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A system of methods to investigate brain metabolism of a mouse model using Hyperpolarized 13C

Abstract

Brain metabolism studies have become increasingly popular as public awareness of the crucial role of metabolic impairment in neurodegenerative and neuroinflammatory diseases grows. With the current proliferation of hyperpolarized 13C (HP 13C) Magnetic Resonance Spectroscopy/Imaging (MRS/I) based on dissolution Dynamic Nuclear Polarization (dDNP), metabolic studies are in an exciting stage. Here a collection of three methods are aggregated, optimized, and presented as a general guideline for HP 13C metabolic studies of the mouse model. Firstly, in vivo Magnetic Resonance Spectroscopy (MRS) was performed utilizing the innovative dDNP of HP [1-13C] pyruvate. Five 12-week-old mice were imaged using a surface coil in a 3 Tesla preclinical system, with varying parameters such as time repetition (TR), flip angle, and pyruvate probe concentration. All spectra produced pyruvate and lactate peaks, and two acquisitions exhibited quantifiable bicarbonate peaks. The second, ex vivo component utilized a near-physiological NMR compatible perfusion system, which was optimized for maintaining viable fresh brain tissue slices. Viability was tested with an electrode measuring O2 levels of media, with nonviable samples consuming little to no O2. Over 7 hours of perfusion, all slices tested were compared to a negative control and deemed viable. Lastly, an enzyme activity assay is included as a robust validation tool. The 3 component system spans across multiple biological hierarchies, and each method balances the strengths and weaknesses of the other. Moving forward, HP 13C studies of brain metabolism utilizing this system will produce clear, robust results that can be applied to nearly any mouse model.

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