Remyelination in Multiple Sclerosis: a PET-MR Longitudinal Study Investigating Individual Profiles of Myelin Repair and the Contribution of Neuroinflammation

Multiple Sclerosis (MS) is an inflammatory disease where the immune cells invade the central nervous system and destroy an essential element of nerve conduction: the myelin. An interesting feature observed in some patients is a regenerative process, called remyelination, which leads to the production of new myelin. However, the extent of remyelination is very heterogeneous among patients, only a minority of patients show a really efficient repair process along the disease course. In this project, our aim is to explore in vivo the biological mechanisms leading to a successful remyelination in some patients and to a failure in remyelination in others. With this purpose in mind we propose to develop a translational research platform where patients with multiple sclerosis will be investigated in vivo for their potential of remyelination through a follow-up with recently developed imaging technologies using a synergistic combination of magnetic resonance imaging (MRI) and positron emission tomography (PET) to visualize and quantify myelin and neuroinflammation. In parallel blood immune cells from patients will be sampled and profiled to investigate how they could influence remyelination. This part will consist in i) grafting patients' lymphocytes in experimental rodent models of demyelination to characterize how they could promote or inhibit remyelination; ii) performing a functional and multi-omics analysis of peripheral macrophages and analyse relationships with remyelination profiles; iii) profiling T lymphocytes at the single cell level to associate specific subpopulation of the T cells with the remyelination potential assessed in patients with MRI/PET images and in grafted animals.


Eligibility Criteria:
Inclusion Criteria:

RRMS patients:

1. Age between 18 and 55 years old
2. RRMS according to the 2017 Mc Donald criteria
3. Less than 5 years of disease duration
4. At least 9 supra-tentorial white matter lesions on T2/FLAIR MRI
5. Last treatment with methylprednisolone should have been performed at least 1 month before PET examinations
6. Interferon-beta, glatiramere acetate and oral first line therapy will such as dimethylfumarate or teriflunomide will be admitted
7. Affiliation to a social security scheme or beneficiary of such a scheme (Except "Aide Médicale d'Etat")

Progressive MS patients:

1. Age between 18 and 55 years old
2. Progressive MS (primary or secondary progressive MS) according to the 2017 Mc Donald criteria
3. Less than 10 years of disease duration in the progressive phase
4. At least 9 supra-tentorial white matter lesions on T2/FLAIR MRI
5. Interferon-beta, glatiramere acetate and oral first line therapy will such as dimethylfumarate or teriflunomide will be admitted
6. Affiliation to a social security scheme or beneficiary of such a scheme (except "Aide Médicale d'Etat")

Healthy volunteers:

1. Age between 18 and 55 years old
2. Without any evolutive pathology
3. Able to understand the study objectives and procedures
4. Affiliation to a social security scheme or beneficiary of such a scheme (except "Aide Médicale d'Etat")

Exclusion Criteria:

For all participants:

1. Any reasons, which does not allow to perform MRI, including claustrophobia, the implant of a pace maker or the presence of an intra-ocular foreign body (a contra-indication questionnaire will be filled in beforehand)
2. PET for clinical research already done within the last 12 months
3. Low Affinity Binding profile (TSPO polymorphism analyzed at screening visit)
4. Pregnancy, breast-feeding, lack of efficient contraception
5. Current symptoms of severe or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary or cardiac disease, or any other chronic neurological diseases
6. Unwillingness to be informed in case of abnormal MRI (with a significant medical anomaly)
7. Know hypersensitivity to Myelin PET : \[18F\]-Florbetaben
8. Patient under legal protection

Additional exclusion criteria for patients:

1. Treatment with cyclophosphamide, mitoxantrone, fingolimod, cladribine, alemtuzumab, anti CD20 antibodies or natalizumab will not be admitted. These treatments may be administered after the Baseline visit.
2. Known allergy to gadoteric acid
3. Allergies (seafood, pollinosis, urticarial) having required a medical intervention
4. Severe renal insufficiency (creatinine clearance \< 60mL/min).