Browsing by Subject "129Xe"
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Item Open Access Dynamic 129Xe Magnetic Resonance Spectroscopy: Development and Application in Diverse Cardiopulmonary Diseases(2021) Bier, Elianna AdaChronic respiratory diseases are one of the leading causes of death in the US and a driving factor in their mortality rate is the presence of comorbid cardiovascular diseases such as pulmonary hypertension (PH). As an increasing number of patients exhibit concomitant cardiac and pulmonary disease it becomes progressively more difficult to determine disease etiology and thus the optimal treatment course. The current standard diagnostic methods are insensitive to the underlying cause of gas exchange impairment, are unable to differentiate between phenotypes, and have limited utility in assessing disease progression or therapy response. The primary diagnostic tools for assessing pulmonary function are collectively referred to as pulmonary function tests (PFTs). While these tests are simple and non-invasive, they are also a global measurement that is effort-dependent and has poor reproducibility. Furthermore, PFTs cannot separate the contribution of concomitant disease on their measurements. The diagnosis of PH and subsequent determination of World Health Organization (WHO) classification requires invasive right heart catheterization (RHC) to meet strict hemodynamic cutoffs. However, the RHC interpretation can be challenging in patients with complex disease because the effect of comorbidities on RHC measurements is unknown. Therefore, new non-invasive diagnostic tools must be developed that can assess gas exchange impairment and pulmonary hemodynamics in tandem for patients to receive optimal treatment.
Hyperpolarized 129Xe MR imaging (MRI) and spectroscopy (MRS) have emerged as a powerful tool for assessing the pulmonary environment due xenon exhibiting distinct chemical shifts as it diffuses from the airspaces, through the alveolar membrane, and interacts with red blood cells (RBCs). This unique property allows the 129Xe signal to be decomposed in order to separately measure or image the three gas exchange compartments (gas, barrier, and RBC). 129Xe gas exchange imaging is beginning to show exquisite sensitivity to a range of obstructive and restrictive diseases. Still, despite this sensitivity to disease burden, 129Xe imaging techniques are unable to probe pulmonary hemodynamics. Thus, it does not provide sensitivity to PH, one of the possible causes of dyspnea. Previous work has demonstrated that in 129Xe MRS the characteristics of the spectral peaks can detect diffusion impairments present in interstitial lung disease (ILD). Yet current 129Xe MRS techniques only investigate static measurements of an inherently dynamic process. It is possible to extend 129Xe MRS and collect spectra as a time-series in dynamic spectroscopy to assess the cardiogenic changes in spectral parameters that may be associated with the hemodynamic changes in PH.
The objective of this work is to establish methods using 129Xe MRI/MRS to differentiate between diverse cardiopulmonary diseases. To this end, we develop the technique of 129Xe dynamic spectroscopy and assesses its utility in differentiating pre-capillary and post-capillary PH. We also investigate quality assurance metrics and tools including the repeatability of spectroscopic measurements and a thermally polarized xenon phantom to help facilitate the transition of 129Xe MRI/MRS into a clinical tool.
The foundation of 129Xe dynamic spectroscopy is the decomposition of each static spectrum into its three separate components. This is achieved by fitting each spectrum in the time-series to a mathematical model that describes the shape of each peak. In Chapter 3, to characterize the spectral parameters more accurately, we analyzed 6 different mathematical models for 129Xe dissolved-phase MR spectroscopy. We demonstrate that the optimized spectroscopic fitting model is a barrier Voigt model where the RBC peak has a Lorentzian lineshape and the barrier peak is a Voigt profile. This model was used in dynamic spectroscopy to extract the area, chemical shift, linewidth, and phase of each peak.
In principle, the dynamic variations in the spectral parameters of each 129Xe resonance detected during the cardiac cycle can contain vital information on pulmonary hemodynamics. Thus, in Chapter 4 we developed techniques to quantify and assess the temporal changes in the spectroscopic parameters during inhale, breath-hold, and exhalation. We observed a distinct cardiogenic oscillation in the amplitude and chemical shift of the RBC peak. This oscillation was quantified by its peak-to-peak height. Furthermore, we identified static and spectral parameters that are statistically different between healthy volunteers and subjects with idiopathic pulmonary fibrosis (IPF). This study demonstrated that that 129Xe dynamic spectroscopy is sensitive to disease.
The initial characterization of a diverse array of diseases is essential to understand the relationship between 129Xe spectroscopy and the cardiopulmonary environment. Thus, Chapter 5 characterizes 129Xe MRI/MRS in healthy volunteers and subjects with chronic obstructive pulmonary disease (COPD), IPF, left heart failure (LHF), and pulmonary arterial hypertension (PAH). The chosen cohorts provide two forms of chronic lung disease (IPF, COPD) and two forms of PH (LHF, PAH) that have different impedance locations with respect to the pulmonary capillary bed. LHF is a form of post-capillary PH because the impedance to blood flow is downstream of the pulmonary capillary bed as left ventricular dysfunction leads to a sustained increase in left atrial pressure. On the other hand, PAH is a form of pre-capillary PH caused by occlusions upstream of the capillary bed. We found that while gas exchange imaging is essential in the discrimination of obstructive and interstitial disease, only the height of oscillations in the RBC amplitude was able to differentiate between the different types of PH.
To test the utility of 129Xe MRI/MRS in differentiating PH status, we designed a diagnostic algorithm in Chapter 6 to distinguish between pre-capillary PH, post-capillary PH, no PH, and interstitial lung disease (ILD). Algorithm performance was tested in a single-blind reader study in which three expert readers used 129Xe MRI/MRS to determine the PH status of 32 test subjects. The algorithm performed well on straightforward cases of PH. For subjects with concomitant disease, the combination of MRI/MRS provided additional insight to the complex pathophysiology that cannot be quantified by hemodynamic measurements alone. This demonstrated that 129Xe dynamic MRS and gas exchange MRI can be used in tandem to uniquely provide non-invasive assessment of both hemodynamics and gas-exchange impairment to aid in the differentiation and detection of PH.
For 129Xe MRI/MRS to be adopted into a clinical setting it is essential to understand the underlying measurement variability. Chapter 7 presents an assessment of the repeatability of the dynamic spectroscopy sequence and quantification methods by acquiring two dynamic spectroscopy acquisitions during a single MR study. We also use these paired scans to develop quantitative criteria to assess the scan quality for inclusion in dynamic analysis. Additionally, as 129Xe MRI/MRS is more broadly implemented it is imperative to have standards for day-to-day validation and for comparing performance at different 129Xe imaging centers. Therefore, Chapter 8 present our development of a thermally polarized xenon phantom assembly and associated imaging protocol to enable rapid quality‐assurance (QA) imaging.
The work in this thesis develops a robust 129Xe dynamic spectroscopy protocol for evaluating the temporal dynamics in the RBC resonance. In particular, the height of RBC amplitude oscillations is found to be sensitive to PH and can be used to differentiate between pre- and post-capillary forms. 129Xe dynamic spectroscopy and 129Xe gas exchange MRI can differentiate between diverse cardiopulmonary diseases and together provide a complete evaluation of pulmonary hemodynamics and gas exchange impairments. This research lays the groundwork for the use of 129Xe MRI/MRS in clinical practice to diagnose and monitor PH and transforms 129Xe MRI/MRS into a more comprehensive tool for investigating the pathogenesis of unexplained dyspnea.
Item Open Access Preclinical Hyperpolarized 129Xe MRI: Development, Applications, and Dissemination(2018) Virgincar, Rohan ShyamHyperpolarized (HP) gas MRI is emerging as a powerful, non-invasive method for imaging lung function. MRI of HP 129Xe and 3He was first introduced in small animals and was soon followed by its clinical implementation. 3He was preferred for imaging since it was more straight-forward to hyperpolarize in large volumes and had favorable magnetic resonance properties for high-resolution. However, the scarcity and high cost of this isotope has driven a transition to abundantly available 129Xe. This transition has stimulated a lot of clinical 129Xe MRI research. 129Xe ventilation, barrier-tissue uptake and red-blood-cell (RBC) transfer can now be depicted separately and three-dimensionally by exploiting xenon solubility and large chemical shifts in different pulmonary micro-environments. With this powerful capability, this technique has found clinical application across a broad range of lung diseases.
As clinical implementation progresses, it has become increasingly important to test these methods in well-controlled animal models. Such preclinical studies enable the testing of experimental drugs, tracking of disease progression by longitudinal imaging, validation against histology, and provide a platform to rapidly develop and validate novel methods of image acquisition and analysis. However, among the ~20 centers worldwide that have HP gas MRI capability, only 5 have demonstrated the capability to conduct preclinical studies. Preclinical 129Xe MRI is challenging owing to extensive requirements of animal handling, reliable delivery of polarized gas, and the challenges of high-resolution multi-breath imaging. While some applications for HP gas MRI in small animals have emerged, these have mostly been with 3He and the handful of work on 129Xe has been limited to 2D imaging. As was the case in the clinic, there is now an equally urgent need to drive the transition from 3He to 129Xe in the preclinical setting, demonstrate sufficient image quality, and rapidly discover new applications.
The objective of this work is to establish a robust and comprehensive 129Xe MRI infrastructure to investigate rodent models of lung disease, and to lay the foundation for the reverse-translation and dissemination of this capability. To this, the work in this thesis describes several milestones toward establishing routine, high-resolution 3D 129Xe MRI of gas-exchange on a modern preclinical imaging platform.
First, we established routine 3D 129Xe MRI in mice on a GE 2 Tesla magnet. Through rigorous optimization of multi-breath image acquisition strategies with constant-volume ventilation, we demonstrated high-resolution imaging of 129Xe gas- and dissolved-phases in mice with 156-µm and 312-µm isotropic resolution. In addition to imaging, we also comprehensively characterized 129Xe spectroscopic lineshapes in mice. The in vivo resonances of 129Xe are sensitive to micron-scale changes in lung physiology, but have been analyzed and reported inconsistently and inaccurately in the literature. Using innovative spectroscopic acquisition methods and robust fitting techniques, we introduced methodology to identify an accurate 129Xe reference frequency in vivo, and characterized the many dissolved-phase resonances that are arise as 129Xe is transported to distal tissues in the thoracic cavity.
Until this point, animal studies using 129Xe MRI required sacrificing the animal upon completion of imaging, owing to the requirement of tracheostomy to ventilate the rodent with HP gas. Also, our experiments could only be conducted on a single 2 Tesla magnet, because the ventilator and physiological monitoring system was hard-wired to this scanner. In order to address these limitations, we built a new ventilator with integrated physiological monitoring with a focus on portability, minimizing cost, and compatibility for longitudinal imaging. The portable and integrated ventilator made possible our first dissemination of preclinical 129Xe MRI—to the University of Oxford, UK.
Our robust 129Xe MRI and spectroscopy protocol was deployed to investigate two key mouse models of lung disease at 2 Tesla: lung cancer and invasive pulmonary aspergillosis (IPA). In lung cancer, longitudinal 129Xe MRI revealed tumors on 1H MRI and histology, and severe ventilation and gas-exchange defects. 129Xe spectroscopy additionally revealed a robust signature of cancer-associated cachexia. 129Xe MRI in IPA also revealed significant and complex ventilation and gas-exchange defects, which was bolstered by spectroscopic features.
Having a portable ventilator enabled experiments to be carried out at other magnets at our center. Since modern preclinical magnets now operate at high field strengths, we established preclinical 129Xe MRI on a Bruker 7 Tesla magnet at our center, to facilitate its broader dissemination. This is the most widely available preclinical imaging platform with an installed base estimated to exceed 500 units. This transition involved a comprehensive characterization and optimization of the noise floor of the system to maximize SNR, and developing several new image acquisition strategies to rapidly image short-lived 129Xe signal at 7 Tesla (dissolved-phase T2* ~0.5 ms). On this platform, we developed a robust 129Xe MRI protocol for quantitative gas-exchange mapping in rats, identical to that used by our clinical program to facilitate translation/reverse translation.
Finally, we used the new 7 Tesla platform to investigate the monocrotaline (MCT) rat model of pulmonary arterial hypertension (PAH). This model was chosen for 2 reasons: first, it provided a unique opportunity to deploy 129Xe gas-exchange MRI in a model that is translationally relevant to current clinical investigations; second, there is also a dire need for non-invasive assays to elucidate the pathogenesis of this disease in the lung, and to enable early detection. In this study, we comprehensively characterized the imaging and spectroscopic markers of this disease and validated results with histology. 129Xe MRI revealed significantly reduced signal in RBCs, as well as interesting abnormalities in the barrier-uptake and gas-phase signal that were consistent with the pathobiology of this disease model. This is the first study to have demonstrated the potential of 129Xe to be a valuable tool for assessing rodent models of pulmonary vascular disease.
This body of work has thus established a robust preclinical 129Xe MRI framework that can be routinely used for imaging across field strengths, vender platforms, rodent species, be translated/reverse-translated to/from our clinical program, and be disseminated to other centers. We have also demonstrated the potential of this imaging platform to identify different disease signatures in several clinically-relevant rodent models. We anticipate that this work will provide a fundamentally new capability to accelerate progress in lung imaging research.