In vivo assessment of beta-hydroxybutyrate metabolism in mouse brain using deuterium (H-2) MRS

PurposeTo monitor the metabolic turnover of beta-hydroxybutyrate (BHB) oxidation using H-2-MRS in conjunction with intravenous administration of H-2 labeled BHB. MethodsNine-month-old mice were infused with [3,4,4,4]-H-2(4)-BHB (d(4)-BHB; 3.11 g/kg) through the tail vein using a bolus variable infusion rate for a period of 90 min. The labeling of downstream cerebral metabolites from the oxidative metabolism of d(4)-BHB was monitored using H-2-MRS spectra acquired with a home-built H-2 surface coil on a 9.4T preclinical MR scanner with a temporal resolution of 6.25 min. An exponential model was fit to the BHB and glutamate/glutamine (Glx) turnover curves to determine rate constants of metabolite turnover and to aid in the visualization of metabolite time courses. ResultsDeuterium label was incorporated into Glx from BHB metabolism through the tricarboxylic acid (TCA) cycle, with an increase in the level of [4,4]-H-2(2)-Glx (d(2)-Glx) over time and reaching a quasi-steady state concentration of similar to 0.6 +/- 0.1 mM following 30 min of infusion. Complete oxidative metabolic breakdown of d(4)-BHB also resulted in the formation of semi-heavy water (HDO), with a four-fold (10.1 to similar to 42.1 +/- 7.3 mM) linear (R-2 = 0.998) increase in its concentration by the end of infusion. The rate constant of Glx turnover from d(4)-BHB metabolism was determined to be 0.034 +/- 0.004 min(-1). Conclusion(2)H-MRS can be used to monitor the cerebral metabolism of BHB with its deuterated form by measuring the downstream labeling of Glx. The integration of H-2-MRS with deuterated BHB substrate provides an alternative and clinically promising MRS tool to detect neurometabolic fluxes in healthy and disease conditions.