent high penetrant genetic cause for amyotrophic lateral sclerosis (ALS) motor neuron disease in populations of European descent. More than 200 missense variants are reported along the SOD1 protein. To limit the production of these aberrant and deleterious SOD1 species, antisense oligonucleotide approaches have recently emerged and showed promising effects in clinical trials. To offer the possibility to any patient with SOD1-ALS to benefit of such a gene therapy, it is necessary to ascertain whether any variant of unknown significance (VUS), detected for example in non-coding sequences, is pathogenic.

Methods: We analysed SOD1 mutation distribution after SOD1 sequencing in a large cohort of 470 French familial ALS (fALS) index cases.

Results: We identified a total of 27 SOD1 variants in 38 families including two SOD1 variants located in nearsplice or intronic regions of the gene. The pathogenicity of the c.358-10T>G nearsplice variant was corroborated based on its high frequency (as the second most frequent SOD1 variant) in French fALS, the segregation analysis confirmed in eight affected members of a large pedigree, the typical SOD1-related phenotype observed (with lower limb onset and prominent lower motor neuron involvement), and findings on postmortem tissues showing SOD1 misaccumulation.

Conclusions: Our results highlighted nearsplice/intronic mutations in are responsible for a significant portion of French fALS and suggested the systematic analysis of the mRNA sequence could become the method of choice for screening, not to miss these specific cases.
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http://dx.doi.org/10.1136/jnnp-2020-325921DOI Listing
March 2021

Effect of familial clustering in the genetic screening of 235 French ALS families.

J Neurol Neurosurg Psychiatry 2021 May 6;92(5):479-484. Epub 2021 Jan 6.

Biochemistry and Molecular Biology Department, Université Francois-Rabelais de Tours, Tours, Centre-Val de Loire, France.

Objectives: To determine whether the familial clustering of amyotrophic lateral sclerosis (ALS) cases and the phenotype of the disease may help identify the pathogenic genes involved.

Methods: We conducted a targeted next-generation sequencing analysis on 235 French familial ALS (FALS), unrelated probands to identify mutations in 30 genes linked to the disease. The genealogy, that is, number of cases and generations with ALS, gender, age, site of onset and the duration of the disease were analysed.

Results: Regarding the number of generations, 49 pedigrees had only one affected generation, 152 had two affected generations and 34 had at least three affected generations. Among the 149 pedigrees (63.4%) for which a deleterious variant was found, an abnormal G4C2 expansion in was found in 98 cases as well as , or mutations in 30, 9 and 7 cases, respectively. Considering pedigrees from the number of generations, abnormal G4C2 expansion in was more frequent in pedigrees with pairs of affected ALS cases, which represented 65.2% of our cohort. mutation involved all types of pedigrees. No nor mutation was present in monogenerational pedigrees. mutation predominated in bigenerational pedigrees with at least three cases and mutation in multigenerational pedigrees with more than seven cases, on average, and with an age of onset younger than 45 years.

Conclusion: Our results suggest that familial clustering, phenotypes and genotypes are interconnected in FALS, and thus it might be possible to target the genetic screening from the familial architecture and the phenotype of ALS cases.
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http://dx.doi.org/10.1136/jnnp-2020-325064DOI Listing
May 2021

Use of a modular ontology and a semantic annotation tool to describe the care pathway of patients with amyotrophic lateral sclerosis in a coordination network.

PLoS One 2021 6;16(1):e0244604. Epub 2021 Jan 6.

Laboratoire d'Informatique Médicale et d'IngéInierie des Connaissances en e-Santé UMR-1142, Sorbonne Université, INSERM, Université Paris 13, Paris, France.

The objective of this study was to describe the care pathway of patients with amyotrophic lateral sclerosis (ALS) based on real-life textual data from a regional coordination network, the Ile-de-France ALS network. This coordination network provides care for 92% of patients diagnosed with ALS living in Ile-de-France. We developed a modular ontology (OntoPaRON) for the automatic processing of these unstructured textual data. OntoPaRON has different modules: the core, medical, socio-environmental, coordination, and consolidation modules. Our approach was unique in its creation of fully defined concepts at different levels of the modular ontology to address specific topics relating to healthcare trajectories. We also created a semantic annotation tool specific to the French language and the specificities of our corpus, the Ontology-Based Semantic Annotation Module (OnBaSAM), using the OntoPaRON ontology as a reference. We used these tools to annotate the records of 928 patients automatically. The semantic (qualitative) annotations of the concepts were transformed into quantitative data. By using these pipelines we were able to transform unstructured textual data into structured quantitative data. Based on data processing, semantic annotations, sociodemographic data for the patient and clinical variables, we found that the need and demand for human and technical assistance depend on the initial form of the disease, the motor state, and the patient age. The presence of exhaustion in care management, is related to the patient's motor and cognitive state.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244604PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787442PMC
May 2021

Genetic screening of ANXA11 revealed novel mutations linked to amyotrophic lateral sclerosis.

Neurobiol Aging 2021 03 23;99:102.e11-102.e20. Epub 2020 Oct 23.

Institut du Cerveau et de la Moelle épinière, ICM, Inserm U1127, CNRS UMR7225, Sorbonne Université, UPMC Univ Paris 6 UMRS1127, Paris, France. Electronic address:

ANXA11 mutations have previously been discovered in amyotrophic lateral sclerosis (ALS) motor neuron disease. To confirm the contribution of ANXA11 mutations to ALS, a large exome data set obtained from 330 French patients, including 150 familial ALS index cases and 180 sporadic ALS cases, was analyzed, leading to the identification of 3 rare ANXA11 variants in 5 patients. The novel p.L254V variant was associated with early onset sporadic ALS. The novel p.D40Y mutation and the p.G38R variant concerned patients with predominant pyramidal tract involvement and cognitive decline. Neuropathologic findings in a p.G38R carrier associated the presence of ALS typical inclusions within the spinal cord, massive degeneration of the lateral tracts, and type A frontotemporal lobar degeneration. This mutant form of annexin A11 accumulated in various brain regions and in spinal cord motor neurons, although its stability was decreased in patients' lymphoblasts. Because most ANXA11 inclusions were not colocalized with transactive response DNA-binding protein 43 or p62 deposits, ANXA11 aggregation does not seem mandatory to trigger neurodegeneration with additional participants/partner proteins that could intervene.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.10.015DOI Listing
March 2021

Grey Matter 150th anniversary of Charcot's description of amyotrophic lateral sclerosis.

Brain 2019 10;142(10):3306-3313

Hôpital des Peupliers, Ramsay Générale de Santé, Paris, France.

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http://dx.doi.org/10.1093/brain/awz280DOI Listing
October 2019

Using Equivalent Classes of an Ontology to Understand Care Pathway in Amyotrophic Lateral Sclerosis.

Stud Health Technol Inform 2019 Jul;262:93-96

Sorbonne Université, INSERM, Univ. Paris 13, LIMICS, Paris, France.

To understand the home-based difficulties encountered in the health care pathways of patients with Amyotrophic Lateral Sclerosis (ALS), we must annotate a large amount of textual data, from a database created by the ALS Île de France coordination network. For this purpose, we have developed a modular ontology, consisting of four modules, and a semantic annotation tool integrating the created ontology. The specificity of our approach is the creation of equivalent classes at different levels of the ontology. These equivalent classes represent variables of interest allowing a statistical approach and a clinical analysis of comprehension of care pathways ruptures causing.
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http://dx.doi.org/10.3233/SHTI190025DOI Listing
July 2019

A ferroptosis-based panel of prognostic biomarkers for Amyotrophic Lateral Sclerosis.

Sci Rep 2019 02 27;9(1):2918. Epub 2019 Feb 27.

Biomedical Imaging Laboratory, CNRS, INSERM, Sorbonne University, Paris, France.

Accurate patient stratification into prognostic categories and targeting Amyotrophic Lateral Sclerosis (ALS)-associated pathways may pave the way for promising trials. We evaluated blood-based prognostic indicators using an array of pathological markers. Plasma samples were collected as part of a large, phase III clinical trial (Mitotarget/TRO19622) at months 1, 6, 12 and 18. The ALSFRS-r score was used as a proxy of disease progression to assess the predictive value of candidate biological indicators. First, established clinical predictors were evaluated in all 512 patients. Subsequently, pathologic markers, such as proxies of neuronal integrity (Neurofilament light chain and phosphorylated heavy chain), DNA oxidation (8-oxo-2'-desoxyguanosine), lipid peroxidation (4-hydroxy-2-nonenal, isoprostane), inflammation (interleukin-6) and iron status (ferritin, hepcidin, transferrin) were assessed in a subset of 109 patients that represented the whole cohort. Markers of neuronal integrity, DNA and lipid oxidation, as well as iron status at baseline are accurate predictors of disability at 18-month follow-up. The composite scores of these markers in association with established clinical predictors enable the accurate forecasting of functional decline. The identified four biomarkers are all closely associated with 'ferroptosis', a recently discovered form of programmed cell death with promising therapeutic targets. The predictive potential of these pathophysiology-based indicators may offer superior patient stratification for future trials, individualised patient care and resource allocation.
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http://dx.doi.org/10.1038/s41598-019-39739-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393674PMC
February 2019

The spinal and cerebral profile of adult spinal-muscular atrophy: A multimodal imaging study.

Neuroimage Clin 2019 28;21:101618. Epub 2018 Nov 28.

Sorbonne Université, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale, Paris, France; APHP, Département de Neurologie, Hôpital Pitié-Salpêtrière, Centre référent SLA, Paris, France; Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute Ulster University, C-TRIC, Altnagelvin Hospital, Derry, Londonderry, United Kingdom. Electronic address:

Spinal muscular atrophy (SMA) type III and IV are autosomal recessive, slowly progressive lower motor neuron syndromes. Nevertheless, wider cerebral involvement has been consistently reported in mouse models. The objective of this study is the characterisation of spinal and cerebral pathology in adult forms of SMA using multimodal quantitative imaging.

Methods: Twenty-five type III and IV adult SMA patients and 25 age-matched healthy controls were enrolled in a spinal cord and brain imaging study. Structural measures of grey and white matter involvement and diffusion parameters of white matter integrity were evaluated at each cervical spinal level. Whole-brain and region-of-interest analyses were also conducted in the brain to explore cortical thickness, grey matter density and tract-based white matter alterations.

Results: In the spinal cord, considerable grey matter atrophy was detected between C2-C6 vertebral levels. In the brain, increased grey matter density was detected in motor and extra-motor regions of SMA patients. No white matter pathology was identified neither at brain and spinal level.

Conclusions: Adult forms of SMA are associated with selective grey matter degeneration in the spinal cord with preserved white matter integrity. The observed increased grey matter density in the motor cortex may represent adaptive reorganisation.
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http://dx.doi.org/10.1016/j.nicl.2018.101618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413472PMC
December 2019

The motor unit number index (MUNIX) profile of patients with adult spinal muscular atrophy.

Clin Neurophysiol 2018 11 13;129(11):2333-2340. Epub 2018 Sep 13.

Sorbonne Université, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale, Paris, France; APHP, Département de Neurologie, Hôpital Pitié-Salpêtrière, Centre référent SLA, Paris, France; Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute Ulster University, C-TRIC, Altnagelvin Hospital, Derry/Londonderry, United Kingdom. Electronic address:

Objective: Objective of this study is the comprehensive characterisation of motor unit (MU) loss in type III and IV Spinal Muscular Atrophy (SMA) using motor unit number index (MUNIX), and evaluation of compensatory mechanisms based on MU size indices (MUSIX).

Methods: Nineteen type III and IV SMA patients and 16 gender- and age-matched healthy controls were recruited. Neuromuscular performance was evaluated by muscle strength testing and functional scales. Compound motor action potential (CMAP), MUNIX and MUSIX were studied in the abductor pollicis brevis (APB), abductor digiti minimi (ADM), deltoid, tibialis anterior and trapezius muscles. A composite MUNIX score was also calculated.

Results: SMA patients exhibited significantly reduced MUNIX values (p < 0.05) in all muscles, while MUSIX was increased, suggesting active re-innervation. Significant correlations were identified between MUNIX/MUSIX and muscle strength. Similarly, composite MUNIX scores correlated with disability scores. Interestingly, in SMA patients MUNIX was much lower in the ADM than in the ABP, a pattern which is distinctly different from that observed in Amyotrophic Lateral Sclerosis.

Conclusions: MUNIX is a sensitive measure of MU loss in adult forms of SMA and correlates with disability.

Significance: MUNIX evaluation is a promising candidate biomarker for longitudinal studies and pharmacological trials in adult SMA patients.
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http://dx.doi.org/10.1016/j.clinph.2018.08.025DOI Listing
November 2018

Extrapyramidal deficits in ALS: a combined biomechanical and neuroimaging study.

J Neurol 2018 Sep 11;265(9):2125-2136. Epub 2018 Jul 11.

Laboratoire CeRSM - EA 2931 Paris Ouest, Nanterre, France.

Introduction: Extrapyramidal deficits are poorly characterised in amyotrophic lateral sclerosis (ALS) despite their contribution to functional disability, increased fall risk and their quality-of-life implications. Given the concomitant pyramidal and cerebellar degeneration in ALS, the clinical assessment of extrapyramidal features is particularly challenging.

Objective: The comprehensive characterisation of postural instability in ALS using standardised clinical assessments, gait analyses and computational neuroimaging tools in a prospective study design.

Methods: Parameters of gait initiation in the anticipatory postural adjustment phase (APA) and execution phase (EP) were evaluated in ALS patients with and without postural instability and healthy controls. Clinical and gait analysis parameters were interpreted in the context of brain imaging findings.

Results: ALS patients with postural instability exhibit impaired gait initiation with an altered APA phase, poor dynamic postural control and significantly decreased braking index. Consistent with their clinical profile, "unsteady" ALS patients have reduced caudate and brain stem volumes compared to "steady" ALS patients.

Interpretation: Our findings highlight that the ALS functional rating scale (ALSFRS-r) does not account for extrapyramidal deficits, which are major contributors to gait impairment in a subset of ALS patients. Basal ganglia degeneration in ALS does not only contribute to cognitive and behavioural deficits, but also adds to the heterogeneity of motor disability.
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http://dx.doi.org/10.1007/s00415-018-8964-yDOI Listing
September 2018

A pharmaco-metabolomics approach in a clinical trial of ALS: Identification of predictive markers of progression.

PLoS One 2018 5;13(6):e0198116. Epub 2018 Jun 5.

Département des Maladies du Système Nerveux, Centre Référent Maladie Rare SLA, Hôpital de la Pitié-Salpétrière, Paris, France.

There is an urgent and unmet need for accurate biomarkers in Amyotrophic Lateral Sclerosis. A pharmaco-metabolomics study was conducted using plasma samples from the TRO19622 (olesoxime) trial to assess the link between early metabolomic profiles and clinical outcomes. Patients included in this trial were randomized into either Group O receiving olesoxime (n = 38) or Group P receiving placebo (n = 36). The metabolomic profile was assessed at time-point one (V1) and 12 months (V12) after the initiation of the treatment. High performance liquid chromatography coupled with tandem mass spectrometry was used to quantify 188 metabolites (Biocrates® commercial kit). Multivariate analysis based on machine learning approaches (i.e. Biosigner algorithm) was performed. Metabolomic profiles at V1 and V12 and changes in metabolomic profiles between V1 and V12 accurately discriminated between Groups O and P (p<5×10-6), and identified glycine, kynurenine and citrulline/arginine as the best predictors of group membership. Changes in metabolomic profiles were closely linked to clinical progression, and correlated with glutamine levels in Group P and amino acids, lipids and spermidine levels in Group O. Multivariate models accurately predicted disease progression and highlighted the discriminant role of sphingomyelins (SM C22:3, SM C24:1, SM OH C22:2, SM C16:1). To predict SVC from SM C24:1 in group O and SVC from SM OH C22:2 and SM C16:1 in group P+O, we noted a median sensitivity between 67% and 100%, a specificity between 66.7 and 71.4%, a positive predictive value between 66 and 75% and a negative predictive value between 70% and 100% in the test sets. This proof-of-concept study demonstrates that the metabolomics has a role in evaluating the biological effect of an investigational drug and may be a candidate biomarker as a secondary outcome measure in clinical trials.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198116PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988280PMC
January 2019

A Modular Ontology for Modeling Service Provision in a Communication Network for Coordination of Care.

Stud Health Technol Inform 2018 ;247:890-894

INSERM, U1142, LIMICS, F-75006, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S1142, LIMICS, F-75006 Paris, France; Université Paris 13, Sorbonne Paris Cité, LIMICS (UMR_S 1142), F-93430, Villetaneuse, France.

This paper presents a modular ontology of health care in the context in Amyotrophic Lateral Sclerosis. 4 modules cover socio-environmental, medical, and care coordination aspects of the domain. They are organized by a core module. Its goal is to understand interruptions in health care provision in the context of a neurodegenerative disease.
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June 2018

Phenotypic and genotypic studies of ALS cases in ALS-SMA families.

Amyotroph Lateral Scler Frontotemporal Degener 2018 08 1;19(5-6):432-437. Epub 2018 Mar 1.

k Clinique du Motoneurone, Explorations neurologiques, CHU Gui de Chauliac , Université de Montpellier , Montpellier , France.

Background: Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the most frequent motor neuron disorders in adulthood and infancy, respectively. There is a growing literature supporting common pathophysiological patterns between those disorders. One important clinical issue for that is the co-occurrence of both diseases within a family.

Objectives: To collect families in which ALS and SMA patients co-exist and describe the phenotype and the genotype of ALS patients.

Patients And Methods: Nine families with co-occurrence of SMA and ALS have been gathered over the last 15 years. Epidemiological, phenotype and genetic status were collected.

Results: Out of the nine families, six corresponded to the criteria of familial ALS (FALS). Clinical data were available for 11 patients out of the 15 ALS cases. Mean age of onset was 58.5 years, site of onset was lower limbs in nine cases (81.8%), median duration was 22 months. Four ALS patients carried a mutation: three mutations in SOD1 gene (G147N in two cases and one with E121G) and one repeat expansion in the C9ORF72 gene. Three patients had abnormal SMN1 copy numbers.

Conclusions: While the high proportion of familial history of ALS cases in these ALS-SMA pedigrees could have suggested that these familial clusters of the two most frequent MND rely on a genetic background, we failed to exclude that this occurred by chance.
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http://dx.doi.org/10.1080/21678421.2018.1440406DOI Listing
August 2018

Novel UBQLN2 mutations linked to amyotrophic lateral sclerosis and atypical hereditary spastic paraplegia phenotype through defective HSP70-mediated proteolysis.

Neurobiol Aging 2017 10 24;58:239.e11-239.e20. Epub 2017 Jun 24.

Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 6 UMRS1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France. Electronic address:

Mutations in UBQLN2 have been associated with rare cases of X-linked juvenile and adult forms of amyotrophic lateral sclerosis (ALS) and ALS linked to frontotemporal dementia (FTD). Here, we report 1 known (c.1489C>T, p.Pro497Ser, P497S) and 3 novel (c.1481C>T, p.Pro494Leu, P494L; c.1498C>T, p.Pro500Ser, P500S; and c.1516C>G, p.Pro506Ala, P506A) missense mutations in the PXX domain of UBQLN2 in familial motor neuron diseases including ALS and spastic paraplegia (SP). A novel missense mutation (c.1462G>A, p.Ala488Thr, A488T) adjacent to this hotspot UBQLN2 domain was identified in a sporadic case of ALS. These mutations are conserved in mammals, are absent from ExAC and gnomAD browsers, and are predicted to be deleterious by SIFT in silico analysis. Patient lymphoblasts carrying a UBQLN2 mutation showed absence of ubiquilin-2 accumulation, disrupted binding with HSP70, and impaired autophagic pathway. Our results confirm the role of PXX repeat in ALS pathogenesis, show that UBQLN2-linked disease can manifest like a SP phenotype, evidence a highly reduced disease penetrance in females carrying UBQLN2 mutations, which is important information for genetic counseling, and underline the pivotal role of ubiquilin-2 in proteolysis regulation pathways.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.06.018DOI Listing
October 2017

Safety and efficacy of ozanezumab in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled, phase 2 trial.

Lancet Neurol 2017 03 28;16(3):208-216. Epub 2017 Jan 28.

Neurosciences Therapy Area Unit, GlaxoSmithKline, Uxbridge, UK. Electronic address:

Background: Neurite outgrowth inhibitor A (Nogo-A) is thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). A monoclonal antibody against Nogo-A showed a positive effect in the SOD1 mouse model of ALS, and a humanised form of this antibody (ozanezumab) was well tolerated in a first-in-human trial. Therefore, we aimed to assess the safety and efficacy of ozanezumab in patients with ALS.

Methods: This randomised, double-blind, placebo-controlled, phase 2 trial was done in 34 centres in 11 countries. Patients aged 18-80 years with a diagnosis of familial or sporadic ALS were randomly assigned (1:1), centrally according to a computer-generated allocation schedule, to receive ozanezumab (15 mg/kg) or placebo as intravenous infusions over 1 h every 2 weeks for 46 weeks, followed by assessments at week 48 and week 60. Patients and study personnel were masked to treatment assignment. The primary outcome was a joint-rank analysis of function (ALS Functional Rating Scale-Revised) and overall survival, analysed at 48 weeks in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01753076, and with GSK-ClinicalStudyRegister.com, NOG112264, and is completed.

Findings: Between Dec 20, 2012, and Nov 1, 2013, we recruited 307 patients, of whom 303 were randomly assigned to receive placebo (n=151) or ozanezumab (n=152). The adjusted mean of the joint-rank score was -14·9 (SE 13·5) for the ozanezumab group and 15·0 (13·6) for the placebo group, with a least squares mean difference of -30·0 (95% CI -67·9 to 7·9; p=0·12). Overall, reported adverse events, serious adverse events, and adverse events leading to permanent discontinuation of study drug or withdrawal from study were similar between the treatment groups, except for dyspepsia (ten [7%] in the ozanezumab group vs four [3%] in the placebo group), depression (11 [7%] vs five [3%]), and diarrhoea (25 [16%] vs 12 [8%]). Respiratory failure was the most common serious adverse event (12 [8%] vs seven [5%]). At week 60, the number of deaths was higher in the ozanezumab group (20 [13%]) than in the placebo group (16 [11%]), mainly as a result of respiratory failure (ten [7%] vs five [3%]). Two deaths were considered related to the study drug (bladder transitional cell carcinoma in the ozanezumab group and cerebrovascular accident in the placebo group).

Interpretation: Ozanezumab did not show efficacy compared with placebo in patients with ALS. Therefore, Nogo-A does not seem to be an effective therapeutic target in ALS.

Funding: GlaxoSmithKline.
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http://dx.doi.org/10.1016/S1474-4422(16)30399-4DOI Listing
March 2017

ATXN2 trinucleotide repeat length correlates with risk of ALS.

Neurobiol Aging 2017 03 24;51:178.e1-178.e9. Epub 2016 Nov 24.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

We investigated a CAG trinucleotide repeat expansion in the ATXN2 gene in amyotrophic lateral sclerosis (ALS). Two new case-control studies, a British dataset of 1474 ALS cases and 567 controls, and a Dutch dataset of 1328 ALS cases and 691 controls were analyzed. In addition, to increase power, we systematically searched PubMed for case-control studies published after 1 August 2010 that investigated the association between ATXN2 intermediate repeats and ALS. We conducted a meta-analysis of the new and existing studies for the relative risks of ATXN2 intermediate repeat alleles of between 24 and 34 CAG trinucleotide repeats and ALS. There was an overall increased risk of ALS for those carrying intermediate sized trinucleotide repeat alleles (odds ratio 3.06 [95% confidence interval 2.37-3.94]; p = 6 × 10), with an exponential relationship between repeat length and ALS risk for alleles of 29-32 repeats (R = 0.91, p = 0.0002). No relationship was seen for repeat length and age of onset or survival. In contrast to trinucleotide repeat diseases, intermediate ATXN2 trinucleotide repeat expansion in ALS does not predict age of onset but does predict disease risk.
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http://dx.doi.org/10.1016/j.neurobiolaging.2016.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302215PMC
March 2017

Early diaphragm pacing in patients with amyotrophic lateral sclerosis (RespiStimALS): a randomised controlled triple-blind trial.

Lancet Neurol 2016 Nov 11;15(12):1217-1227. Epub 2016 Oct 11.

Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Service de Pneumologie et Réanimation Médicale (Département "R3S"), Paris, France.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder associated with respiratory muscle weakness and respiratory failure. Non-invasive ventilation alleviates respiratory symptoms and prolongs life, but is a palliative intervention. Slowing the deterioration of diaphragm function before respiratory failure would be desirable. We aimed to assess whether early diaphragm pacing could slow down diaphragm deterioration and would therefore delay the need for non-invasive ventilation.

Methods: We did a multicentre, randomised, controlled, triple-blind trial in patients with probable or definite ALS in 12 ALS centres in France. The main inclusion criterion was moderate respiratory involvement (forced vital capacity 60-80% predicted). Other key eligibility criteria were age older than 18 years and bilateral responses of the diaphragm to diagnostic phrenic stimulation. All patients were operated laparoscopically and received phrenic stimulators. Clinicians randomly assigned patients (1:1) to receive either active or sham stimulation with a central web-based randomisation system (computer-generated list). Investigators, patients, and an external outcome allocation committee were masked to treatment. The primary outcome was non-invasive ventilation-free survival, analysed in the intention-to-treat population. Safety outcomes were also assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01583088.

Findings: Between Sept 27, 2012, and July 8, 2015, 74 participants were randomly assigned to receive either active (n=37) or sham (n=37) stimulation. On July 16, 2015, an unplanned masked analysis was done after another trial showed excess mortality with diaphragm pacing in patients with hypoventilation (DiPALS, ISRCTN 53817913). In view of this finding, we analysed mortality in our study and found excess mortality (death from any cause) in our active stimulation group. We therefore terminated the study on July, 16, 2015. Median non-invasive ventilation-free survival was 6·0 months (95% CI 3·6-8·7) in the active stimulation group versus 8·8 months (4·2-not reached) in the control (sham stimulation) group (hazard ratio 1·96 [95% CI 1·08-3·56], p=0·02). Serious adverse events (mainly capnothorax or pneumothorax, acute respiratory failure, venous thromboembolism, and gastrostomy) were frequent (24 [65%] patients in the active stimulation group vs 22 [59%] patients in the control group). No treatment-related death was reported.

Interpretation: Early diaphragm pacing in patients with ALS and incipient respiratory involvement did not delay non-invasive ventilation and was associated with decreased survival. Diaphragm pacing is not indicated at the early stage of the ALS-related respiratory involvement.

Funding: Hospital Program for Clinical Research, French Ministry of Health; French Patients' Association for ALS Research (Association pour la Recherche sur la Sclérose Latérale Amyotrophique); and Thierry de Latran Foundation.
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http://dx.doi.org/10.1016/S1474-4422(16)30233-2DOI Listing
November 2016

Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.

Nat Genet 2016 09 25;48(9):1043-8. Epub 2016 Jul 25.

Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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http://dx.doi.org/10.1038/ng.3622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556360PMC
September 2016

Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis.

JAMA Neurol 2016 07;73(7):812-20

Academic Neurology Unit, Department of Neuroscience, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield, England.

Importance: Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder with a poor prognosis and a median survival of 3 years. However, a significant proportion of patients survive more than 10 years from symptom onset.

Objective: To identify gene variants influencing survival in ALS.

Design, Setting, And Participants: This genome-wide association study (GWAS) analyzed survival in data sets from several European countries and the United States that were collected by the Italian Consortium for the Genetics of ALS and the International Consortium on Amyotrophic Lateral Sclerosis Genetics. The study population included 4256 patients with ALS (3125 [73.4%] deceased) with genotype data extended to 7 174 392 variants by imputation analysis. Samples of DNA were collected from January 1, 1993, to December 31, 2009, and analyzed from March 1, 2014, to February 28, 2015.

Main Outcomes And Measures: Cox proportional hazards regression under an additive model with adjustment for age at onset, sex, and the first 4 principal components of ancestry, followed by meta-analysis, were used to analyze data. Survival distributions for the most associated genetic variants were assessed by Kaplan-Meier analysis.

Results: Among the 4256 patients included in the analysis (2589 male [60.8%] and 1667 female [39.2%]; mean [SD] age at onset, 59 [12] years), the following 2 novel loci were significantly associated with ALS survival: at 10q23 (rs139550538; P = 1.87 × 10-9) and in the CAMTA1 gene at 1p36 (rs2412208, P = 3.53 × 10-8). At locus 10q23, the adjusted hazard ratio for patients with the rs139550538 AA or AT genotype was 1.61 (95% CI, 1.38-1.89; P = 1.87 × 10-9), corresponding to an 8-month reduction in survival compared with TT carriers. For rs2412208 CAMTA1, the adjusted hazard ratio for patients with the GG or GT genotype was 1.17 (95% CI, 1.11-1.24; P = 3.53 × 10-8), corresponding to a 4-month reduction in survival compared with TT carriers.

Conclusions And Relevance: This GWAS robustly identified 2 loci at genome-wide levels of significance that influence survival in patients with ALS. Because ALS is a rare disease and prevention is not feasible, treatment that modifies survival is the most realistic strategy. Therefore, identification of modifier genes that might influence ALS survival could improve the understanding of the biology of the disease and suggest biological targets for pharmaceutical intervention. In addition, genetic risk scores for survival could be used as an adjunct to clinical trials to account for the genetic contribution to survival.
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http://dx.doi.org/10.1001/jamaneurol.2016.1114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556366PMC
July 2016

Semantic and nonfluent aphasic variants, secondarily associated with amyotrophic lateral sclerosis, are predominant frontotemporal lobar degeneration phenotypes in TBK1 carriers.

Alzheimers Dement (Amst) 2015 Dec 30;1(4):481-6. Epub 2015 Oct 30.

Institut du Cerveau et de la Moelle épinière (ICM), CNRS UMR 7225, INSERM U 1127, Sorbonne Universités, Université Pierre et Marie, Univ Paris 06, UPMC-P6 UMR S 1127 - Hôpital Pitié-Salpêtrière, Paris, France; APHP, Département des Maladies du Système Nerveux, Hôpital de la Salpêtrière, Paris, France; Centre de Référence des Démences Rares, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France.

Introduction: TBK1 mutations represent a rare novel genetic cause of amyotrophic lateral sclerosis (ALS) without or with dementia. The full spectrum of TBK1 phenotypes has not been completely defined so far.

Methods: We describe the clinical and neuroimaging characteristics of loss-of-function mutation carriers initially presenting with frontotemporal lobar degeneration (FTLD) phenotypes.

Results: Two carriers initially presented semantic variant of FTLD (svFTLD); two other developed nonfluent variant of FTLD (nfvFTLD) and corticobasal syndrome (CBS), associated with severe anterior temporal and opercular atrophy. All secondarily developed ALS.

Discussion: This study enlarges the phenotypic spectrum of TBK1 mutations, including svFTLD and nfvFTLD/CBS, not reported so far. Aphasic presentations seem to be more evocative of TBK1 genotype than behavioral variant of FTLD, and TBK1 should be analyzed in patients with isolated FTLD at onset, particularly in rare aphasic cases secondarily associated with ALS.
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http://dx.doi.org/10.1016/j.dadm.2015.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879495PMC
December 2015

Unusual association of amyotrophic lateral sclerosis and myasthenia gravis: A dysregulation of the adaptive immune system?

Neuromuscul Disord 2016 06 29;26(6):342-6. Epub 2016 Mar 29.

APHP, Hôpital Pitié-Salpêtrière, Département des Maladies du Système Nerveux, Centre référent SLA, Paris, France; Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France. Electronic address:

Myasthenia gravis is an autoimmune disorder affecting neuromuscular junctions that has been associated with a small increased risk of amyotrophic lateral sclerosis (ALS). Here, we describe a retrospective series of seven cases with a concomitant diagnosis of ALS and myasthenia gravis, collected among the 18 French reference centers for ALS in a twelve year period. After careful review, only six patients strictly met the diagnostic criteria for both ALS and myasthenia gravis. In these patients, limb onset of ALS was reported in five (83%) cases. Localization of myasthenia gravis initial symptoms was ocular in three (50%) cases, generalized in two (33%) and bulbar in one (17%). Median delay between onset of the two conditions was 19 months (6-319 months). Anti-acetylcholine receptor antibodies testing was positive in all cases. All patients were treated with riluzole and one had an associated immune-mediated disease. In the one last ALS case, the final diagnosis was false-positivity for anti-acetylcholine receptor antibodies. The co-occurrence of ALS and myasthenia gravis is rare and requires strict diagnostic criteria. Its demonstration needs thoughtful interpretation of electrophysiological results and exclusion of false positivity for myasthenia gravis antibody testing in some ALS cases. This association may be triggered by a dysfunction of adaptive immunity.
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http://dx.doi.org/10.1016/j.nmd.2016.03.004DOI Listing
June 2016

Cervical Spinal Cord Atrophy Profile in Adult SMN1-Linked SMA.

PLoS One 2016 18;11(4):e0152439. Epub 2016 Apr 18.

Sorbonne Universités, UPMC Univ Paris 06, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale, F-75013, Paris, France.

Purpose: The mechanisms underlying the topography of motor deficits in spinal muscular atrophy (SMA) remain unknown. We investigated the profile of spinal cord atrophy (SCA) in SMN1-linked SMA, and its correlation with the topography of muscle weakness.

Materials And Methods: Eighteen SMN1-linked SMA patients type III/V and 18 age/gender-matched healthy volunteers were included. Patients were scored on manual muscle testing and functional scales. Spinal cord was imaged using 3T MRI system. Radial distance (RD) and cord cross-sectional area (CSA) measurements in SMA patients were compared to those in controls and correlated with strength and disability scores.

Results: CSA measurements revealed a significant cord atrophy gradient mainly located between C3 and C6 vertebral levels with a SCA rate ranging from 5.4% to 23% in SMA patients compared to controls. RD was significantly lower in SMA patients compared to controls in the anterior-posterior direction with a maximum along C4 and C5 vertebral levels (p-values < 10-5). There were no correlations between atrophy measurements, strength and disability scores.

Conclusions: Spinal cord atrophy in adult SMN1-linked SMA predominates in the segments innervating the proximal muscles. Additional factors such as neuromuscular junction or intrinsic skeletal muscle defects may play a role in more complex mechanisms underlying weakness in these patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152439PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835076PMC
August 2016

TBK1 mutation frequencies in French frontotemporal dementia and amyotrophic lateral sclerosis cohorts.

Neurobiol Aging 2015 Nov 14;36(11):3116.e5-3116.e8. Epub 2015 Aug 14.

Institut du Cerveau et de la Moelle épinière (ICM), INSERM U1127, CNRS UMR 7225, Sorbonne Universités, Université Pierre et Marie Curie, Univ Paris 06, UPMC-P6 UMR S 1127 Hôpital de la Pitié-Salpêtrière, Paris, France; Département des Maladies du Système Nerveux, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France; Département de Génétique et Cytogénétique, Unité Fonctionnelle de Génétique Clinique, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France. Electronic address:

TANK1-binding kinase 1 (TBK1) has been recently identified as a new amyotrophic lateral sclerosis (ALS) gene. Loss-of-function (LoF) mutations in TBK1 could be responsible for 0.4%-4% of ALS. Considering the strong genetic overlap existing between frontotemporal dementia (FTD) and ALS, we have evaluated the frequencies of TBK1 mutations in a cohort of French FTD and of ALS patients. We identified 5 LoF mutations, in 4 FTD-ALS and 1 ALS patients. We also identified 5 heterozygous missense variants, predicted to be deleterious, in 1 isolated FTD, 1 FTD-ALS, and 3 ALS cases. Our results demonstrate that TBK1 loss-of-function mutations are more frequent in patients with FTD-ALS (10.8%) than in isolated ALS. TBK1 should thus also be sequenced, after exclusion of C9orf72 mutation, in patients presenting FTD, particularly in cases secondarily associated with ALS.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.08.009DOI Listing
November 2015

Endplate denervation correlates with Nogo-A muscle expression in amyotrophic lateral sclerosis patients.

Ann Clin Transl Neurol 2015 Apr 16;2(4):362-72. Epub 2015 Feb 16.

Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM F-75013, Paris, France ; APHP, Hôpital Pitié-Salpêtrière, Centre de référence de pathologie neuromusculaire Paris-Est, Institut de Myologie Paris, France.

Objective: Data from mouse models of amyotrophic lateral sclerosis (ALS) suggest early morphological changes in neuromuscular junctions (NMJs), with loss of nerve-muscle contact. Overexpression of the neurite outgrowth inhibitor Nogo-A in muscle may play a role in this loss of endplate innervation.

Methods: We used confocal and electron microscopy to study the structure of the NMJs in muscle samples collected from nine ALS patients (five early-stage patients and four long-term survivors). We correlated the morphological results with clinical and electrophysiological data, and with Nogo-A muscle expression level.

Results: Surface electromyography assessment of neuromuscular transmission was abnormal in 3/9 ALS patients. The postsynaptic apparatus was morphologically altered for almost all NMJs (n = 430) analyzed using confocal microscopy. 19.7% of the NMJs were completely denervated (fragmented synaptic gutters and absence of nerve terminal profile). The terminal axonal arborization was usually sparsely branched and 56.8% of innervated NMJs showed a typical reinnervation pattern. Terminal Schwann cell (TSC) morphology was altered with extensive cytoplasmic processes. A marked intrusion of TSCs in the synaptic cleft was seen in some cases, strikingly reducing the synaptic surface available for neuromuscular transmission. Finally, high-level expression of Nogo-A in muscle was significantly associated with higher extent of NMJ denervation and negative functional outcome.

Interpretation: Our results support the hypothesis that morphological alterations of NMJs are present from early-stage disease and may significantly contribute to functional motor impairment in ALS patients. Muscle expression of Nogo-A is associated with NMJ denervation and thus constitutes a therapeutic target to slow disease progression.
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http://dx.doi.org/10.1002/acn3.179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402082PMC
April 2015

Coordinated care affects hospitalization and prognosis in amyotrophic lateral sclerosis: a cohort study.

BMC Health Serv Res 2015 Apr 2;15:134. Epub 2015 Apr 2.

ALS Community Network, Hôpital de la Salpêtrière, 47 Boulevard de l'Hôpital, Paris, 75013, France.

Background: To determine whether an integrated approach to coordination of care influences hospitalization and clinical outcomes in a chronic neurological disease, amyotrophic lateral sclerosis.

Methods: We followed up 2452 patients with probable or definite amyotrophic lateral sclerosis from 2000 to 2012. Two cohorts were compared before and after the creation of a community care network for this disease in Ile de France in 2006. During these two periods, the medical and paramedical care teams and formal standards of care were identical; the only difference was the coordination by the network. To investigate hospital and emergency department use, we used number of patients, number of stays, and number of days. For clinical outcomes, we used slopes of functional deterioration, and Kaplan-Meier and Cox models for survival.

Results: All hospitalization variables decreased after the creation of the network, which was not explained by admissions elsewhere. The slope of functional deterioration was significantly different before (1.03 ± 1.57 points/month) and after (0.79 ± 0.80 points/month; p = 0.002) creation of the network. Patients included in the network had a median survival time of 13.2 months more (log rank test; p < 0.001). In the Cox model, the network intervention was associated with a 45% decrease in relative risk of death during the period of the study (p < 0.001).

Conclusions: Network care was associated with fewer hospital admissions, reduced functional deterioration and later mortality in ALS. These results suggest that proactive coordination between carers in chronic and complex diseases could have a positive impact on hospitalization and the clinical course of the disease.
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http://dx.doi.org/10.1186/s12913-015-0810-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4384378PMC
April 2015

Mitochondrial abnormalities and low grade inflammation are present in the skeletal muscle of a minority of patients with amyotrophic lateral sclerosis; an observational myopathology study.

Acta Neuropathol Commun 2014 Dec 14;2:165. Epub 2014 Dec 14.

Département des Maladies du Système Nerveux, APHP, Reseau SLA IDF Groupe Hospitalier Pitié-Salpêtrière, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Laboratoire d'Imagerie Biomédicale (LIB), Paris, F-75005, France.

Background: Amyotrophic lateral sclerosis (ALS) is a primary progressive neurodegenerative disease characterised by neuronal loss of lower motor neurons (in the spinal cord and brainstem) and/or upper motor neurons (in the motor cortex) and subsequent denervation atrophy of skeletal muscle.

Aim: A comprehensive examination of muscle pathology from a cohort of clinically confirmed ALS patients, including an investigation of inflammation, complement activation, and deposition of abnormal proteins in order to compare them with findings from an age-matched, control group.

Material And Methods: 31 muscle biopsies from clinically confirmed ALS patients and 20 normal controls underwent a comprehensive protocol of histochemical and immunohistochemical stains, including HLA-ABC, C5b-9, p62, and TDP-43.

Results: Neurogenic changes were confirmed in 30/31 ALS cases. In one case, no neurogenic changes could be detected. Muscle fibre necrosis was seen in 5/31 cases and chronic mononuclear inflammatory cell infiltration in 5/31 (2 of them overlapped with those showing muscle necrosis). In four biopsies there was an increase in the proportion of cytochrome oxidase (COX) negative fibres (2-3%). p62 faintly stained cytoplasmic bodies in eight cases and none were immunoreactive to TDP-43.

Conclusion: This large series of muscle biopsies from patients with ALS demonstrates neurogenic atrophy is a nearly uniform finding and that mild mitochondrial abnormalities and low-grade inflammation can be seen and do not rule out the diagnosis of ALS. These findings could lend support to the notion that ALS is a complex and heterogeneous disorder.
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http://dx.doi.org/10.1186/s40478-014-0165-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297389PMC
December 2014

The El Escorial criteria: strengths and weaknesses.

Amyotroph Lateral Scler Frontotemporal Degener 2015 Mar 8;16(1-2):1-7. Epub 2014 Dec 8.

San Raffaele Scientific Institute and Vita-Salute San Raffaele University , Milan , Italy.

The El Escorial criteria for the diagnosis of amyotrophic lateral sclerosis (ALS) were established 20 years ago and have been used as inclusion criteria for clinical trials. However, concerns have been raised concerning their use as diagnostic criteria in clinical practice. Moreover, as modern genetics have shed new light on the heterogeneity of ALS and the close relationship between ALS and frontotemporal dementia (FTD) recognized, the World Federation of Neurology Research Group on ALS/MND has initiated discussions to amend and update the criteria, while preserving the essential components for clinical trial enrolment purposes.
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http://dx.doi.org/10.3109/21678421.2014.964258DOI Listing
March 2015