Novel techniques for metabolic imaging using hyperpolarized carbon-13 compounds

Magnetic resonance imaging (MRI) using hyperpolarized carbon-13 compounds is an emerging tool to image real-time in vivo cellular metabolism with applications in studying tumor metabolism, understanding cardiac energetics, probing metabolic diseases, and assessing therapeutic response. In this work, we present several advances of this technology. First, in an imaging study using hyperpolarized [1-13C] pyruvate to assess the metabolic response in rat C6 glioma model treated with an anti-Vascular Endothelial Growth Factor (anti-VEGF) drug, we measured the relative preponderance of in vivo glycolysis and oxidative phosphorylation. We show that a single time-point measurement of the 13C lactate to bicarbonate ratio, 48 hours post-treatment, predicts survival and introduce the concept of cancer metabolic therapy index as a potential biomarker to evaluate treatment efficacy. Asymmetry of the C2 doublet in a sample of [1,2-13C] pyruvate has been suggested as a measure of in vivo polarization, a parameter necessary for quantitative studies. In the second part of this thesis, using product operator formalism, we present a theory for the asymmetry arising from the longitudinal two-spin order in hyperpolarized [1,2-13C] pyruvate. A model utilizing Redfield theory and three different relaxation mechanisms is proposed to explain the experimentally observed time-evolution of the asymmetry parameter. We show that the dipolar relaxation mechanism is dominant during the initial evolution of asymmetry, whereas, the cross-relaxation terms, arising from the interaction of chemical shift anisotropy and dipolar coupling, drive the asymmetry beyond its thermal equilibrium value. We further demonstrate that the knowledge of initial polarization is necessary for the estimation of instantaneous polarization using an asymmetry metric. Metabolic imaging using [2-13C] pyruvate simultaneously provides a direct measure of glycolysis and real-time window into the Krebs cycle. However, the difficulties due to the spread of the metabolite NMR signals over a large spectral range and the low SNR of [2-13C] lactate have limited its use. Here, we propose a hybrid imaging sequence alternately employing a fully resolved spectroscopic imaging to image the mitochondrial metabolites and a lactate-selective imaging sequence to simultaneously acquire real-time in vivo information related to oxidative phosphorylation and glycolysis. Additionally, we introduce two new techniques for resolving the J-modulated artifact in the imaging of [2-13C] lactate, one based on the idea of quadrature imaging and the other using a narrowband excitation pulse. In the concluding part of this thesis, two polarization transfer techniques that enhance the sensitivity of lactate detection in a hyperpolarized metabolic imaging experiment are presented. By transferring the polarization from the C2 carbon in hyperpolarized [2-13C] lactate to its J-coupled proton, an ~3X SNR gain as compared to direct carbon detection is achieved. To solve the problem of the lactate doublet buried under large water and lipid signals, a time-series based water-suppression method is developed that delivers over 3 orders of reduction in water signal. A second technique, called GREEDI, uses gradient waveforms to split the coherences into two pathways such that an anti-phase and an in-phase component combine to give a singlet at the time of signal collection. This effective decoupling method with built-in water suppression, makes imaging of [2-13C] lactate possible without any ghosting artifacts, thus providing a tool to simultaneously assess in vivo oxidative phosphorylation and glycolysis using hyperpolarized [2-13C] pyruvate metabolic imaging

Keywords: Electrical Engineering.
Advisor: Spielman Daniel (Daniel Mark)
Nishimura Dwight George 
Pauly John (John M.)