Background Assessing functional impairment, therapeutic response, and disease progression in patients with idiopathic pulmonary fibrosis (IPF) continues to be challenging. Hyperpolarized 129Xe MRI can address this gap through its unique capability to image gas transfer three-dimensionally from airspaces to interstitial barrier tissues to RBCs. This must be validated by testing the degree to which it correlates with pulmonary function tests (PFTs) and CT scores and its spatial distribution reflects known physiology and patterns of disease. Methods 13 healthy individuals (33.6±15.7 years) and 12 IPF patients (66.0±6.4 years) underwent 129Xe MRI to generate 3D quantitative maps depicting the 129Xe ventilation distribution, its uptake in interstitial barrier tissues, and its transfer to RBCs. For each map, mean values were correlated with PFTs and CT fibrosis scores and their patterns were tested for the ability to depict functional gravitational gradients in healthy lung, and to detect the known basal and peripheral predominance of disease in IPF. Results 129Xe MRI depicted functional impairment in IPF patients, whose mean barrier uptake increased by 188% compared to the healthy reference population. 129Xe MRI metrics correlated poorly and insignificantly with CT fibrosis scores, but strongly with pulmonary function tests. Barrier uptake and RBC transfer both correlated significantly with DLCO (r=−0.75, p<0.01 and r=0.72, p<0.01), while their ratio (RBC/barrier) correlated strongly (r=0.94, p<0.01). RBC transfer exhibited significant anterior-posterior gravitational gradients in healthy volunteers, but not in IPF, where it was significantly impaired in the basal (p=0.02) and sub-pleural (p<0.01) lung. Conclusions Hyperpolarized 129Xe MRI is a rapid and well-tolerated exam that provides region-specific quantification of interstitial barrier thickness and RBC transfer efficiency. With further development, it could become a robust tool for measuring disease progression and therapeutic response in IPF patients, sensitively and non-invasively.

Purpose: Hyperpolarized 129 Xe magnetic resonance imaging (MRI) using Dixon-based decomposition enables single-breath imaging of 129 Xe in the airspaces, interstitial barrier tissues, and red blood cells (RBCs). However, methods to quantitatively visualize information from these images of pulmonary gas transfer are lacking. Here, we introduce a novel method to transform these data into quantitative maps of pulmonary ventilation, and 129 Xe gas transfer to barrier and RBC compartments. Methods: A total of 13 healthy subjects and 12 idiopathic pulmonary fibrosis (IPF) subjects underwent thoracic 1 H MRI and hyperpolarized 129 Xe MRI with one-point Dixon decomposition to obtain images of 129 Xe in airspaces, barrier and red blood cells (RBCs). 129 Xe images were processed into quantitative binning maps of all three compartments using thresholds based on the mean and standard deviations of distributions derived from the healthy reference cohort. Binning maps were analyzed to derive quantitative measures of ventilation, barrier uptake, and RBC transfer. This method was also used to illustrate different ventilation and gas transfer patterns in a patient with emphysema and one with pulmonary arterial hypertension (PAH). Results: In the healthy reference cohort, the mean normalized signals were 0.51 AE 0.19 for ventilation, 4.9 AE 1.5 x 10 -3 for barrier uptake and 2.6 AE 1.0 9 10 -3 for RBC (transfer). In IPF patients, ventilation was similarly homogenous to healthy subjects, although shifted toward slightly lower values (0.43 AE 0.19). However, mean barrier uptake in IPF patients was nearly 29 higher than in healthy subjects, with 47% of voxels classified as high, compared to 3% in healthy controls. Moreover, in IPF, RBC transfer was reduced, mainly in the basal lung with 41% of voxels classified as low. In healthy volunteers, only 15% of RBC transfer was classified as low and these voxels were typically in the anterior, gravitationally nondependent lung. Conclusions: This study demonstrates a straightforward means to generate semiquantitative binning maps depicting 129 Xe ventilation and gas transfer to barrier and RBC compartments. These initial results suggest that the method could be valuable for characterizing both normal physiology and pathophysiology associated with a wide range of pulmonary disorders.

In this study, hyperpolarized (HP) 129Xe MR ventilation and 1H anatomical images were obtained from 3 subject groups: young healthy volunteers (HV), subjects with chronic obstructive pulmonary disease (COPD), and age-matched control subjects (AMC). Ventilation images were quantified by 2 methods: an expert reader-based ventilation defect score percentage (VDS%) and a semi-automatic segmentation-based ventilation defect percentage (VDP). Reader-based values were assigned by two experienced radiologists and resolved by consensus. In the semi-automatic analysis, 1H anatomical images and 129Xe ventilation images were both segmented following registration, to obtain the thoracic cavity volume (TCV) and ventilated volume (VV), respectively, which were then expressed as a ratio to obtain the VDP. Ventilation images were also characterized by generating signal intensity histograms from voxels within the TCV, and heterogeneity was analyzed using the coefficient of variation (CV). The reader-based VDS% correlated strongly with the semi-automatically generated VDP (r = 0.97, p < 0.0001), and with CV (r = 0.82, p < 0.0001). Both 129Xe ventilation defect scoring metrics readily separated the 3 groups from one another and correlated significantly with FEV1 (VDS%: r = -0.78, p = 0.0002; VDP: r = -0.79, p = 0.0003; CV: r = -0.66, p = 0.0059) and other pulmonary function tests. In the healthy subject groups (HV and AMC), the prevalence of ventilation defects also increased with age (VDS%: r = 0.61, p = 0.0002; VDP: r = 0.63, p = 0.0002). Moreover, ventilation histograms and their associated CVs distinguished between COPD subjects with similar ventilation defect scores but visibly different ventilation patterns.

Rationale and Objectives Clinical deployment of hyperpolarized (HP) 129Xe MRI requires accurate quantification and visualization of the ventilation defect percentage (VDP). Here, we improve the robustness of our previous semi-automated analysis method to reduce operator dependence, correct for B1 inhomogeneity and vascular structures, and extend the analysis to display multiple intensity clusters. Materials and Methods Two segmentation methods were compared—seeded region-growing, previously validated by expert reader scoring, and a new linear-binning method that corrects for the effects of bias field and vascular structures. The new method removes nearly all operator intervention by re-scaling the 129Xe MRI to the 99th percentile of the cumulative distribution and applying fixed thresholds to classify 129Xe voxels into 4 clusters: defect, low, medium, and high intensity. The methods were applied to 24 subjects including chronic obstructive pulmonary disease (COPD) subjects (n = 8), age-matched controls (n = 8), and healthy normal subjects (n = 8). Results Linear-binning enabled a faster and more reproducible workflow, and enabled analysis of an additional 0.25 ± 0.18 L of lung volume by accounting for vasculature. Like region-growing, linear-binning VDP correlated strongly with reader scoring (R2 = 0.93, p<0.0001), but with less systematic bias. Moreover, linear-binning maps clearly depict regions of low and high intensity that may prove useful for phenotyping subjects with COPD. Conclusions Corrected linear-binning provides a robust means to quantify 129Xe ventilation images, yielding VDP values that are indistinguishable from expert reader scores, while exploiting the entire dynamic range to depict multiple image clusters.

Purpose The aim of this study was to evaluate the effect of hyperpolarized 129Xe dose on image signal-to-noise ratio (SNR) and ventilation defect conspicuity on both multi-slice gradient echo and isotropic 3D-radially acquired ventilation MRI. Materials and Methods Ten non-smoking older subjects (ages 60.8 ± 7.9 years) underwent hyperpolarized (HP) 129Xe ventilation MRI using both GRE and 3D-radial acquisitions, each tested using a 71 ml (high) and 24 ml (low) dose equivalent (DE) of fully polarized, fully enriched 129Xe. For all images SNR and ventilation defect percentage (VDP) was calculated. Results Normalized SNR (SNRn), obtained by dividing SNR by voxel volume and dose was higher for high-DE GRE acquisitions (SNRn=1.9±0.8 ml-2) than low-DE GRE scans (SNRn=0.8±0.2 ml-2). Radially acquired images exhibited a more consistent, albeit lower SNRn (High-DE: SNRn=0.5±0.1 ml-2, low-DE: SNRn=0.5±0.2 ml-2). VDP was indistinguishable across all scans. Conclusions These results suggest images acquired using the high-DE GRE sequence provided the highest SNRn, which was in agreement with previous reports in the literature. 3D-radial images had lower SNRn, but have advantages for visual display, monitoring magnetization dynamics, and visualizing physiological gradients. By evaluating normalized SNR in the context of dose-equivalent formalism, it should be possible to predict 129Xe dose requirements and quantify the benefits of more efficient transmit/receive coils, field strengths, and pulse sequences.

Although some central aspects of pulmonary function (ventilation and perfusion) are known to be heterogeneous, the distribution of diffusive gas exchange remains poorly characterized. A solution is offered by hyperpolarized 129Xe magnetic resonance (MR) imaging, because this gas can be separately detected in the lung's air spaces and dissolved in its tissues. Early dissolved-phase 129Xe images exhibited intensity gradients that favored the dependent lung. To quantitatively corroborate this finding, we developed an interleaved, three-dimensional radial sequence to image the gaseous and dissolved 129Xe distributions in the same breath. These images were normalized and divided to calculate "129Xe gas-transfer" maps. We hypothesized that, for healthy volunteers, 129Xe gas-transfer maps would retain the previously observed posture-dependent gradients. This was tested in nine subjects: when the subjects were supine, 129Xe gas transfer exhibited a posterior-anterior gradient of -2.00 ± 0.74%/cm; when the subjects were prone, the gradient reversed to 1.94 ± 1.14%/cm (P < 0.001). The 129Xe gas-transfer maps also exhibited significant heterogeneity, as measured by the coefficient of variation, that correlated with subject total lung capacity (r = 0.77, P = 0.015). Gas-transfer intensity varied nonmonotonically with slice position and increased in slices proximal to the main pulmonary arteries. Despite substantial heterogeneity, the mean gas transfer for all subjects was 1.00 ± 0.01 while supine and 1.01 ± 0.01 while prone (P = 0.25), indicating good "matching" between gas- and dissolved-phase distributions. This study demonstrates that single-breath gas- and dissolved-phase 129Xe MR imaging yields 129Xe gas-transfer maps that are sensitive to altered gas exchange caused by differences in lung inflation and posture.

Purpose To accurately characterize the spectral properties of hyperpolarized 129Xe in patients with idiopathic pulmonary fibrosis (IPF) compared to healthy volunteers. Methods Subjects underwent hyperpolarized 129Xe breath-hold spectroscopy, during which 38 dissolved-phase free induction decays (FIDs) were acquired after reaching steady state (TE/TR=0.875/50 ms, BW=8.06 kHz, flip angle≈22°). FIDs were averaged and then decomposed into multiple spectral components using time-domain curve fitting. The resulting amplitudes, frequencies, linewidths, and starting phases of each component were compared among groups using a Mann–Whitney–Wilcoxon U-test. Results Three dissolved-phase resonances, consisting of red blood cells (RBCs) and two barrier compartments, were consistently identified in all subjects. In subjects with IPF relative to healthy volunteers, the RBC frequency was 0.70 ppm more negative (P=0.05), the chemical shift of barrier 2 was 0.6 ppm more negative (P=0.009), the linewidths of both barrier peaks were ~2 ppm narrower (P<0.001), and the starting phase of barrier 1 was 20.3 degrees higher (P=0.01). Moreover, the ratio RBC:barriers was reduced by 52.9% in IPF (P<0.001). Conclusions The accurate decomposition of 129Xe spectra not only has merit for developing a global metric of pulmonary function, but also provides necessary insights to optimize phase-sensitive methods for imaging 129Xe gas-transfer.

A variety of pulmonary pathologies, in particular interstitial lung diseases, are characterized by thickening of the pulmonary blood-gas barrier tissues, and this thickening results in reduced gas exchange. Such diffusive impairment is challenging to quantify spatially, because the distributions of the metabolically relevant gases (CO2 and O2) cannot be detected directly within the lungs. Hyperpolarized (HP) 129Xe is a promising surrogate for these metabolic gases, because MR spectroscopy and imaging allow gaseous alveolar 129Xe to be detected separately from 129Xe dissolved in the red blood cells (RBCs) and in the adjacent barrier tissues (blood plasma and lung interstitium). Further, because 129Xe reaches the RBCs by diffusing across the same barrier tissues as O2barrier thickening will delay 129Xe transit and, thus, reduce RBC-specific 129Xe MR signal. Here we exploited these properties to generate 3D, MR images of 129Xe uptake by the RBCs in two groups of rats. In the experimental group, unilateral fibrotic injury was generated prior to imaging by instilling Bleomycin into one lung. In the control group, a unilateral sham instillation of saline was performed. Uptake of 129Xe by the RBCs, quantified as the fraction of RBC signal relative to total dissolved 129Xe signal, was significantly reduced (P = 0.03) in the injured lungs of Bleomycin-treated animals. In contrast, no significant difference (P=0.56) was observed between the saline-treated and untreated lungs of control animals. Together, these results indicate that 3D MRI of HP 129Xe dissolved in the pulmonary tissues can provide useful biomarkers of impaired diffusive gas exchange resulting from fibrotic thickening.