Theranostic Metabolic Imaging of Oxidative Stress in Multiple Sclerosis.

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ABSTRACT Oxidative stress plays a crucial role in Multiple Sclerosis (MS). Importantly, oxidative stress is more prominent in primary and secondary progressive MS (PP/SPMS) than in the relapsing remitting (RRMS) form, and alternative treatment strategies targeting oxidative stress are being tested for PP/SPMS. Unfortunately, there are presently limited in vivo methods for measuring oxidative stress. Hyperpolarized 13C Magnetic Resonance Spectroscopic Imaging (HP 13C MRSI) is a safe method that detects metabolic reactions in vivo post injection of HP probes. HP [1-13C]-dehydroxyascorbate (DHA) has shown potential for in vivo imaging of oxidative stress in vivo, but causes transient respiratory arrest and pancreatic toxicity, limiting its translational potential. There is thus a need for a new imaging strategy to assess oxidative stress in the brain in vivo. N-acetylcysteine (NAC) is the N-acetyl derivative of the naturally occurring amino acid, L-cysteine, and has been used as an antioxidant in clinical practice for decades. In people living with MS, a recent study reported that NAC significantly increased cerebral glucose metabolism and cognitive function, identifying NAC as a potential therapy. Based on all these findings, we propose to: Aim 1: Optimize and validate HP [1,4-13C]NAC as a theranostic probe to non-invasively detect cerebral redox status in MS mice at clinical field strength: The concentration of [1,4-13C]NAC and the MRSI acquisition scheme will be optimized for detection of the metabolism of [1,4-13C]NAC in the brain of MS mice, to provide the best data quality. Correlations between ex vivo oxidative stress markers and in vivo HP Ac/Cys-to-NAC will be performed to biologically validate our imaging method. Completion of this aim will provide an optimized tool for quantifying in vivo redox state in the MS mouse brain. Aim 2. Apply theranostic metabolic imaging of oxidative stress to monitor response to therapies: We will apply a multimodal metabolic imaging approach combining both HP [1,4-13C]NAC and HP [1-13C]DHA strategies, as well as complementary biological assays, to investigate the effects of a clinically-relevant therapy dimethylfumarate (DMF), a novel potential therapeutic molecule affecting oxidative stress (Acivicin) as well as the effect of NAC itself used as treatment, in a preclinical model of MS. Correlations between ex vivo oxidative stress markers and in vivo HP ratios will be performed to biologically validate our imaging approaches, and compare HP [1,4-13C]NAC and HP [1-13C]DHA strategies. Completion of this aim will validate a new metabolic imaging tool for monitoring therapeutic response linked to changes in oxidative stress in MS in vivo. Overall Impact: The expected overall impact is that, through validation of a new theranostic MR imaging approach allowing for assessment of oxidative stress, and upon clinical translation, results from this project will likely improve the clinical management for MS patients – especially for the SPMS/PPMS population in high need of improved care -, help refine therapy regimens and, ultimately lead to better outcome and patient quality of life.