The Energetic Origin of Neurodegeneration in MS

NCT04532944 | Unknown

• 2 other identifiers: C19-202019-A01931-56
• Study Type: interventional
• Target: 55
• Locations: 0 countries
• Sites: N/A

Brief Summary

In multiple sclerosis (MS), the sequence of events leading to irreversible neuro-axonal degeneration, which is a major determinant of clinical disability, is poorly understood. Recently, the key role of neuronal energy dysfunction in driving axonal degeneration has been highlighted. In the neuronal injury pathway triggered by inflammation and myelin disruption, multiple adaptive changes force the neuron to a temporary condition of "virtual hypoxia", characterized by a mismatch between energy demand and supply. If this condition of energy dysregulation is not reversed within an appropriate time-window, neurons enter an irreversible axonal degeneration. Two key questions on the relationship between early energy dysregulation and neurodegeneration remain unanswered: i) whether brain energy dysfunction measured at a given time point can predict the subsequent occurrence of neurodegeneration; ii) to what extent and for how long neurons can bear this "virtual hypoxia" before undergoing structural damage. Tracking the "energetic signature" of MS and defining its temporal distance from irreversible damage is essential for the development of neuroprotective therapies.The recent optimization of innovative magnetic resonance (MR)-based techniques such as sodium (23Na) MRI, phosphorus MR spectroscopy (31P-MRS), and diffusion-weighted 1H MRS (DW-MRS) has allowed the generation of promising in vivo data on cellular energy dysregulation in MS. The main objective of this project is to explore whether MR-derived metrics of energy dysregulation predict MR-derived parameters of cortical neurodegeneration developing over 2 years, as reflected by cortical atrophy. To address this key question, the Investigators will use a combination of 23Na MRI, 31P MRS, and DW-MRS associated with advanced MRI sequences to explore energy dysregulation in the sensorimotor region, and measurements of cortical atrophy in the same area after 24 months in 40 patients with either relapsing-remitting or progressive MS and 15 age- and gender-matched healthy controls. The Investigators will also test whether MR-derived metrics of energy dysregulation at study entry correlate, both cross-sectionally and longitudinally, with: i) global cortical atrophy; ii) functional cortical reorganization resulting from the condition of energy dysregulation, which precedes the occurrence of structural damage; iii) cortical demyelination and remyelination; iv) clinical, neuropsychological and biological measures.

Conditions

Multiple Sclerosis

Keywords

energy dysfunction; neurodegeneration; 7 T MRI; sodium imaging; phosphorus spectroscopy; diffusion-weighted spectroscopy

Outcome Measures

Primary Outcomes (4)

• Energy dysregulation in the whole brain with sodium imaging

  Evaluation of the levels of total, intracellular and extracellular sodium quantified through 23Na MRI in the whole brain.

  0-12 months

• Energy dysregulation in the motor-sensory region (MSR) with phosphorus spectroscopy

  Evaluation of ATP and PCr concentrations measured through 31P MRS in a voxel centred on the left MSR

  0-12 months

• Energy dysregulation in the motor-sensory region with diffusion-weighted spectroscopy

  Evaluation of the ADC of tCr (Cr + PCr) measured through DW-MRS in a voxel centred on the left MSR.

  0-12 months

• Neurodegeneration in the MSR after 24 months

  Neurodegeneration after 24 months will be evaluated by the measurements of the following parameters: Evaluation of MSR cortical thickness after 24 months and relative change in MSR cortical thickness between study entry and 24 months measured with Freesurfer (https://surfer.nmr.mgh.harvard.edu).

  0-24 months

Secondary Outcomes (8)

• Patient-specific profiles of energy dysregulation

  0-12 months

• cortical demyelination and remyelination

  0-12 months

• neuro-axonal damage over time

  0-12-24 months

• functional changes in brain connectivity

  0-12-24 months

• serum markers of tissue damage

  0-12-24 months

Study Arms (2)

patients with MS

OTHER

20 relapsing-remitting and 20 progressive MS patients

Diagnostic Test: imaging of energy dysfunction

healthy controls

OTHER

15 age- and sex-matched healthy controls

Diagnostic Test: imaging of energy dysfunction

Interventions

imaging of energy dysfunction DIAGNOSTIC_TEST

7T sodium imaging, phosphorus spectroscopy and 3T diffusion-weighted spectroscopy

healthy controls; patients with MS

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• RR-MS patients with a disease duration of less than 10 years:
• years
• clinically defined RR-MS according to the 2017 revised McDonald's criteria (MS diagnostic criteria 2017)
• disease duration \<10 years
• ability to understand the research objectives and the procedure details, and to sign the informed consent
• affiliation with the French National Health Insurance, Universal Medical Coverage (CMU) or any equivalent
• Patients with progressive MS (primary or secondary) of less than 10 years:
• years
• clinically defined progressive MS according to the 2017 revised McDonald's criteria
• disease duration \<10 years from the beginning of the progressive phase
• ability to understand the research objectives and the procedure details, and to sign the informed consent
• affiliation with the French National Health Insurance, Universal Medical Coverage (CMU) or any equivalent
• years (matched with patients)
• no known general pathologies
• ability to understand the research objectives and the procedure details, and to sign the informed consent

You may not qualify if:

• Pregnant or breastfeeding women
• severe cardiac, pulmonary, hepatic, hematologic renal, gastrointestinal disease, or cancer
• severe renal failure (clearance of creatinine \< 30ml/min)
• history of allergic reactions to gadolinium salts
• any other chronic neurological disorders associated
• persons deprived of liberty by law or by administrative decision
• Persons under legal protection
• Pregnant or breastfeeding women
• severe cardiac, pulmonary, hepatic, hematologic renal, gastrointestinal disease, or cancer
• contraindications to MRI : claustrophobia, pace-maker implant, any surgical magnetic clips, ocular implants, any intraocular or intracranial metallic fragments, any metallic objects able to concentrate the radiofrequency field, cochlear implants, cardiac or brain stimulators, any tattoos or permanent makeup on the face
• person not willing to be informed of any possible cerebral malformations incidentally discovered at the MRI exam
• associated chronic neurological disorders
• persons deprived of liberty by law or by administrative decision
• Persons under legal protection

Sponsors & Collaborators

• Institut National de la Santé Et de la Recherche Médicale, France: lead

MeSH Terms

Conditions

Multiple Sclerosis; Nerve Degeneration

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Model Details: 40 patients with MS and 15 healthy controls

Study Record Dates

• First Submitted: July 30, 2020
• First Posted: August 31, 2020
• Study Start: September 15, 2020
• Primary Completion: September 15, 2022
• Study Completion: March 15, 2024
• Last Updated: August 31, 2020

Record last verified: 2020-08