Quantitative Hyperpolarized 129Xe Gas exchange MRI: Development and Applications

Pulmonary diseases are one of the leading causes of death and contribute to major healthcare cost in the United States. However, clinical treatment of these diseases has long been constrained by lack of sensitive diagnostic methods, reliable disease phenotypes, and difficulty to detect therapeutic response. Pulmonary function testing (PFT), the main diagnostic tool to measure pulmonary function such as ventilation and gas exchange (gas exchange), are limited to global measurements and incapable of assessing regional disease burden. Recently, this gap has been addressed by the application of hyperpolarized (HP) 129Xe magnetic resonance imaging (MRI). HP 129Xe ventilation imaging generates 3D images of 129Xe distributed in the lungs to probe ventilation function and reveal regional ventilation defect. It has been applied in clinical research on healthy subjects and patients with asthma and chronic obstructive pulmonary disease (COPD), which has demonstrated strong sensitivity to ventilation impairment and repeatable ventilation defect quantification.

Besides ventilation, HP 129Xe can be used to directly measure gas exchange function. When inhaled, 1-2% of HP 129Xe dissolves into pulmonary interstitial barrier tissue and Red Blood Cells (RBCs), exhibiting distinct resonant frequency shifts (198 ppm in barrier tissues and 217 ppm in RBCs). These distinct frequency shifts allow 3D images to be acquired depicting 129Xe in airways, its barrier uptake and RBC transfer in one breath-hold. This imaging capability makes 129Xe gas exchange (gas exchange) MRI an ideal probe of pulmonary gas exchange function to determine the pulmonary causes of dyspnea such as obstructive and interstitial diseases. While the imaging approach is capable of spatially resolving heterogeneous disease burden, whole-lung dynamic spectroscopy, spectra acquired every 20ms, provides additional temporal resolution to characterize capillary hemodynamics. The array of imaging and spectroscopic methods presents an appealing approach to phenotype cardiopulmonary diseases.

While the ability to acquire these images represents an important technical advancement, methods to quantify and interpret these images are lacking. The weak barrier and RBC signal relative to the gas signal limits the ability of quantifying and visualizing images using simple grayscale, especially for subject comparison and longitudinal studies. Therefore, a reliable and sensitive quantification method is urgently needed to benchmark increased barrier uptake, as might be expected in interstitial lung diseases, or decreased barrier uptake, as might be seen in emphysema, and further determine the extent to which these factors are affecting regional RBC transfer in a broad array of pulmonary disorders.

In patients with idiopathic pulmonary fibrosis (IPF), an interstitial disease characterized by chronic fibrosis and progressive lung function decline, the ratio of 129Xe uptake in RBCs to barrier tissues is dramatically reduced. However, to date it is not clear whether the reduction is caused by decreased 129Xe transfer in RBCs, increased 129Xe uptake in barrier or a combination of both. In Chapter 3, we demonstrate an approach in which local ratios of barrier/gas and RBC/gas can be visualized by appealing to a healthy reference cohort and applying quantitative thresholds based on such reference population. We applied this quantification method to healthy subjects and IPF patients to assess regional gas exchange function. Our results showed increased 129Xe barrier uptake and reduced RBC transfer in IPF patients compared to the healthy reference, which likely result from the thickened barrier tissue of IPF. Our preliminary results on a COPD patient and a pulmonary arterial hypertension (PAH) patient indicate that this method can be applied beyond IPF.

While our initial quantitative analysis approach was built around 1.5T acquisitions, translation to future multi-center trials would require transitioning our entire program to 3 Tesla, as MR vendors are increasingly transitioning their multi-nuclear capabilities to higher field strength. This introduces specific challenges for the acquisition, primarily due to faster decay of transverse magnetization with shortened T2*. Chapter 4 describes our comprehensive re-engineering of methods to transition this capability at 3 Tesla and establish a practice for adoption at higher field strength. We implemented fast excitation/readout to mitigate signal decay and designed randomized 3D trajectory against subject early exhalation. We generalized the threshold method based on healthy reference to accommodate subject scans from different acquisition settings. We validated our newly established capability by obtaining representative healthy subject and patient scans at 3 Tesla, building a new healthy reference cohort and comparing it with ones obtained at different acquisition settings. The consistent quantification results suggest that our acquisition and quantification methods can be employed for acquisitions across different field strengths and bandwidths.

The successful establishment of 129Xe gas exchange MRI at 3 Tesla laid the groundwork to evaluate the method across cardiopulmonary diseases to identify distinguishing features. Our 129Xe gas exchange imaging and spectroscopy provide a non-invasive evaluation with spatial and temporal resolution, sensitive to regional gas exchange impairment and hemodynamics alteration, which is not directly measured by conventional PFTs. These advantages provide potential for 129Xe MRI to overcome the limitation of standard diagnostic criteria on patients exhibiting concomitant cardiac and pulmonary diseases. In Chapter 5, we applied 129Xe gas exchange imaging and spectroscopy to identify patterns of regional gas exchange impairment and altered hemodynamics that are uniquely associated with COPD, IPF, left heart failure (LHF), and PAH. We identified 129Xe MR metrics that when combined, uniquely distinguish each of these disease cohorts. We further proposed alveolar-capillary models for these disease phenotypes to explain the observed 129Xe measurements. Finally, we developed a diagnostic algorithm using these metrics systematically, which distinguishes pre-capillary pulmonary hypertension (PH) from post-capillary PH.

While 129Xe gas exchange MRI provides unique signatures for a wide range of pulmonary obstructive, interstitial and cardiopulmonary disease, the physiological interpretation of regional RBC transfer remains to be established. Moreover, the simple RBC-barrier ratio, which was reported to corelate strongly with DLCO in IPF patients and healthy subjects, does not account for factors such as emphysematous loss of membrane conductance or accessible alveolar volume (VA). Thus, in Chapter 6 we seek to develop a comprehensive means to interpret 129Xe MRI across a broad range of pathologies. First, we evaluated the extent to which 129Xe RBC transfer imaging reflects local perfusion by testing its spatial correlation to 99mTc scintigraphy. We specifically focused on patients with chronic thromboembolic pulmonary hypertension (CTEPH), where regional mismatch between the 2 image modalities are often observed, indicating different underlying mechanism of 99mTc perfusion and 129Xe RBC transfer. Second, we proposed a generalized model that uses 129Xe gas exchange MRI to reveal both the membrane and capillary blood volume conductance contributions to the transfer coefficient KCO. We then used the ventilation images to estimate accessible VA, and thereby calculate the diffusing capacity DLCO. This compact framework allows us to interpret a patient’s DLCO with underlying factors that contribute to it, enabling assessment of therapy that addresses individual contributing component. In sum, the strong correlation to 99mTc scintigraphy on most patients, the regional mismatch particularly on CTEPH patients, and the correlation to KCO and DLCO suggest that 129Xe RBC imaging is sensitive to capillary blood volume, instead of perfusion. With 129Xe gas exchange MRI, this combined capability to see both perfusion and gas exchange provides a comprehensive context to evaluate potential treatments and may ultimately allow us to better predict clinical outcomes.

The 129Xe gas exchange imaging measurements require non-standard radial reconstruction and comprehensive post-acquisition quantification. Such reconstruction and image processing would ideally be standardized and automized to facilitate clinical studies, disseminate to other institutes and support collaborative future clinical trials. In Chapter 7, we seek to standardize the entire workflow, probe its repeatability, and deploy it for multiple applications. We first developed a lung segmentation approach using neural networks that automatically generates accurate thoracic masks. We then established a centralized processing pipeline for real-time reconstruction and quantitative reporting of 129Xe gas exchange MRI. We continued by benchmarking our method for its repeatability, reproducibility and validation of underlying assumptions in quantification.

This quantification workflow is now being applied more broadly in other studies. We evaluated gas exchange function evolution on patients undergoing radiation therapy, stratified IPF patients for disease progression, characterized patients with Nonspecific Interstitial Pneumonia (NSIP), and quantified treatment response on patients with PH and COPD. In fact, the workflow is also planned for a major 5-center study of COPD therapy. These various applications assert the clinical value of this technology and encourage us to further improve quantification accuracy and repeatability.

The work in this thesis has transitioned 129Xe gas exchange imaging from a proof of concept to a tool that provide comprehensive evaluation of pulmonary gas exchange function in patients with diverse pulmonary disorders. Using this method, we have shown that we can robustly quantify pulmonary ventilation, interstitial barrier uptake, and RBC transfer within one breath-hold, and obtain results in real-time for clinical interpretation. Moreover, we propose signatures for distinguishing obstructive, interstitial and pulmonary vascular diseases using 129Xe metrics, that can also be used collectively to predict clinical metrics. These metrics are guiding our effort to develop criteria for early diagnosis. Finally, the standardization of the method has facilitated a wide range of fruitful clinical applications, which encourage the dissemination of 129Xe gas exchange imaging for multi-institute studies and thereby create significant value for the medical society.