MR Metabolic Imaging of Multiple Sclerosis

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ABSTRACT For people living with multiple sclerosis (MS), numerous clinical and Magnetic Resonance Imaging (MRI) sessions are needed to assess symptoms and/or presence of lesions. Even then, outcome prediction and treatment choice are challenging. To realize the full potential of personalized medicine, specific biomarkers reflecting function (e.g. inflammation, redox) are needed for comprehensive characterization and phenotyping. Over the initially funded 5-year period of this grant, we have firmly established that hyperpolarized (HP) 13C MR Spectroscopic Imaging (MRSI) is a highly valuable neuroimaging method for assessment of MS lesions. We were the first to show that 13C MRSI of HP [1-13C]pyruvate can detect increased HP lactate-to-pyruvate, linked to proinflammatory microglia/macrophages (MPs) in a MS mouse model, a finding further confirmed in other models. We also demonstrated that HP 13C MR could monitor early response to immunomodulatory therapies, e.g. dimethylfumarate (DMF). Additionally, we showed that, as MPs phenotype is linked to levels of Reactive Oxygen Species (ROS), HP [1-13C]dehydroxyascorbic acid (DHA), a redox-sensing HP probe, could differentiate between M1 and M2 MPs, thus non-invasively assessing these orthogonal processes. In this renewal, we will build upon the successes of the first funded period and 1/develop improved HP 13C metabolic imaging approaches to assess neuroinflammation and oxidative stress in MS and 2/conduct the first human study applying HP 13C metabolic imaging to monitor therapy response in people living with MS. Specific Aim 1. Provide a comprehensive picture of metabolic impairment in MS using HP [1- 13C]pyruvate. 13C MRSI of HP [1-13C]pyruvate will be optimized at clinical field strength to simultaneously detect oxidative and glycolytic metabolism through assessment of bicarbonate and lactate kinetics, respectively, in two preclinical MS models at 3 Tesla. Spatial genomics, immunostainings and biochemical assays will be performed on paired ex vivo samples to investigate the underlying mechanisms driving the HP readouts. Specific Aim 2. Differentiate orthogonal neuroinflammatory processes using HP g-Glutamyl-[1- 13C]Glycine. We will investigate the potential of g-Glu-[1-13C]Gly to assess oxidative stress as a read-out of M1/M2 status in two MS models. To do so, 13C MRSI of HP g-Glu-[1-13C]Gly will be optimized to measure GGT activity in vivo through detection of HP [1-13C]Glycine in preclinical MS models at 3 Tesla. Ex vivo analysis of tissue samples will be performed as in Aim 1 to investigate the underlying mechanisms driving the HP readouts. Specific Aim 3. Perform the first study of MS patients using HP [1-13C]pyruvate: 3A. We will perform a pilot study on 8 RRMS patients naïve to disease modifying therapies (DMTs), to optimize HP [1-13C] pyruvate MRI parameters for improved resolution at 3 Tesla. 3B. We will then image 32 RRMS patients naïve to DMTs using parameters defined in 3A, at baseline, and after 1 and 3 months of DMF/MMF therapy. Associations between new metabolic imaging markers and standard clinical MRI (T1 pre/post Gd, T2) will be evaluated.