Exploring in Vivo the Energetic Origin of Neurodegeneration in Multiple Sclerosis: a Ultra-high Field Sodium Imaging, Phosphorus Spectroscopy and Diffusion-weighted Spectroscopy Study.
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 59
- 试验地点
- 1
- 主要终点
- Energy dysregulation in the whole brain with sodium imaging
研究概览
简要总结
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.
详细描述
1. RESEARCH JUSTIFICATION
1.1 Energy dysregulation is a key process in the physiopathology of neurodegeneration in MS
Several mechanisms have been suggested to play a major role in the physiopathology of neurodegeneration in multiple sclerosis (MS), among which: inflammatory demyelination, excitotoxicity, oxidative stress and ionic channel dysfunction. Each of these mechanisms is potentially implicated in inducing an energy dysregulation. Moreover, the notion that early neuronal energy failure may play a key role in axonal degeneration is being more and more acknowledged. In these physiological conditions, myelin sheath integrity not only allows efficient saltatory conduction of the action potential, but it also helps to maintain the environment for neuronal survival by assuring the correct amount of cellular energy.
Following myelin disruption and inflammation, multiple adaptive changes force the neurone to enter a temporary state of "virtual hypoxia". Indeed, the loss of axonal coverage determines the VGSC redistribution along the axon and the re-expression of NaV1.2.
Furthermore, demyelination induces mitochondrial proliferation along damaged axons, together with a complex for hyperactivity in order to support the sodium/potassium pump. These compensatory mechanisms initially overcome the conduction block resulting from demyelination, but in such conditions transmembrane electrochemical gradients are maintained at the cost of an increased energy demand.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •RR-MS patients with a disease duration of less than 10 years:
- •18-55 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:
- •18-55 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
- •Inclusion Criteria for healthy controls:
- •18-55 years (matched with patients)
- •no known general pathologies
- •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
排除标准
- •Pregnant or breastfeeding women
- •Last infusion of cyclophosphamide, mitoxantrone or methylprednisolone realized less than 1 month before inclusion
- •last clinical relapse less than one month before inclusion
- •severe cardiac, pulmonary, hepatic, hematologic renal, gastrointestinal disease, or cancer
- •contraindications to MRI: claustrophobia, pace-maker implant, any surgical ferromagnetic 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, renal failure (exclusion criterion for gadolinium injection) patients not willing to be informed of any possible cerebral malformations incidentally discovered at the MRI exam
- •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
- •Exclusion Criteria for healthy controls:
- •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
研究组 & 干预措施
patients with MS
20 relapsing-remitting and 20 progressive MS patients
干预措施: imaging of energy dysfunction (Diagnostic Test)
healthy controls
15 age- and sex-matched healthy controls
干预措施: imaging of energy dysfunction (Diagnostic Test)
结局指标
主要结局
Energy dysregulation in the whole brain with sodium imaging
时间窗: 0-12 months
Evaluation of the levels of total, intracellular and extracellular sodium quantified through 23Na MRI in the whole brain.
Energy dysregulation in the motor-sensory region (MSR) with phosphorus spectroscopy
时间窗: 0-12 months
Evaluation of ATP and PCr concentrations measured through 31P MRS in a voxel centred on the left MSR
Energy dysregulation in the motor-sensory region with diffusion-weighted spectroscopy
时间窗: 0-12 months
Evaluation of the ADC of tCr (Cr + PCr) measured through DW-MRS in a voxel centred on the left MSR.
Neurodegeneration in the MSR after 24 months
时间窗: 0-24 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).
次要结局
- 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)
- physical and cognitive dysfunction(0-12-24 months)