Amyotrophic Lateral Sclerosis, Motor Neuron Disease
Conditions
Keywords
multimodal biomarkers, prognosis, endophenotypes
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).
Interventions
OTHERbiomarkers (composite analysis)
biological, imaging, electrophysiological and anatomopathological examinations
Sponsors
University Hospital, Lille
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of biomarkers of survival | From date of randomization until the date of first documented progression , assessed up to 100 months | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change of biomarkers of disease progression | baseline, 3 months, 6 months, 9 months, 12 months, 15 months, 24 months, 36 months, 48 months (average) | 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 |
| Clinical endophenotypes 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 | The determination of the different clinical, biological, radiological and electrophysiological endophenotypes (clusters of the same characteristics) according to the survival duration |
| Genetic endophenotypes | 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 | 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,...) |
Countries
France
Contacts
STUDY_CHAIRDavid Devos, MD, PhD
University Hospital, Lille
Outcome results
None listed