Chemical Exchange Saturation Transfer Imaging Of Endogenous Metabolites For Monitoring Oxidative Phosphorylation And Glycolysis In Vivo

Oxidative phosphorylation (OXPHOS) and glycolysis are two cellular metabolic pathways that play a crucial role in the functions of biological systems. Currently, magnetic resonance spectroscopy (MRS) (13C, 31P, and 1H) and positron emission tomography (PET) methods are used to investigate changes in these pathways that result from metabolic dysfunction. However, MRS methods are limited by low resolution and long acquisition times. While 18F-fluoro-2-deoxy-D-glucose (18F-FDG) PET is a widely used clinical modality, it requires the use of radioactive ligands. Thus, there is an unmet need for techniques to image these metabolic processes noninvasively, and with higher resolution in vivo. In this dissertation, we exploited the chemical exchange saturation (CEST) phenomenon to develop and optimize endogenous CEST magnetic resonance imaging (MRI) methods to measure OXPHOS and glycolysis, and demonstrated application of those techniques to study impaired metabolism in vivo. These CEST methods offer several orders of magnitude higher sensitivity compared to traditional spectroscopic techniques. Recently developed CEST imaging of free creatine (CrCEST) was targeted as a means of measuring OXPHOS. We optimized and validated this technique in healthy human skeletal muscle, showing that CrCEST imaging in dynamic exercise studies provides a measure of the mitochondrial rate of OXPHOS. CrCEST imaging was then implemented in a cohort of subjects affected by genetic disorders of the mitochondria. The results of these studies demonstrate that CrCEST has the capability to distinguish between healthy and impaired OXPHOS in muscle. In some diseases with altered metabolism, like cancer, aerobic glycolysis dominates, leading to increased lactate production. Existing methods for imaging lactate in vivo involve expensive, radiolabeled tracers. In this work, we demonstrated the feasibility of imaging lactate with CEST (“LATEST”) in phantoms with physiological concentrations. Then, we validated the method dynamically in vivo by measuring lactate production and clearance in intensely exercised human skeletal muscle, which utilizes anaerobic glycolysis. Finally, we infused rats bearing lymphoma tumors with non-labeled pyruvate and demonstrated the ability of LATEST MRI to image tumors and measure dynamic lactate changes over time. Together, these studies demonstrate that metabolic processes can be monitored in vivo using CEST MRI, with potential for widespread clinical applications

Theory of Combined Photoassociation and Feshbach Resonances in a Bose-Einstein Condensate

We model combined photoassociation and Feshbach resonances in a Bose-Einstein condensate, where the shared dissociation continuum allows for quantum interference in losses from the condensate, as well as a dispersive-like shift of resonance. A simple analytical model, based on the limit of weakly bound molecules, agrees well with numerical experiments that explicitly include dissociation to noncondensate modes. For a resonant laser and an off-resonant magnetic field, constructive interference enables saturation of the photoassociation rate at user-friendly intensities, at a value set by the interparticle distance. This rate limit is larger for smaller condensate densities and, near the Feshbach resonance, approaches the rate limit for magnetoassociation alone. Also, we find agreement with the unitary limit--set by the condensate size--only for a limited range of near-resonant magnetic fields. Finally, for a resonant magnetic field and an off-resonant laser, magnetoassociation displays similar quantum interference and a dispersive-like shift. Unlike photoassociation, interference and the fieldshift in resonant magnetoassociation is tunable with both laser intensity and detuning. Also, the dispersive-like shift of the Feshbach resonance depends on the size of the Feshbach molecule, and is a signature of non-universal physics in a strongly interacting system.Comment: 10 pages, 5 figures, 82 reference

In vivo Magnetic Resonance Imaging of Tumor Protease Activity

Increased expression of cathepsins has diagnostic as well as prognostic value in several types of cancer. Here, we demonstrate a novel magnetic resonance imaging (MRI) method, which uses poly-L-glutamate (PLG) as an MRI probe to map cathepsin expression in vivo, in a rat brain tumor model. This noninvasive, high-resolution and non-radioactive method exploits the differences in the CEST signals of PLG in the native form and cathepsin mediated cleaved form. The method was validated in phantoms with known physiological concentrations, in tumor cells and in an animal model of brain tumor along with immunohistochemical analysis. Potential applications in tumor diagnosis and evaluation of therapeutic response are outlined