Browsing by Author "Driehuys, Bastiaan"

129Xe MRI has emerged as a promising means of imaging ventilation distribution. Recently, interest has turned from only imaging ventilation to exploring solubility and chemical shifts to characterize gas exchange, including images of gas exchange patterns that are sensitive to a wide array of disease. The next challenge is to differentiate the underlying causes of gas exchange impairment to begin enabling not just detection, but diagnosis. This prompted us to investigate the relatively unexplored dynamics of 129Xe spectroscopy.

Hyperpolarized 129Xe is a powerful noninvasive tool for studying the physiological environment of the lung due to its distinct chemical shifts as xenon diffuses from the airspaces, through the alveolar membrane, and into red blood cells (RBCs). Previous work has shown that the spectral characteristics (amplitude, chemical shift, line width, and phase) of each resonance are sensitive to disease. In principle, the dynamic variations in four spectral parameters of each 129Xe resonance detected over inhalation, breath hold, and cardiac cycle can contain vital information on the origins of reduced lung function. In this work, our objective was to a) develop a framework for evaluating dynamics, b) assess temporal differences in spectroscopic parameters between patients with idiopathic pulmonary fibrosis (IPF) and healthy volunteers, c) understand the interplay between lineshape and dynamics, and d) create metrics to test the sensitivity of dynamic spectroscopy to underlying lineshapes and signal to noise.

The developed analysis methods were used to characterize the spectral dynamics of 14 healthy volunteers and 10 subjects with IPF. In all subjects, the breathing maneuver (inhale, breath hold, exhale) was reflected in the chemical shift and line width of the 129Xe RBC, barrier, and gas resonances. When comparing a representative IPF and healthy subject, we found that the subject with IPF had an RBC chemical shift that was initially 2 ppm lower and decreased by 0.5 ppm throughout a 5 s breath hold. Over the breath hold, we observed oscillations at the cardiac pulsation frequency in all of the spectral parameters of the RBC resonance. A mean peak-to-peak change of 7.9% ± 2.8% in amplitude of the RBC resonance was consistent across both cohorts. However, the oscillations in the chemical shift and phase of subjects with IPF were three times higher than in healthy volunteers. In light of the known relationship between RBC chemical shift and blood oxygenation levels, these findings suggest that we are sensitive to pathologically driven changes in blood oxygenation on the timescale of the cardiac cycle.

To analyze the effects of our spectral analysis in comparison to a known spectral model, we developed a digital dynamic spectroscopy phantom that simulated clinical free induction decays (FIDs) similar to what we collect during a dynamic spectroscopy acquisition based on specified spectral parameters. This phantom was used to validate our analysis techniques and explore the dependence of RBC signal oscillations on spectral structure. Additionally, motivated by a recent report that dissolved-phase xenon spectra is best fit to three dissolved-phase peaks, we performed a lineshape analysis on stationary spectra from a data set with higher spectral resolution. It was concluded that fitting to non-Lorentzian line shapes reduced the residual error of the fit and that the barrier resonance can potentially be represented by a linear combination of two Lorentzians where the spectral characteristics of the second peak are completely dependent on the first.

129Xe dynamic spectroscopy can be used to evaluate the temporal variations in gas exchange, although additional work must be done to properly characterize the spectral structure. The derived dynamic metrics have the potential to be useful biomarkers for disease progression and help discriminate between different pathologies that affect gas exchange.

Chronic 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.

In Pulmonary diseases, such as chronic obstructed pulmonary diseases (COPD), fibrosis, and asthma, are responsible for substantial health and financial burden in the world. In 2016, COPD claimed more than 3 million lives, which is also the 3rd leading cause of mortality. The treatment for pulmonary diseases continues to be hampered by the lack of reliable metrics to diagnose, as well as assess disease progression and therapeutic response. The current tools to diagnose and monitor pulmonary diseases are the pulmonary function tests (PFT) consisting of spirometry and plethysmography, and diffusing capacity of the lungs for carbon monoxide (DLCO). However, these metrics are effort-dependent, tend to have poor reproducibility, and measure lung as a whole, which allow subtle or regional diseases to be ‘hidden’. Alternatively, computed tomography (CT) is capable of characterizing lung structures in exquisite details, which is commonly applied in detecting the presence of both emphysema and pulmonary fibrosis. However, these structure details do not necessarily correlate well to how patients feel, the lung function, and the treatment effect. Thus, this information is much better assessed by characterizing the functions of the lung. Nuclear medicine, employing 133Xe ventilation and 99Tcm-macroaggregated albumin perfusion scan (ventilation/perfusion V/Q scan) can assess the inequality of airflow and blood flow in the lung. However, this V/Q scan evolves the usage of radioactive tracers and is limited by both poor temporal and spatial resolution. Thus, there has been considerable interest in developing methods that can comprehensively evaluate lung function non-invasively and can provide 3D resolution. Therefore, there has been considerable interest in developing methods that can evaluate lung function comprehensively, non-invasively, and 3-dimensionality.

In recent years, the introduction of hyperpolarized (HP) 129Xe magnetic resonance imaging (MRI) into clinical research has provided a robust and non-invasive 3D imaging technique, capable of both high-resolution imaging of pulmonary ventilation and gas exchange. Notably, gas exchange imaging is enabled by the solubility and unique frequency shifts of xenon in interstitial barrier tissues and capillary red blood cells (RBC). These features offer the potential for 129Xe MRI to be used, not only to evaluate lung obstruction, but also interstitial and vascular diseases. With the capability for both ventilation and gas exchange imaging, robust and reproducible strategies are essential for both visualizing and qualifying the resulting images. Before that, a standardized acquisition with a well-understood relationship between 129Xe dose and image quality needs to be established for efficient and cost-effective acquisitions. Moreover, we also seek to understand the origins of ventilation defects as well as alterations in barrier uptake and RBC transfer. Until such fundamental issues are addressed, it will not be possible to disseminate 129Xe MRI for multi-center clinical trials.

The objective of this work is to establish a robust and comprehensive 129Xe ventilation MRI clinical workflow to investigate pulmonary disorders, and to lay the foundation for clinical deployment and multi-center dissemination. To this end, this work describes several milestones toward establishing a routine, high signal-to-noise ratio (SNR) 129Xe ventilation MRI acquisition with the minimum sufficient volume 129Xe gas, and associated robust quantification pipeline for our clinical platforms. Moreover, we compared our quantification pipeline to other approaches in the field, as well as on different types of acquisition strategies (multi-slice GRE vs. 3D-radial).

To date, various quantification methods have been established for 129Xe ventilation MRI, yet no agreement has been reached on how to calculate the ventilation defect percentage (VDP). Thus, this work begins by developing a quantification workflow with semi-automatic delineation of the 1H thoracic cavity images, automatic pulmonary vasculature extraction, and inhomogeneity correction of the 129Xe ventilation images. It employs a robust linear binning classification that characterizes the entire ventilation distribution while being grounded in a healthy reference population. This quantification method can help evaluate, with high repeatability, how aging, diseases, and treatment influence ventilation distribution.

To further evaluate the robustness of this linear binning quantification method, its performance was assessed against another commonly used clustering method – K-means, on quantifying ventilation images. As part of the investigation, the methods were tested on images for which SNR had been artificially degraded. Through this evaluation, the minimum image SNR was established for an adequate quantification. We have also made the SNR-degraded image sets publicly available at Harvard Dataverse. These shared image sets could be used to evaluate the robustness of various quantification methods in the field. This endeavor is intended to help the pulmonary functional MRI community to standardize the analysis methods and laid the groundwork for future multi-center comparison studies.

We further address the fact that 129Xe ventilation MRI can be and has been conducted using a variety of pulse sequences, scan duration, and 129Xe doses. With more acceptance of the general utility of 129Xe MRI, imaging protocols must be standardized to enable multi-center trials. We thus sought to establish a rational basis for understanding the dose requirements and evaluating how different pulse sequences and 129Xe doses can influence 129Xe ventilation quantification. From that, the minimum required 129Xe dose for an adequate 129Xe ventilation quantification can be derived.

Maybe the emergence and development of 129Xe gas transfer MRI has introduced not only the ability to regionally assess gas exchange, but has introduced the interesting problem that it also delivers ventilation data from the same breath. However, the gas phase is acquired differently, with low resolution and isotropically. This raises the question as to how to generalize the ventilation quantification approach previously introduced specifically for multi-slice GRE. Therefore, we sought to generalize the linear binning approach for rescaling the intensity histogram, which enables the application of linear binning analysis to any ventilation MRI acquisition. We also investigated whether, and to what extent, 3D-radial acquisition can provide similar diagnostic information as from a dedicated multi-slice GRE acquisition. Through these efforts, we evaluated the possibility to employ a more efficient scan protocol for future routine clinical application.

During the course of this work, several practical engineering challenges were raised. First, hyperpolarized MRI has so far mostly been demonstrated at 1.5 Tesla (T), while most MRI vendors are transitioning multi-nuclear platforms to 3 T. This transition from 1.5 T to 3 T requires a reconsideration of optimal imaging acquisition and further optimization of quantification method. Moreover, preparation for multi-center dissemination points to the need for future centralized processing. This leads to the interest in cloud-based processing. However, in order to make this possible, manual segmentation of the thoracic cavity must be replaced by automatic methods. This, in turn requires the use of a novel neural network-based approaches. To this end, we first optimized the sequence on the transition to our new 3 T system. After completing the transition, the linear binning quantification method was further optimized with an enhanced vasculature segmentation and a neural network based 1H thoracic cavity segmentation. We also exploited the emergence of RBC transfer and implemented a framework to interpret these images by comparing them to more well-established approaches such as Gd-enhanced dynamic contrast-enhanced (DCE) perfusion MRI. To this end, we also developed a quantitative perfusion imaging pipeline that could be used to interpret the causes of RBC defects in our gas exchange imaging.

Taken together, results presented in this dissertation provide the step by step development of our rapid clinical exam workflow for hyperpolarized 129Xe MRI. This clinical workflow, not only demonstrates a comprehensive image quantification pipeline with applications to the 129Xe ventilation images and Gd-enhanced DCE MRI, but also the considerations for the acquisition sequence and delivered 129Xe dose. Overall, the established quantification pipeline offers a robust and sensitive way for diseases phenotyping, disease monitoring, and treatment planning. Moreover, this thesis work has hopefully laid the groundwork for standardized quantification, that could be deployed for future multi-center clinical trials.

Pulmonary fibrosis is the process of lung tissue becoming damaged and scarred, losing its elastic and diffusive properties needed for proper lung function. This change in tissue structure can make it difficult to draw in a breath (ventilation) and cause a decrease in the amount of oxygen and carbon dioxide that can transfer between the alveoli and blood vessels (gas exchange). Therefore, the most common symptom of progressive pulmonary fibrosis is shortness of breath, or dyspnea. Pulmonary fibrosis can be caused by environmental pollutants, treatment-related toxicity from a drug or therapy, or interstitial lung diseases.

Regardless of its origin, pulmonary fibrosis can have devastating outcomes for patients. For example, the median survival for patients with idiopathic pulmonary fibrosis (IPF), an interstitial lung disease of unknown origin, is historically less than 3 years. For patients with IPF, the path of clinical decline is often sporadic and plagued with acute exacerbations and hospitalizations. Idiopathic pulmonary fibrosis currently affects between 100,000-200,000 people in the United States alone, and over a million worldwide. Unfortunately, the tools currently available to classify disease severity, determine prognosis, and assess disease progression or treatment response are simply inadequate. Patients with IPF exhibit distinct and unpredictable clinical trajectories, and a tool with the ability to predict these trajectories could improve targeted interventions. One such set of tools, pulmonary function tests (PFTs) can measure global ventilation and gas exchange, but have high variability and no spatial information. Another, high resolution computed tomography (HRCT), provides a 3D image, but function must be inferred from tissue density or structure, which comes with a number of limitations. A new tool that can spatially resolve and quantify regional pulmonary function could be invaluable in improving the clinical management of IPF.

In addition to fibrotic lung diseases, such as IPF, pulmonary fibrosis may also transpire as a treatment-related toxicity. Over 100,000 people per year in the U.S. will receive thoracic radiation therapy (RT) as treatment for cancer, putting them at risk for radiation-induced lung injury (RILI). Approximately 5-25% of patients that receive conventional thoracic RT develop clinically significant symptomatic radiation pneumonitis (RP), the acute form of RILI, causing patients to experience dyspnea, persistent coughing, pain, and fever. Radiation pneumonitis can lead to chronic radiation pulmonary fibrosis (RPF), or even result in death for an estimated 1-2% of patients. Current methods to assess RILI and grade RP rely on a clinical diagnosis and patient- and physician-reported symptoms. This leads to large variability in toxicity grading for thoracic RT clinical trials, hampering the effort to design treatments that reduce side effects. Further, a recently proposed treatment planning technique, “functional avoidance”, was designed to preserve pulmonary function and reduce the incidence or severity of RP by minimizing radiation dose to areas with high pulmonary function. However, clinically available tools can only measure ventilation or perfusion, neither of which are a true representation of end-to-end pulmonary gas exchange, a fact that may be limiting the potential effectiveness of this technique. Once again, a tool that can spatially resolve and quantify regional pulmonary function could offer improvements to functional avoidance treatment planning and the prevention of RP. If such a tool was sensitive enough to detect radiation-induced changes in function, this could reduce the variability in the current guidelines for the toxicity grading of RP.

In this work, we investigated non-invasive hyperpolarized-129Xe gas exchange magnetic resonance imaging (MRI), which acquires 3D maps of lung ventilation, alveolar barrier uptake, and capillary red blood cell (RBC) transfer. This unique tool can quantify and spatially resolve the gas exchange capabilities of a human lung in a single 15-second breath-hold MRI acquisition. Currently limited to research studies, the clinical utility of this new technique is yet to be firmly established. Therefore, the objectives of this dissertation are to: 1) identify metrics from baseline 129Xe gas exchange MRI that are predictive of clinical outcomes in IPF; 2) quantify the extent to which ventilation and gas exchange distributions are spatially correlated, and the effect that this may have on functional avoidance treatment planning; and 3) establish a relationship between regional changes in gas exchange and local radiation therapy dose in RT patients.

First, we sought to identify 129Xe gas exchange MRI features in IPF patients, and establish 129Xe-based imaging metrics to be used for classifying patients into groups, as detailed in Chapter 3. As previously mentioned, subjects with IPF exhibit distinct clinical trajectories that are difficult to predict prospectively using currently available means. We acquired baseline 129Xe MRI for 12 newly diagnosed IPF patients, and prospectively grouped these subjects based on percentage-volumes of abnormal barrier uptake and RBC transfer, using thresholds we derived from 129Xe MRI of a healthy subject cohort (N=13). We then followed these subjects for 36 months and analyzed the clinically acquired PFT and outcome data. We examined the differences in clinical outcomes and temporal changes in PFTs based on these groupings. We also observed changes in 129Xe metrics over time for those subjects with serial time-point imaging. Our results indicated that 129Xe MRI characteristics appear to group disease in a way that was distinct from traditional clinical or radiographic approaches; in particular, excessive volumes of lung with elevated barrier uptake and reduced RBC transfer were associated with poor clinical outcome. This study provided preliminary evidence that IPF patients can be classified by 129Xe MRI, and that this classification may predict clinical outcomes. These results open the door for larger, prospective studies using 129Xe MRI in IPF. More generally, and perhaps most importantly, this work established 129Xe gas exchange MRI as a prognostic biomarker in fibrotic lung disease.

Our results from Chapter 3 established that, when accompanied by an increase in 129Xe MRI barrier signal, which is a hallmark characteristic of IPF, a reduction in RBC transfer signal is associated with clinical decline in IPF patients. Extending this work to fibrotic lung processes beyond IPF, we hypothesize that the RBC signal is an important marker for regional lung function, and preserving and protecting the volumes of lung exhibiting “healthy” RBC transfer could translate to preservation of overall pulmonary function. In RT treatment planning, the concept of avoiding excess radiation dose to highly functioning areas of lung is not new; “functional avoidance” (or “functional guidance”) has previously been proposed and implemented using both perfusion and ventilation imaging. In Chapter 4, however, we establish 129Xe gas exchange MRI as a unique marker of regional lung function compared to ventilation, which is the most popular functional avoidance planning technique due to its “free” derivation from the 4 dimensional (4D) CT acquired during the RT planning process. In this chapter, we examined the correlation of ventilation and RBC signals in a healthy volunteer cohort and a handful of thoracic RT patients. Our results indicated a weak-to-moderate correlation, which determined that the RBC signal was indeed spatially unique from the ventilation signal, but did not explore the extent to which this affects functional plans created using one or the other (ventilation or RBC gas exchange) for guidance. Therefore, Chapter 5 details our study of 11 patients that received RT for treatment of lung cancer in which we re-planned these patients’ clinically approved plans using ventilation and RBC gas exchange functional information. This study established a methodology for 129Xe gas exchange MRI functional avoidance planning, and the results showed that, for some RP-predictive metrics, gas exchange-guided planning produced significantly different dose distributions than ventilation-guided planning.

Finally, in Chapter 6 we focused on furthering our understanding of RILI in RT patients, and examined the sensitivity of 129Xe MRI for detecting pulmonary radiation damage. In this study, we quantified changes in regional gas exchange as a function of radiation dose for six patients undergoing conventional radiotherapy for lung cancer. As briefly described earlier, RT of tumors in or around the thorax is known to cause regional lung injury, with the acute injury phase symptoms of RP typically emerging 1-6 months after RT. Previous studies using SPECT have established that perfusion changes are dose-dependent and evident at 3-6 months after RT. Therefore, we acquired 129Xe MRI scans before RT and at 3- and 6-months after RT to evaluate the progression of the acute inflammatory phase of RILI, as it relates to changes in regional gas exchange. We co-registered the MRI data to the RT treatment planning data, to evaluate regional changes in ventilation, barrier uptake, and RBC transfer, as a function of delivered radiation dose. Our results indicated that the barrier uptake signal increased with radiation doses above 20 Gy, and that the magnitude of change was dose-dependent. This potentially confirms increased barrier uptake as a marker of regional inflammation. In addition, we observed that the RBC transfer signal decreased with radiation doses above 35 Gy, possibly quantifying a reduction in overall gas exchange properties of the tissue at these high doses. Our observations of this dose-dependent relationship are consistent with historic ventilation and perfusion data, and gives rise to the idea that 129Xe MRI may be a powerful tool in furthering understanding of the subclinical progression of RILI and potentially other causes of lung fibrosis.

Overall, we have demonstrated the potential of 129Xe-MRI gas exchange to 1) improve disease classification in IPF, 2) add unique functional information to the planning of thoracic radiation treatments, and 3) assess RT-associated subclinical changes in regional lung function. We have established a strong foundation for this non-invasive technology, enabling further development and validation of these MRI biomarkers in larger studies. The work presented herein marks the beginning of a journey to advance our understanding of fibrotic progression in IPF, RILI, and all other causes of pulmonary fibrosis.

Hyperpolarized (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.

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.

Hyperpolarized (HP) 129Xe MRI has emerged as a viable tool for evaluating lung function without ionizing radiation. HP 129Xe has already been used to image ventilation and quantify ventilation defects. However, this thesis aims to further develop imaging techniques that are capable of imaging, not just ventilation, but also gas transfer within the lung. This ability to image gas transfer directly is enabled by the solubility and chemical shifts of 129Xe that provide separate MR signatures in the airspaces, barrier tissue, and red blood cells (RBCs).

While 129Xe in the airspace (referred to as gas-phase 129Xe) can be readily imaged with standard vendor-provided imaging sequences, 129Xe in the barrier and RBC compartments (collectively referred to as dissolved-phase 129Xe) has such a rapid T2* (<2 msec at 2T) that even simple gradient recalled echo (GRE) sequences are ineffective at imaging the limited signal before it decays. To minimize these losses from T2* decay, the 3D radial sequence offers much shorter TEs that can image the dissolved-phase 129Xe. Despite their ability to image dissolved-phase signal, however, 3D radial sequences have not yet been widely adopted within the hyperpolarized gas community. In order to demonstrate the potential of the 3D radial pulse sequence, chapter 3 uses standard 129Xe ventilation imaging to compare 3D radial image quality and defect conspicuity with that of the conventional GRE. Since the 3D radial sequence offered comparable performance in ventilation imaging, and also provided the ability to image dissolved-phase 129Xe, chapter 3 establishes that the 3D radial sequence is well-suited for imaging 129Xe in humans.

Though 3D radial acquisition offers clear advantages for functional 129Xe lung imaging, its non-Cartesian sampling of k-space complicates image reconstruction. Chapter 4 carefully explains the process of gridding-based reconstruction, and describes how problems arising from non-selective RF pulses and undersampling, both of which are commonly employed in hyperpolarized 129Xe imaging, can be avoided by using appropriate reconstruction techniques. Furthermore, we detail a generalized procedure to optimize reconstruction parameters, then demonstrate the benefits of our improved reconstruction methods across both 1H anatomical imaging as well as functional imaging of 129Xe in the gas- and dissolved-phases.

These dissolved-phase images are particularly interesting because they consist of separate contributions from 129Xe in the RBCs and barrier tissue. Once these two resonances are disentangled from one another, they provide a noninvasive means to measure gas exchange regionally. However, such decomposition of these two resonances is predicated on prior knowledge of their spectroscopic properties. To that end, chapter 5 describes a non-linear spectroscopic curve fitting toolbox that we developed to more accurately characterize the 129Xe spectrum in vivo. Though previously, only two dissolved-phase resonances have ever been described within the lung, our fitting tools were able to identify a third dissolved-phase resonance in both healthy volunteers and healthy controls. Furthermore, we describe several spectroscopic features that differ statistically between our healthy volunteers and IPF subjects to demonstrate that this technique is sensitive to even subtle functional changes within the lung. These spectroscopic measurements provide the basis for imaging gas transfer.

Describing lung function regionally requires phase-sensitive imaging techniques that can decompose the dissolved-phase signal into images that represent the contribution from the RBC and barrier resonances. To date, only two implementations have been demonstrated, and both suffered from poor SNR and challenges in quantifying gas transfer. Chapter 6 adds quantitative processing techniques that improve phase sensitive imaging of 129Xe gas transfer. These methods 1) normalize both the RBC and barrier uptake images by gas-phase magnetization so that intensities can be compared across subjects, 2) compress the dynamic range of these functional images to enhance their perceived SNR, and 3) derive colormap thresholds from a healthy reference population to give intensities meaningful context.

To show the value of our quantitative gas transfer imaging, chapter 7 applies these techniques to a cohort of healthy volunteers and another of IPF patients. Since patients with IPF exhibit a progressive thickening and hardening of the pulmonary interstitium that severely restricts the transport of gases between the lungs and blood, they represent an ideal population to prove out our methods. This analysis identifies several patterns to the RBC and barrier distributions which could potentially represent different stages of disease. Furthermore, we demonstrate that our MRI-based findings correlate well with DLCO and FVC, and to a lesser extent with the structural cues seen in CT. This suggests that 129Xe imaging offers complimentary functional information that can’t be derived from CT, while also describing its spatial distribution unlike PFTs.

The work in this thesis has transitioned our HP 129Xe gas transfer studies from a proof of concept to an optimized and quantitative imaging protocol with robust processing pipelines. Using these MRI methods, we have shown that we can directly and quantitatively probe pulmonary ventilation and gas transfer within a single breath hold. In IPF, such noninvasive imaging methods are desperately needed to monitor the efficacy of these new treatments to ensure that the associated medical expense is justified with positive changes in outcomes. Finally, these new functional contrasts will be useful in studying other cardiopulmonary diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary arterial hypertension.

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Hyperpolarized (HP) 129Xe Magnetic Resonance Imaging (MRI) is a promising approach for the non-invasive diagnosis of pulmonary pathophysiology and has recently received FDA approval. This technique has emerged as a valuable diagnostic tool for investigating various lung diseases and holds significant potential for non-invasive investigation of lung disorders. HP 129Xe MRI is typically utilized to evaluate regional pulmonary ventilation and gas exchange functions. Hyperpolarized (HP) 129Xe MR spectroscopy has emerged as an equally valuable addition to the repertoire of imaging diagnostic tools available. The application of HP 129Xe MR spectroscopy enables us to investigate blood oxygenation levels, as evidenced through 129Xe red blood cell (RBCs) shifts. It also provides an insight into hemodynamics through cardiogenic oscillations. Despite its potential clinical utility, the use of HP 129Xe MR spectroscopy has been limited by the lack of established standards for measuring and interpreting its signal quality. In particular, there is currently no consensus on how to calculate the signal-to-noise ratio (SNR) of HP 129Xe spectroscopic data or how to determine the appropriate dose of HP 129Xe necessary to achieve high-quality NMR signals suitable for clinical analysis. To address these issues, this study developed a reliable approach in calculating the 129Xe MR spectroscopic SNR from clinical data using recommended acquisition protocols. We focused on developing a method for estimating the SNR that takes into account the inherent variability of HP 129Xe signals and the effects of noise and artifact, such as those arising from cariogenic signal oscillations, in the acquired data. Our method involves acquiring multiple repetitions of the HP 129Xe signal and using a combination of statistical techniques and signal processing algorithms to estimate the SNR from the resulting time series data. In addition to developing a method for calculating the HP 129Xe SNR, we also investigated the relationship between the administered dose equivalent of the HP 129Xe and the resulting SNR. By acquiring NMR signals over a range of doses, we were able to establish a quantitative relationship between dose and SNR that can be used to guide the selection of an appropriate HP 129Xe dose for a given clinical application. In addition to the findings of a recent investigation that evaluated the quality of scans conducted in our laboratory with a 5-point Likert scale, our study has defined empirical thresholds for requisite SNR and dosage necessary to achieve high-quality static measurements of RBC/Membrane ratio, RBC chemical shifts, and dynamic measurements of RBC amplitude oscillations using HP 129Xe MRS. Overall, our approach represents an important step towards standardizing the use of HP 129Xe MR spectroscopy in clinical practice. Through the provision of a trustworthy and quantitative measurement of SNR, as well as the establishment of a clear correlation between dosage and SNR, our study ensures that the acquisition and analysis of HP 129Xe MRS scan is executed in a consistent and reproducible manner across different institutions and studies. Besides its potential impact on clinical practice across different sites, this study also has implications for ongoing research efforts. By providing a more robust method for measuring signal quality, this study will be helpful to facilitate future studies aimed at advancing our understanding of the underlying physiology of pulmonary disease and evaluating the efficacy of new treatments.

Since the inception of hyperpolarized 129Xe MRI, the field has yearned for more efficient production of more highly polarized 129Xe. For nearly all polarizers built to date, both peak 129Xe polarization and production rate fall far below theoretical predictions. This thesis sought to develop a fundamental understanding of why the observed performance of large-scale 129Xe hyperpolarization lagged so badly behind theoretical predictions.

This is done by thoroughly characterizing a high-volume, continuous-flow polarizer using optical cells having three different internal volumes, and employing two different laser sources. For each of these 6 combinations, 129Xe polarization was carefully measured as a function of production rate across a range of laser absorption levels. The resultant peak polarizations were consistently a factor of 2-3 lower than predicted across a range of absorption levels, and scaling of production rates deviated badly from predictions based on spin exchange efficiency.

To bridge this gap, we propose that paramagnetic, activated Rb clusters form during spin exchange optical pumping (SEOP), and depolarize Rb and 129Xe, while unproductively scattering optical pumping light. When a model was built that incorporated the effects of clusters, its predictions matched observations for both polarization and production rate for all 6 systems studied. This permits us to place a limit on cluster number density of <2 × 109 cm-3.

The work culminates with deploying this framework to identify methods to improve polarization to above 50%, leaving the SEOP cell. Combined with additional methods of preserving polarization, the polarization of a 300-mL batch of 129Xe increased from an average of 9%, before this work began, to a recent value of 34%.

We anticipate that these developments will lay the groundwork for continued advancement and scaling up of SEOP-based hyperpolarization methods that may one day permit real-time, on-demand 129Xe MRI to become a reality.

The diagnosis and treatment of pulmonary diseases still rely on pulmonary function tests that offer archaic or insensitive biomarkers of lung structure and function. As a consequence, chronic obstructive pulmonary disease is the third leading cause of death in the US, and the hospitalization costs for asthma are on the order of $29 Billion. Pulmonary diseases have created a large and unsustainable economic burden, and hence there is still a dire need for biomarkers that can predict early changes in lung function. The work presented in this thesis looks to address this very issue, by taking advantage of the unique properties of hyperpolarized (HP) 129Xe in conjunction with magnetic resonance imaging (MRI), to probe the fundamental function of the lung - gas-exchange.

While a bulk of the inhaled HP 129Xe stays in the alveolar spaces, its moderate solubility in the pulmonary tissues causes a small fraction of this xenon in the alveolar spaces to diffuse into the pulmonary barrier tissue and plasma, and further into the red blood cells (RBC). Additionally, when in either of these compartments, xenon experiences a unique shift in its resonance frequency from the gas-phase (barrier - 198 ppm, RBC - 217 ppm). These unique resonances are collectively called the dissolved-phase of xenon. As the pathway taken by xenon to reach the RBCs is identical to that of oxygen, this dissolved-phase offers a non-invasive probe to study the oxygen transfer pathway, and imaging its distribution, to first order, would give us an image of gas-exchange in the lung.

Gas-exchange is controlled by ventilation, perfusion, and lastly diffusion of gases across the capillary membrane. This process of diffusion is dictated by Fick's first law of diffusion, and hence the volume of gas taken up by the capillary blood stream depends on the alveolar surface area, and the interstitial thickness. Interestingly, changes in these factors can be measured using the resonances of xenon. Changes in the alveolar surface area brought on by diseases like emphysema will increase the diffusion of xenon within the alveolus. Thus, by using diffusion-weighted imaging of the gas-phase of 129Xe, which is the focus of chapter 3, one can extract the `apparent diffusion coefficient' (ADC) of xenon, that is sensitive to the changes in the alveolar surface area. The dissolved-phase on the other hand, while sensitive to the surface area, is also sensitive to subtle changes in the interstitial thickness. In fact, after the application of an RF pulse on the dissolved-phase, the recovery time for the xenon signal in the RBCs is significantly delayed by micron scale thickening of the interstitium. This delayed signal recovery can be used as a sensitive marker for diffusion impairment in the lung.

While direct imaging of the dissolved-phase was shown to be feasible, truly quantifying gas-exchange in the lung will require two additional technical advances - 1) As the gas-phase is the source magnetization for the dissolved-phase signal, it is imperative to acquire both the gas and dissolved-phase images in a single breath. The technical details of this achievement are discussed in chapters 4 and 5. 2) As the dissolved-phase consists of both the barrier and the RBC components, obtaining a fundamental image of gas-exchange in the lung will require creating independent images of 129Xe in the barrier and 129Xe in the RBCs. This goal first required creating a global metric of gas-transfer in the lung (chapter 6), which aided the implementation of the 1-point Dixon acquisition strategy to separate the components of the dissolved-phase. In conjunction with aim 1, it was finally possible to image all three resonances of 129Xe in a single breath (chapter 7). These 129Xe-RBC images were acquired in healthy volunteers and their efficacy was tested in subjects with idiopathic pulmonary fibrosis (IPF). These IPF subjects are known for their characteristic diffusion limitation, and in regions of fibrosis shown on their CT scans, the 129Xe-RBC images showed gas-transfer defects.

Hyperpolarized 129Xe MRI thus provides a non-invasive, ionizing radiation free method to probe ventilation, microstructural changes and most importantly, gas-exchange. These preliminary results indicate that xenon MRI has potential as a sensitive tool in therapeutic clinical trials to evaluate longitudinal changes in lung function.