PET with [18F]Flumazenil As an Index of Neurodegeneration in MS

PET with [18F]Flumazenil As an Index of Neurodegeneration in MS: Sensitivity At an Early Disease Stage and Pathophysiological Meaning

Beyond white matter pathology, grey matter damage is considered as a key player in disability onset and progression in Multiple Sclerosis (MS). The underlying substratum of grey matter damage is complex and pluriform, ranging from cortical demyelinating lesions, synapse and dendrite disappearance to neuronal cell death. Current Magnetic Resonance Imaging MRI techniques fail to fully assess and quantify grey matter pathology in this disease. The development of a quantitative marker of neurodegeneration for MS patients would allow: (i) to better understand the pathophysiological mechanisms underlying the distinct forms of MS; (ii) to stratify patients according to their prognosis; and (iii) to evaluate new therapies aimed at promoting neuroprotection. would allow to better understand the mechanisms underlying the distinct forms of MS, to stratify patients according to their prognosis, and to evaluate new therapies aimed at promoting neuroprotection.

The investigators have recently shown that PET (Tomographie par Émission de Positrons) with [11C]Flumazenil ([11C]FMZ), that binds to the benzodiazepine site of GABA-A receptors, allowed to quantify and map neuronal damage in MS patients.

In the present project, the investigators will assess neuronal damage in MS using PET with [18F]Flumazenil ([18F]FMZ), at the early phase of either relapsing or primary progressive MS, and investigate the pathophysiological meaning of this neuronal damage by combining PET with Flumazenil with MRI at 7T and 3T.

The main objective will be to quantify and map [18F]FMZ binding changes in the grey matter of MS patients compared to controls, both at the group and the individual level. Secondary and exploratory objectives will be to investigate the relationship between Flumazenil binding changes and: i) cortical demyelinating lesions identified by several 7T MRI sequences ; ii) dendritic arborisation assessed by 3T DWI; ii) available MRI metrics obtained on a clinical 3T scan (grey matter atrophy MTR modifications, resting state connectivity); iv) clinical metrics.

This study will develop and assess a new imaging biomarker that has the potential to be used as an index of neurodegeneration in MS.

Inclusion Criteria:

• Patient group:

  • Aged 18-55 years old
  • Diagnosis of RRMS or PPMS according to the 2010 Mc Donald criteria
  • Disease duration < 10 years
  • Able to understand the study objective and procedure
  • Efficient contraception for women of potential child-bearing
  • Inscription to the national health care system
  • Having signed the written consent form
  • No current benzodiazepine or other GABAA-interacting drug (that have to be stopped 15 days before inclusion)
  • Accept to be informed of any incidental finding on imaging acquisitions

• Healthy subjects

  • Aged 18-55 years old
  • No evolutive pathology
  • Able to understand the study objective and procedure
  • Efficient contraception for women of potential child-bearing
  • Inscription to the national health care system
  • Having signed the written consent form
  • No concurrent benzodiazepine or other GABAA-interacting drug treatment (that have to be stopped 15 days before inclusion)
  • Accept to be informed of any incidental finding on imaging acquisitions

Exclusion Criteria:

• Any reason, which does not allow to perform MRI, including claustrophobia, the implant of a pace-maker or the presence of an intra-ocular foreign body.
• For women: pregnancy, lactation, lack of efficient contraception. A positive pregnancy test conducted at visit 2 will lead to the immediate exclusion of the subject.
• Current symptoms of severe or uncontrolled renal, hepatic, hematological, gastrointestinal pulmonary or cardiac disease.
• Radiation exposure during the last year before inclusion due to prior participations to other research protocols
• Other chronic neurological diseases.