Study of Predictive Factors of Progression of Motor Neurone Disease

Study Overview
=================
Brief Summary
-----------------
Amyotrophic lateral sclerosis (ALS) is a complex polymorph and devastating neurodegenerative disease. Although the pathophysiological mechanisms underlying the development of ALS remain to be fully elucidated, there have been significant advances in the understanding of ALS pathogenesis, with evidence emerging of a complex interaction between genetic factors and dysfunction of vital molecular pathways. However, the numerous randomized clinical trials (RCT) for ALS have failed to generate improved drug treatments. Biomarkers able to bring prognostic value and to distinguish the different endophenotypes of this polymorphic disease could help to better select clusters of patients in order to improve the RCT outcomes. However, little progress has been made in the development of viable diagnostic, prognostic and monitoring markers. This could be explained by common shortcomings, such as relatively small sample sizes, statistically underpowered study designs, lack of disease controls and poorly characterized patient cohorts. It is yet crucial that the investigators further develop and validate ALS biomarkers and incorporate these biomarkers into the drug development pipeline for ALS. The aim of the present study is therefore to determine the clinical, biological, imaging, and electrophysiological biomarkers of prognosis of survival without events (i.e. severe comorbidity, 24 hours of non invasive ventilation, tracheotomy). This is a prospective observational multicentric French study of a cohort of 1000 ALS patients. This large multimodal database will be open for international fruitful scientific collaborations.

Detailed Description
-----------------
This is a prospective observational multicentric French study of a cohort of 1000 ALS patients, 100 neurological controls and 200 healthy controls followed from the first signs to the end of the disease. The aim of the present study is therefore to determine the clinical, biological, imaging, and electrophysiological biomarkers of prognosis of survival without events (i.e. severe comorbidity, 24 hours of non invasive ventilation, tracheotomy). Secondary objectives will notably include i) the biomarkers of disease progression ii) biomarkers of diagnosis as compared with controls iii) the determination of the different endophenotypes according to the prognosis, the genetic profiles and the initial clinical presentations. Criteria of assessment will notably include detailed medical history, habitus, past and present treatments, vascular risk factors, ALSFRS-R, muscular testing, respiratory parameters including early nocturnal saturation and apneal profile, the detailed and predetermined clinical presentations, extensive cognitive and behavioral examination, extensive blood, cerebrospinal fluid, urines biological tests, genetic analyses, multiple brain and spinal MRI sequences, and electrophysiological tests (i.e. electromyogram, MUNIX, triple stimulation). Invasive tests will be optional (i.e. lumbar puncture, skin biopsies, muscular biopsies). The large number of patients will allow in depth statistical analyses, notably to establish decisional trees (CHAID).

Official Title
-----------------
Study of Predictive Factors of Progression of Motor Neurone Disease Prognosis and Endophenotype Biomarkers French Database Set up

Conditions
-----------------
Amyotrophic Lateral Sclerosis, Motor Neuron Disease

Intervention / Treatment
-----------------
* Other: biomarkers (composite analysis)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria for ALS patients: Patients with suspicion of Amyotrophic lateral sclerosis Since the first signs (cramps fasciculation) or first deficit at the diagnosis work up Patient older than 18 years Patient able to provide informed consent Inclusion Criteria for healthy controls: Subjects older than 18 years (matched population for age and sex with ALS) Neurological testing and examination showing no neurological disorders. Not having severe disease or life- functional prognosis Inclusion Criteria for neurological controls: Patients having a typical neurodegenerative diseases other than ALS (Parkinson's disease, Alzheimer's disease) Not having severe disease or life- functional prognosis Patient older than 18 years (matched population for age and sex with ALS) Patient able to provide informed consent Exclusion Criteria: Subjects younger than 18 years Patient unable to provide informed consent Having severe disease or life- functional prognosis Contraindications MRI

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| patients<br>follow up of patients with amyotrophic lateral sclerosis from the first signs to the end of the disease | Other: biomarkers (composite analysis)<br>* biological, imaging, electrophysiological and anatomopathological examinations<br>|
| neurological controls<br>patients with other neurological disease | Other: biomarkers (composite analysis)<br>* biological, imaging, electrophysiological and anatomopathological examinations<br>|
| healthy controls<br>age matched healthy controls | Other: biomarkers (composite analysis)<br>* biological, imaging, electrophysiological and anatomopathological examinations<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of biomarkers of survival | The predictive value of the clinical, biological, imaging, and electrophysiological biomarkers of survival will be analyzed according to the life duration (months) without events (i.e. severe comorbidity, 24 hours of non invasive ventilation, tracheotomy) | From date of randomization until the date of first documented progression , assessed up to 100 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of biomarkers of disease progression | The predictive value of the clinical, biological, imaging, and electrophysiological biomarkers of prognosis will be analyzed according to the rate of progression of the ALSFRS-R score | baseline, 3 months, 6 months, 9 months, 12 months, 15 months, 24 months, 36 months, 48 months (average) | 
| Clinical endophenotypes according to the survival duration | The determination of the different clinical, biological, radiological and electrophysiological endophenotypes (clusters of the same characteristics) according to the survival duration | From date of randomization until the date of death related with ALS or tracheotomy or continuous non invasive ventilation (24 hours a day), whichever came first, assessed up to 100 months | 
| Genetic endophenotypes | the determination of the different clinical, biological, radiological and electrophysiological endophenotypes (clusters of the same characteristics) according to the according to the genetic forms (SOD1, TDP43, FUS, C9orf72,...) | the date of death related with ALS or tracheotomy or continuous non invasive ventilation (24 hours a day), whichever came first, assessed up to 100 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
multimodal biomarkers, prognosis, endophenotypes