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Development of Dynamic Phosphorus-31 and Oxygen-17 DEVELOPMENT OF DYNAMIC PHOSPHORUS-31 AND OXYGEN-17 MAGNETIC RESONANCE SPECTROSCOPY AND IMAGING TECNIQUES FOR PRECLINICAL ASSESSMENT OF ENERGY METABOLISM IN VIVO by YUCHI LIU Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Biomedical Engineering CASE WESTERN RESERVE UNIVERSITY January, 2018 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of Yuchi Liu candidate for the degree of Doctor of Philosophy*. Committee Chair Dr. Nicole Seiberlich Committee Member Dr. Xin Yu Committee Member Dr. Mark Griswold Committee Member Dr. Nicola Lai Committee Member Dr. John Kirwan Date of Defense July 19th, 2017 *We also certify that written approval has been obtained for any proprietary material contained therein. 2 Table of Contents Table of Contents .................................................................................................... 3 List of Tables .......................................................................................................... 6 List of Figures ......................................................................................................... 7 Acknowledgements ............................................................................................... 10 List of Abbreviations ............................................................................................ 11 Abstract ................................................................................................................. 14 Chapter 1. Introduction ......................................................................................... 16 1.1. Metabolism and Oxidative Phosphorylation .............................................. 16 1.2. Assessing Mitochondrial Function Using 31P MRS/MRI .......................... 20 1.2.1. Steady-state 31P MRS .......................................................................... 21 1.2.2. Dynamic 31P MRS ............................................................................... 24 1.2.3. Single Voxel Spectroscopy (SVS) ....................................................... 26 1.2.4. Chemical Selective Imaging Methods ................................................. 27 1.2.5. MRSI Methods .................................................................................... 30 1.3. Assessing Oxygen Metabolism Using 17O MRS/MRI ............................... 34 1.3.1. Concept of 17O MRI for Investigating Cerebral Oxygen Metabolism and Water Movement across the Blood-Brain Barrier (BBB) ...................... 34 1.3.2. 17O MR Properties ............................................................................... 35 1.3.3. Quantification of CMRO2 in Small Animals ....................................... 37 1.3.4. 17O MRS/MRI Methods ...................................................................... 38 1.4. Motivations and Objectives ........................................................................ 40 Chapter 2. Mitochondrial Function Assessed by 31P MRS and BOLD MRI in Non-obese Type 2 Diabetic Rats .......................................................................... 42 2.1. Introduction ................................................................................................ 42 2.2. Materials and Methods ............................................................................... 45 2.2.1. Animals ................................................................................................ 45 2.2.2. Experimental Protocol ......................................................................... 45 2.2.3. MRI and MRS Studies ......................................................................... 46 2.2.4. Data Analysis ....................................................................................... 47 3 2.2.5. Statistics ............................................................................................... 48 2.3. Results ........................................................................................................ 49 2.3.1. Animal Characteristics ........................................................................ 49 2.3.2. 31P MRS ............................................................................................... 49 2.3.3. BOLD MRI .......................................................................................... 52 2.4. Discussion and Conclusions ....................................................................... 53 Chapter 3. High Resolution Dynamic 31P MRSI of Ischemia-Reperfusion in Rat Hindlimb Using a Low-rank Tensor Model .......................................................... 59 3.1. Introduction ................................................................................................ 59 3.2. Methods ...................................................................................................... 61 3.2.1. Signal Model........................................................................................ 61 3.2.2. Data Acquisition .................................................................................. 62 3.2.3. Data Processing ................................................................................... 63 3.2.4. In vivo MRI Experiments .................................................................... 64 3.3. Results ........................................................................................................ 65 3.4. Discussion and Conclusions ....................................................................... 68 Chapter 4. Development of Dynamic 17O MRI Using Golden-ratio–based Radial Sampling and k-space–weighted Image Reconstruction ...................................... 71 4.1. Introduction ................................................................................................ 71 4.2. Methods ...................................................................................................... 74 4.2.1. Golden-Ratio-Based Radial Sampling and k-Space-Weighted Image Reconstruction ............................................................................................... 74 4.2.2. Simulations .......................................................................................... 76 4.2.3. Phantom Experiments .......................................................................... 78 4.2.4. Image Reconstruction and Analysis .................................................... 79 4.3. Results ........................................................................................................ 79 4.3.1. Simulations for Injection Studies ........................................................ 79 4.3.2. Simulations for Inhalation Studies ...................................................... 81 4.3.3. Phantom Experiments .......................................................................... 82 4.4. Discussion and Conclusions ....................................................................... 83 4 17 Chapter 5. In vivo Applications of Dynamic O MRI: Assessment of Water Movement across BBB in a Mouse Model of GBM and Cerebral Oxygen Metabolism in a Mouse Model of MCAO ............................................................ 87 5.1. Introduction ................................................................................................ 88 5.2. Methods ...................................................................................................... 89 5.2.1. GBM Animal Model ............................................................................ 89 5.2.2. Stroke Animal Model .......................................................................... 90 5.2.3. In Vivo MRI Experiments in GBM Mice ............................................ 90 5.2.4. In Vivo MRI Experiments in the Stroke Mouse .................................. 92 5.2.5. Image Reconstruction and Analysis .................................................... 94 5.2.6. Histology ............................................................................................. 95 5.2.7. Statistics ............................................................................................... 96 5.3. Results ........................................................................................................ 96 5.3.1. In Vivo Results in GBM Mice ............................................................. 96 5.3.2. In Vivo Results in the Stroke Mouse ................................................... 99 5.4. Discussion and Conclusions ..................................................................... 100 Chapter 6. Conclusions and Future Perspectives ................................................ 105 6.1. Further Improvements of the 31P and 17O MRS/I Methods ...................... 105 6.1.1. Coil Design ........................................................................................ 106 6.1.2. Sequence Design for 31P Studies ....................................................... 107 6.1.3. Sequence Design for 17O Studies ...................................................... 108 6.1.4. Dynamic MRI Techniques................................................................. 109 6.2. Preclinical and Clinical Applications of 31P MRS/I in General ............... 110 6.3. Potential Clinical Applications of 17O MRI in Stroke Patients ................ 112 Bibliography ....................................................................................................... 114 5 List of Tables Table 1.1. A summary of typical
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