Proton diffusion spectroscopy and modeling of brain metabolism at 14.1T

Abstract

As a field at the CIBM, Nuclear magnetic resonance (NMR)spectroscopy can be applied non-invasively to explore the metabolic fate of energy fuel substrates, as well as the rate at which they are consumed, using 13C and 1H nuclei. The work of this thesis encompasses both nuclei, and focuses on (1) improving the quantification and modeling of glucose-derived metabolites; and (2) characterizing diffusion-related parameters of the purportedly glial-specific energy substrate, acetate. Both aim to quantitatively explore cerebral energy metabolism, at ultra-high magnetic field, in vivo, in the healthy rat. 13C NMR spectroscopy, as a tool, enables measuring the progressive incorporation of 13C-glucose into brain glucose and then NMR detectable amino acids (glutamate and glutamine); this relies on the infusion of the 13C-labeled energy substrate. The experimentally obtained 13C labelling curves are analyzed using suitable mathematical models to provide an estimation of cerebral metabolic rates. Here, a dynamic model of time-courses of 13C multiplets arising from isotopomers was considered. So beyond the two-compartment neuronal-glial model, we took into account additional data on the dynamics of 13C isotopomers, available from the fine structure multiplets in 13C spectra of glutamate and glutamine, measured under prolonged [1-6,13C] glucose infusion. We concluded that the dynamic analyses of 13C multiplet time courses of glutamate and glutamine resulted in a higher precision for estimating the absolute values of most cerebral metabolic rates. Acetate metabolism is challenging because dynamic metabolic modeling requires prior knowledge of the transport and uptake kinetics of infused acetate. We sought this information by determining the apparent concentration and distribution volume (V_d) of cerebral acetate between the intracellular and the extracellular compartments. Experimentally, the diffusion characteristics of cerebral acetate were measured, relative to that of N-Acetylaspartate (NAA, known to be mainly intracellular) using diffusion-weighted 1H NMR spectroscopy at 14.1T, under prolonged acetate infusion. The detection of an acetate and NAA signal at large diffusion weighting provided direct experimental evidence of intracellular cerebral acetate and NAA, although a substantial fraction of acetate was extracellular. To estimate the apparent concentration of in vivo brain acetate, T1 and T2 relaxation times of acetate were measured. The longer T1 relaxation and shorter T2 relaxation times of acetate compared with NAA provided evidence of its small molecular size, and possibly different chemical environment. Our experimentally determined value of V_dled to cerebral metabolic rates of acetate (CMR acetate) of the same order reported for the glial Kreb’s cycle rate, an indication that estimates of CMR acetate are highly dependent on V_d. Finally, in order to pursue metabolic mapping of cerebral acetate uptake in the rat, in vivo, at 14.1 T, the design and construction of a combined transmit-birdcage coil and receive-quadrature pair surface coil was considered. Its performance was compared to a single birdcage coil in the transmit/receive mode. So far, the preliminary results of the 2-coil configuration are promising: homogenous excitation and a gain in sensitivity up to a distance of 5 mm are achievable. Improvements are ongoing for NMR spectroscopic and imaging applications at 14.1 T.