HYPERPOLARIZED CARBON-13 MAGNETIC RESONANCE MEASUREMENTS OF TISSUE PERFUSION AND METABOLISM

Hyperpolarized Magnetic Resonance Imaging (HP MRI) is an emerging modality that enables non-invasive interrogation of cells and tissues with unprecedented biochemical detail. This technology provides rapid imaging measurements of the activity of a small quantity of molecules with a strongly polarized nuclear magnetic moment. This polarization is created in a polarizer separate from the imaging magnet, and decays continuously towards a non-detectable thermal equilibrium once the imaging agent is removed from the polarizer and administered by intravenous injection. Specialized imaging strategies are therefore needed to extract as much information as possible from the HP signal during its limited lifetime. In this work, we present innovative strategies for measurement of tissue perfusion and metabolism with HP MRI. These techniques include the capacity to sensitize the imaging signal to the diffusive motion of HP molecules, providing improved accuracy and reproducibility for assessment of agent uptake in tissue. The proposed methods were evaluated in numerical simulations, implemented on a preclinical MRI system and demonstrated in vivo in rodents through imaging of HP 13C urea. Using the simulation and imaging infrastructure developed in this work, established methods for encoding HP chemical signals were compared quantitatively. Lastly, our method was adapted for imaging of [2-13C]dihydroxyacetone, a novel HP agent that probes enzymatic flux through multiple biochemical pathways in vivo. Our results demonstrate the capacity of HP MRI to measure tissue perfusion and metabolism in ways not possible with the imaging modalities currently available in the clinic. As the use of HP MRI advances in clinical investigations of human disease, these imaging measurements can offer real-time and individualized information on disease states for early detection and therapeutic guidance

Hyperpolarized Xenon-129 Magnetic Resonance Imaging of Functional Lung Microstructure

Hyperpolarized 129Xe (HXe) is a non-invasive contrast agent for lung magnetic resonance imaging (MRI), which upon inhalation follows the functional pathway of oxygen in the lung by dissolving into lung tissue structures and entering the blood stream. HXe MRI therefore provides unique opportunities for functional lung imaging of gas exchange which occurs from alveolar air spaces across the air-blood boundary into parenchymal tissue. However challenges in acquisition speed and signal-to-noise ratio have limited the development of a HXe imaging biomarker to diagnose lung disease. This thesis addresses these challenges by introducing parallel imaging to HXe MRI. Parallel imaging requires dedicated hardware. This work describes design, implementation, and characterization of a 32-channel phased-array chest receive coil with an integrated asymmetric birdcage transmit coil tuned to the HXe resonance on a 3 Tesla MRI system. Using the newly developed human chest coil, a functional HXe imaging method, multiple exchange time xenon magnetization transfer contrast (MXTC) is implemented. MXTC dynamically encodes HXe gas exchange into the image contrast. This permits two parameters to be derived regionally which are related to gas-exchange functionality by characterizing tissue-to-alveolar-volume ratio and alveolar wall thickness in the lung parenchyma. Initial results in healthy subjects demonstrate the sensitivity of MXTC by quantifying the subtle changes in lung microstructure in response to orientation and lung inflation. Our results in subjects with lung disease show that the MXTC-derived functional tissue density parameter exhibits excellent agreement with established imaging techniques. The newly developed dynamic parameter, which characterizes the alveolar wall, was elevated in subjects with lung disease, most likely indicating parenchymal inflammation. In light of these observations we believe that MXTC has potential as a biomarker for the regional quantification of 1) emphysematous tissue destruction in chronic obstructive pulmonary disease (using the tissue density parameter) and 2) parenchymal inflammation or thickening (using the wall thickness parameter). By simultaneously quantifying two lung function parameters, MXTC provides a more comprehensive picture of lung microstructure than existing lung imaging techniques and could become an important non-invasive and quantitative tool to characterize pulmonary disease

Current Methods for Hyperpolarized [1-13C]pyruvate MRI Human Studies

MRI with hyperpolarized (HP) 13C agents, also known as HP 13C MRI, can measure processes such as localized metabolism that is altered in numerous cancers, liver, heart, kidney diseases, and more. It has been translated into human studies during the past 10 years, with recent rapid growth in studies largely based on increasing availability of hyperpolarized agent preparation methods suitable for use in humans. This paper aims to capture the current successful practices for HP MRI human studies with [1-13C]pyruvate - by far the most commonly used agent, which sits at a key metabolic junction in glycolysis. The paper is divided into four major topic areas: (1) HP 13C-pyruvate preparation, (2) MRI system setup and calibrations, (3) data acquisition and image reconstruction, and (4) data analysis and quantification. In each area, we identified the key components for a successful study, summarized both published studies and current practices, and discuss evidence gaps, strengths, and limitations. This paper is the output of the HP 13C MRI Consensus Group as well as the ISMRM Hyperpolarized Media MR and Hyperpolarized Methods & Equipment study groups. It further aims to provide a comprehensive reference for future consensus building as the field continues to advance human studies with this metabolic imaging modality

Hyperpolarized 129Xe Apparent Diffusion Coefficient Anisotropy in an Elastase- Instilled Rat Model of Emphysema

In recent years, hyperpolarized noble gas magnetic resonance diffusion measurements have shown remarkable sensitivity for diagnosing emphysema. The apparent diffusion coefficient (ADC) of hyperpolarized gases has also been shown to behave anisotropically in the lung at short diffusion times. In this work, we investigate hyperpolarized Xe gas anisotropic ADCs of the Yablonskiy model in vivo in an elastase-instilled rat model of emphysema. Diffusion simulations in a budded cylinder model estimated that the transverse anisotropic ADC (Dr) may have optimal sensitivity at measuring airways enlargements, and that the optimal diffusion time to measure Dj with xenon is close to 5 ms. Measurements in sham and elastase-instilled rats were performed for a range of diffusion times, and the only significant increase of ADC was observed for Dj at 6 ms (p \u3c 0.005), and a strong correlation between Dj and the mean linear intercepts from lung histology was observed (r = 0.90)

Metabolic Imaging of Early Radiation-Induced Lung Injury Using Hyperpolarized 13C-Pyruvate in Rodent Lungs

Lung cancer is the leading cause of cancer related death. Radiation therapy is a prominent treatment method but leads to adverse consequences. Radiation-Induced Lung Injury (RILI) is the primary adverse consequence that limits further radiation therapy and develops in 5-37% of the treated patients. RILI proceeds in two distinct phases: a) early and reversible Radiation Pneumonitis (RP), and b) late and irreversible radiation fibrosis. Clinically, Dose Volume Histogram (DVH) parameters derived from radiation therapy planning stage are used to determine outcome and severity of RP but have been demonstrated to possess a very low predictive power. Computed Tomography (CT) is the most commonly used modality for the imaging of RP, but often only detects very late RP that leaves little room for intervention to abort the progress to irreversible radiation fibrosis. Early detection of RP using imaging may allow for interventional treatment and management of the disease and the associated symptoms in a better manner. Improvement in Dynamic Nuclear Polarization (DNP) technology has led to advancement of hyperpolarized 13-Carbon-Magnetic Resonance Imaging (13C-MRI). In this thesis, we present the investigation of early detection of RP with 13C-MRI in an animal model with the use of hyperpolarized 13C-pyruvate. A pilot study demonstrated the proof of concept along with a qualitative histological confirmation. 13C-MRI data and histology data were collected 2 weeks post irradiation of whole thorax in rodents. In the subsequent study, regional and longitudinal 13C-MRI and quantitative histology data were analyzed to demonstrate the early organ-wide response of RP. These data were collected at day 5, 10, 15 and 25 post conformal irradiation of the right rodent lung. Finally, we demonstrate a novel approach to map pH using hyperpolarized 13C-bicarbonate with the use of spiral-Iterative Decomposition of water and fat with Echo Asymmetry and Least squares estimation (IDEAL) pulse sequence. Validation of this approach by comparison to Chemical Shift Imaging (CSI) pH measurement and standard pH measurement with the aid of phantoms along with hyperpolarized 13C-bicarbonate is presented. pH mapping may play a role in the staging and therapeutic intervention of cancer

Magnetic Resonance Imaging Techniques For Contrast - Enhanced Cellular And Molecular Imaging

Ph.DDOCTOR OF PHILOSOPH

Quantitative Mapping of Lung Ventilation Using Hyperpolarized Gas Magnetic Resonance Imaging

The main objective of this project was to develop and implement techniques for high-resolution quantitative imaging of ventilation in lungs using hyperpolarized gas magnetic resonance imaging (MRI). Pulmonary ventilation is an important aspect of lung function and is frequently compromised through several different mechanisms and at varying degrees in presence of certain lung conditions, such as chronic obstructive pulmonary diseases. The primary focus of this development is on large mammalian species as a steppingstone towards translation to human subjects. The key deliverables of this project are a device for real-time mixing and delivery of hyperpolarized gases such as 3He and 129Xe in combination with O2, an MRI acquisition scheme for practical imaging of ventilation signal build-up in the lungs, and a robust mathematical model for estimation of regional fractional ventilation values at a high resolution. A theoretical framework for fractional gas replacement in the lungs is presented to describe MRI signal dynamics during continuous breathing of a mixture of hyperpolarized gases in presence of several depolarization mechanisms. A hybrid ventilation and imaging acquisition scheme is proposed to acquire a series of images during short end-inspiratory breath-holds over several breaths. The sensitivity of the estimation algorithm is assessed with respect to noise, model uncertainty and acquisition parameters, and subsequently an optimal set of acquisition parameters is proposed to minimize the fractional ventilation estimation error. This framework is then augmented by an undersampled parallel MRI scheme to accelerate image acquisition to enable fractional ventilation imaging over the entire lung volume in a single pass. The image undersampling was also leveraged to minimize the coupling associated with signal buildup in the airways and the irreversible effect of RF pulses. The proposed technique was successfully implemented in pigs under mechanical ventilation, and preliminary measurements were performed in an adult human subject under voluntary breathing

Development of pulse sequences for hyperpolarized 13C magnetic resonance spectroscopic imaging of tumour metabolism

Metabolic imaging with hyperpolarized 13C-labeled cell substrates is a promising technique for imaging tissue metabolism in vivo. However, the transient nature of the hyperpolarization - and its depletion following excitation - limits the imaging time and the number of excitation pulses that can be used. A single-shot 3D imaging sequence has been developed and it is shown in this thesis to generate 13C MR images in tumour-bearing mice injected with hyperpolarized [1-13C]pyruvate. The pulse sequence acquires a stack-of-spirals at two spin echoes after a single excitation pulse and encodes the kz-dimension in an interleaved manner to enhance robustness to B0 inhomogeneity. Spectral-spatial pulses are used to acquire dynamic 3D images from selected hyperpolarized 13C-labeled metabolites. A nominal spatial/temporal resolution of 1.25 x 1.25 x 2.5 $mm^3$ x 2 s was achieved in tumour images of hyperpolarized [1-13C]pyruvate and [1-13C]lactate acquired in vivo. An advanced sequence is also described in this thesis in a later study to acquire higher resolution images with isotropic voxels (1.25 x 1.25 x 1.25 $mm^3$) at no cost of temporal resolution. EPI is a sequence widely used in hyperpolarized 13C MRI because images can be acquired rapidly with limited RF exposure. However, EPI suffers from Nyquist ghosting, which is normally corrected for by acquiring a reference scan. In this thesis a workflow for hyperpolarized 13C EPI is proposed that requires no reference scan and, therefore, that does not sacrifice a time point in the dynamic monitoring of tissue metabolism. To date, most of the hyperpolarized MRI on metabolism are based on 13C imaging, while 1H is a better imaging target for its 4 times higher gyromagnetic ratio and hence 16 times signal. In this thesis the world’s first dynamic 1H imaging in vivo of hyperpolarized [1-13C]lactate is presented, via a novel double-dual-spin-echo INEPT sequence that transfers the hyperpolarization from 13C to 1H, achieving a spatial resolution of 1.25 x 1.25 $mm^2$