Imaging remyelination in multiple sclerosis using metabolic and ultra-short echo time MRI

ABSTRACT Damage to myelin sheaths and demyelination of axons is a hallmark of multiple sclerosis (MS) leading to neurological signs and symptoms of MS. Failure to remyelinate is an important factor contributing to disability accumulation in progressive MS. Presently, there is a lack of non-invasive imaging methods to monitor myelin changes and remyelination in preclinical and clinical settings. Formation of new myelin sheaths and remyelination is an energetically demanding process ensured by oligodendrocytes, which is associated with modulation of cerebral metabolism. Lactate has emerged as an important metabolite to promote remyelination as it is used by oligodendrocytes for lipid synthesis and myelin formation. Hyperpolarized 13C magnetic resonance spectroscopic imaging (HP 13C MRSI) is an innovative metabolic MR method that enables to monitor enzymatic reactions in vivo in real-time. This method opens new avenues to investigate metabolic alterations and lactate metabolism during successful/unsuccessful remyelination. Although quantification of myelin levels using noninvasive means remains challenging, a recently developed acquisition scheme combining ultra-short echo time and magnetization transfer (UTE-MT) has shown high sensitivity to myelin content in both white and grey matter areas in a demyelinating MS mouse model. However, UTE-MT imaging has not yet been applied to study early remyelination and therapy response. In this project, we propose to investigate the potential of HP [1-13C]lactate and UTE-MT imaging to non-invasively study the role of lactate metabolism and remyelination in two MS mouse models with different remyelination capabilities, during disease progression and following response to a remyelinating therapy. To do so, HP 13C MRSI and UTE-MT imaging sessions will be performed at key time points during lesion formation and during spontaneous recovery/remyelination. Next, HP [1-13C]lactate and UTE-MT will be used to evaluate treatment response from a remyelinating therapy to investigate HP [1-13C]lactate and UTE-MT potential to serve as biomarkers of repair. MRI findings will be confirmed using ex vivo correlates of enzyme activities and histopathological markers for myelin and lesion characterization. Development and validation of the MR imaging tools proposed here has high potential to increase our knowledge on mechanisms involved in remyelination success and failure. Importantly, because the methods developed here are clinically translatable, they hold great promise to providing new tools for diagnosis and monitoring of therapies in MS, and helping define optimal therapeutic windows to speed up repair and prevent disability accumulation.