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Le Touquet – Paris-Plage, France

Meininger V.,Center Referent Maladies Rares
Archives Italiennes de Biologie

The most important challenge of ALS remains finding biomarkers. Clinical features remain of key importance in the diagnosis and for follow up. Neurophysiology remains difficult to use in clinical trials. Neuroimaging have some utility for upper motor neuron integrity and function. Among proteins and chemical markers, one of the most promising marker is the level of Nogo in muscle biopsy. In CSF, many candidate proteins have been suggested but their sensitivity and specificity remains disappointing. Recently, omics technologies have been applied to try to discover biomarkers in ALS, including genomic, proteomic and metabolomic methodologies. Source

Agosta F.,Vita-Salute San Raffaele University | Al-Chalabi A.,Kings College London | Filippi M.,Vita-Salute San Raffaele University | Hardiman O.,Trinity College Dublin | And 7 more authors.
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

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. © 2014 Informa Healthcare. Source

Fornai F.,University of Pisa | Fornai F.,Neurobiology of Movement Disorder Unit INM IRCCS Neuromed | Meininger V.,Center Referent Maladies Rares | Silani V.,University of Milan
Archives Italiennes de Biologie

Classic concepts on amyotrophic lateral sclerosis led to define the disease as a selective degeneration of upper and lower motor neurons. At present such selectivity is questioned by novel findings. For instance, the occurrence of frontotemporal dementia is now increasingly recognized in the course of ALS. Again, areas outside the central nervous system are targeted in ALS. In keeping with motor areas other cell types surrounding motor neurons such as glia and interneurons are key in the pathogenesis of ALS. This multiple cell involvement may be due to a prion-like diffusion of specific misfolded proteins which are altered in ALS. This is the case of FUS and TDP-43 which harbor a prion domain prone to pathological misfolding. These misfolded proteins are metabolized by the autophagy, but in ALS there is evidence for a specific deficit of autophagy which impedes the clearance of these proteins. These concepts lead to re-analyze the potential therapeutics of ALS. In fact, mere cell substitution (stem cell) therapy appears insufficient to contrast all the alterations in the various pathways affected by ALS. Although preclinical data speed the application of stem cells in human clinical trials, several hurdles limit their translation into new therapies. Future treatments are expected to consider the need to target both motor neurons and neighboring cells which may contribute to the diffusion and persistence of the disease. On this basis the present manuscript describes which future strategies need to be pursued in order to design optimal therapeutic trial in ALS. Source

Gordon P.H.,Center Referent Maladies Rares | Delgadillo D.,Center Referent Maladies Rares | Piquard A.,Center Referent Maladies Rares | Piquard A.,University of Versailles | And 8 more authors.
Amyotrophic Lateral Sclerosis

Our objective was to assess the spectrum and clinical associations of cognitive impairment in French patients with ALS, and determine the effect of cognitive impairment on survival in this population. One hundred and thirty-one patients were enrolled in a cross-sectional cohort study of neuropsychological test performance. ANOVA and χ 2 tests assessed differences in clinical characteristics between impaired and unimpaired patients; multiple regression determined which features contributed most strongly to cognitive status, and Cox models compared survival. Fifty-three patients (40%) were categorized as cognitively impaired based on test performance. Thirteen (10%) patients had frontotemporal dementia (FTD) clinically; all scored in the moderate to severely impaired range on testing. Impaired patients had less education (p = 0.001), and severely impaired patients were more likely to have bulbar onset than unimpaired patients (p < 0.001). Severe cognitive impairment predicted shorter survival (p = 0.007), even when controlled for motor severity (p = 0.001). In summary, 10% of a consecutive series of French ALS patients had overt dementia and 40% were cognitively impaired by neuropsychological testing. We conclude that lower education level and possibly bulbar-onset ALS were associated with impairment. As in other causes of dementia, higher education attainment may protect against clinical cognitive deterioration in ALS. French patients with severe cognitive impairment have shorter survival time. © 2011 Informa Healthcare. Source

Conraux L.,Sanofi S.A. | Pech C.,Sanofi S.A. | Guerraoui H.,Sanofi S.A. | Loyaux D.,Sanofi S.A. | And 8 more authors.

The diagnostic of Amyotrophic lateral sclerosis (ALS) remains based on clinical and neurophysiological observations. The actual delay between the onset of the symptoms and diagnosis is about 1 year, preventing early inclusion of patients into clinical trials and early care of the disease. Therefore, finding biomarkers with high sensitivity and specificity remains urgent. In our study, we looked for peptide biomarkers in plasma samples using reverse phase magnetic beads (C18 and C8) and MALDI-TOF mass spectrometry analysis. From a set of ALS patients (n=30) and healthy age-matched controls (n=30), C18- or C8-SVM-based models for ALS diagnostic were constructed on the base of the minimum of the most discriminant peaks. These two SVM-based models end up in excellent separations between the 2 groups of patients (recognition capability overall classes > 97%) and classify blinded samples (10 ALS and 10 healthy age-matched controls) with very high sensitivities and specificities (>90%). Some of these discriminant peaks have been identified by Mass Spectrometry (MS) analyses and correspond to (or are fragments of) major plasma proteins, partly linked to the blood coagulation. © 2013 conraux et al. Source

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