The Energetic Origin of Neurodegeneration in MS

Plain-language 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.

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