Translational Imaging of Pulmonary Gas-Exchange Using Hyperpolarized 129Xe Magnetic Resonance Imaging

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.