Rohan S. Virgincar

Quantitative analysis of hyperpolarized 129Xe ventilation imaging in healthy volunteers and subjects with chronic obstructive pulmonary disease

In this study, hyperpolarized 129Xe MR ventilation and 1H anatomical images were obtained from three subject groups: young healthy volunteers (HVs), subjects with chronic obstructive pulmonary disease (COPD) and age‐matched controls (AMCs). Ventilation images were quantified by two methods: an expert reader‐based ventilation defect score percentage (VDS%) and a semi‐automated segmentation‐based ventilation defect percentage (VDP). Reader‐based values were assigned by two experienced radiologists and resolved by consensus. In the semi‐automated analysis, 1H anatomical images and 129Xe ventilation images were both segmented following registration to obtain the thoracic cavity volume and ventilated volume, 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 thoracic cavity volume, 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 three groups from one another and correlated significantly with the forced expiratory volume in 1 s (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 (HVs and AMCs), 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 subjects with COPD with similar ventilation defect scores, but visibly different ventilation patterns. Copyright

3D MRI of impaired hyperpolarized 129Xe uptake in a rat model of pulmonary fibrosis

A variety of pulmonary pathologies, in particular interstitial lung diseases, are characterized by thickening of the pulmonary blood–gas barrier, 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 the adjacent tissues, which comprise blood plasma and lung interstitium. Because 129Xe reaches the RBCs by diffusing across the same barrier tissues (blood plasma and interstitium) as O2, barrier thickening will delay 129Xe transit and, thus, reduce RBC‐specific 129Xe MR signal. Here we have 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. Copyright

Dose and pulse sequence considerations for hyperpolarized 129Xe ventilation MRI

PURPOSE The aim of this study was to evaluate the effect of hyperpolarized (129)Xe 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±7.9years) underwent hyperpolarized (HP) (129)Xe ventilation MRI using both GRE and 3D-radial acquisitions, each tested using a 71ml (high) and 24ml (low) dose equivalent (DE) of fully polarized, fully enriched (129)Xe. For all images SNR and ventilation defect percentage (VDP) were calculated. RESULTS Normalized SNR (SNRn), obtained by dividing SNR by voxel volume and dose was higher for high-DE GRE acquisitions (SNRn=1.9±0.8ml(-2)) than low-DE GRE scans (SNRn=0.8±0.2ml(-2)). Radially acquired images exhibited a more consistent, albeit lower SNRn (High-DE: SNRn=0.5±0.1ml(-2), low-DE: SNRn=0.5±0.2ml(-2)). VDP was indistinguishable across all scans. CONCLUSIONS These results suggest that 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 (129)Xe dose requirements and quantify the benefits of more efficient transmit/receive coils, field strengths, and pulse sequences.

Using hyperpolarized 129Xe MRI to quantify regional gas transfer in idiopathic pulmonary fibrosis

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 red blood cells (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 patients with IPF (66.0±6.4 years) underwent 129Xe MRI to generate three-dimensional 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 patients with IPF, whose mean barrier uptake increased by 188% compared with the healthy reference population. 129Xe MRI metrics correlated poorly and insignificantly with CT fibrosis scores but strongly with PFTs. Barrier uptake and RBC transfer both correlated significantly with diffusing capacity of the lungs for carbon monoxide (r=−0.75, p<0.01 and r=0.72, p<0.01), while their ratio (RBC/barrier) correlated most 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 subpleural (p<0.01) lung. Conclusions Hyperpolarized129Xe 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 patients with IPF, sensitively and non-invasively.

Hyperpolarized 129Xenon Magnetic Resonance Imaging to Quantify Regional Ventilation Differences in Mild to Moderate Asthma: A Prospective Comparison Between Semiautomated Ventilation Defect Percentage Calculation and Pulmonary Function Tests.

Objectives The aim of this study was to investigate ventilation in mild to moderate asthmatic patients and age-matched controls using hyperpolarized (HP) 129Xenon magnetic resonance imaging (MRI) and correlate findings with pulmonary function tests (PFTs). Materials and Methods This single-center, Health Insurance Portability and Accountability Act–compliant prospective study was approved by our institutional review board. Thirty subjects (10 young asthmatic patients, 26 ± 6 years; 3 males, 7 females; 10 older asthmatic patients, 64 ± 6 years; 3 males, 7 females; 10 healthy controls) were enrolled. After repeated PFTs 1 week apart, the subjects underwent 2 MRI scans within 10 minutes, inhaling 1-L volumes containing 0.5 to 1 L of 129Xe. 129Xe ventilation signal was quantified by linear binning, from which the ventilation defect percentage (VDP) was derived. Differences in VDP among subgroups and variability with age were evaluated using 1-tailed t tests. Correlation of VDP with PFTs was tested using Pearson correlation coefficient. Reproducibility of VDP was assessed using Bland-Altman plots, linear regression (R2), intraclass correlation coefficient, and concordance correlation coefficient. Results Ventilation defect percentage was significantly higher in young asthmatic patients versus young healthy subjects (8.4% ± 3.2% vs 5.6% ± 1.7%, P = 0.031), but not in older asthmatic patients versus age-matched controls (16.8% ± 10.3% vs 11.6% ± 6.6%, P = 0.13). Ventilation defect percentage was found to increase significantly with age (healthy, P = 0.05; asthmatic patients, P = 0.033). Ventilation defect percentage was highly reproducible (R2 = 0.976; intraclass correlation coefficient, 0.977; concordance correlation coefficient, 0.976) and significantly correlated with FEV1% (r = −0.42, P = 0.025), FEF25%–75% (r = −0.45, P = 0.019), FEV1/FVC (r = −0.71, P < 0.0001), FeNO (r = 0.69, P < 0.0001), and RV/TLC (r = 0.51, P = 0.0067). Bland-Altman analysis showed a bias for VDP of −0.88 ± 1.52 (FEV1%, −0.33 ± 7.18). Conclusions 129Xenon MRI is able to depict airway obstructions in mild to moderate asthma and significantly correlates with PFTs.

Quantitative analysis of hyperpolarized 129Xe gas transfer MRI

Purpose Hyperpolarized 129Xe magnetic resonance imaging (MRI) using Dixon‐based decomposition enables single‐breath imaging of 129Xe 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 129Xe gas transfer to barrier and RBC compartments. Methods A total of 13 healthy subjects and 12 idiopathic pulmonary fibrosis (IPF) subjects underwent thoracic 1H MRI and hyperpolarized 129Xe MRI with one‐point Dixon decomposition to obtain images of 129Xe in airspaces, barrier and red blood cells (RBCs). 129Xe 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 ± 0.19 for ventilation, 4.9 ± 1.5 x 10‐3 for barrier uptake and 2.6 ± 1.0 × 10‐3 for RBC (transfer). In IPF patients, ventilation was similarly homogenous to healthy subjects, although shifted toward slightly lower values (0.43 ± 0.19). However, mean barrier uptake in IPF patients was nearly 2× 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 129Xe 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.

Uncovering a third dissolved‐phase 129Xe resonance in the human lung: Quantifying spectroscopic features in healthy subjects and patients with idiopathic pulmonary fibrosis

The purpose of this work was to accurately characterize the spectral properties of hyperpolarized 129Xe in patients with idiopathic pulmonary fibrosis (IPF) compared to healthy volunteers.PURPOSE The purpose of this work was to accurately characterize the spectral properties of hyperpolarized 129 Xe in patients with idiopathic pulmonary fibrosis (IPF) compared to healthy volunteers. METHODS Subjects underwent hyperpolarized 129 Xe breath-hold spectroscopy, during which 38 dissolved-phase free induction decays (FIDs) were acquired after reaching steady state (echo time/repetition time = 0.875/50 ms; bandwidth = 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, line widths, 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 parts per million (ppm) more negative (P = 0.05), the chemical shift of barrier 2 was 0.6 ppm more negative (P = 0.009), the line widths of both barrier peaks were ∼2 ppm narrower (P < 0.001), and the starting phase of barrier 1 was 20.3 ° higher (P =  0.01). Moreover, the ratio RBC:barriers was reduced by 52.9% in IPF (P < 0.001). CONCLUSIONS The accurate decomposition of 129 Xe 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 129 Xe gas transfer. Magn Reson Med 78:1306-1315, 2017.

Establishing an accurate gas phase reference frequency to quantify 129Xe chemical shifts in vivo

129Xe interacts with biological media to exhibit chemical shifts exceeding 200 ppm that report on physiology and pathology. Extracting this functional information requires shifts to be measured precisely. Historically, shifts have been reported relative to the gas‐phase resonance originating from pulmonary airspaces. However, this frequency is not fixed—it is affected by bulk magnetic susceptibility, as well as Xe–N2, Xe–Xe, and Xe–O2 interactions. In this study, we addressed this by introducing a robust method to determine the 0 ppm 129Xe reference from in vivo data.

A portable ventilator with integrated physiologic monitoring for hyperpolarized 129Xe MRI in rodents

Hyperpolarized (HP) 129Xe MRI is emerging as a powerful, non-invasive method to image lung function and is beginning to find clinical application across a range of conditions. As clinical implementation progresses, it becomes important to translate back to well-defined animal models, where novel disease signatures can be characterized longitudinally and validated against histology. To date, preclinical 129Xe MRI has been limited to only a few sites worldwide with 2D imaging that is not generally sufficient to fully capture the heterogeneity of lung disease. To address these limitations and facilitate broader dissemination, we report on a compact and portable HP gas ventilator that integrates all the gas-delivery and physiologic monitoring capabilities required for high-resolution 3D hyperpolarized 129Xe imaging. This ventilator is MR- and HP-gas compatible, driven by inexpensive microcontrollers and open source code, and allows for precise control of the tidal volume and breathing cycle in perorally intubated mice and rats. We use the system to demonstrate data acquisition over multiple breath-holds, during which lung motion is suspended to enable high-resolution 3D imaging of gas-phase and dissolved-phase 129Xe in the lungs. We demonstrate the portability and versatility of the ventilator by imaging a mouse model of lung cancer longitudinally at 2 Tesla, and a healthy rat at 7 Tesla. We also report the detection of subtle spectroscopic fluctuations in phase with the heart rate, superimposed onto larger variations stemming from the respiratory cycle. This ventilator was developed to facilitate duplication and gain broad adoption to accelerate preclinical 129Xe MRI research.

Vagal innervation is required for pulmonary function phenotype in Htr4−/− mice

Human genome-wide association studies have identified over 50 loci associated with pulmonary function and related phenotypes, yet follow-up studies to determine causal genes or variants are rare. Single nucleotide polymorphisms in serotonin receptor 4 (HTR4) are associated with human pulmonary function in genome-wide association studies and follow-up animal work has demonstrated that Htr4 is causally associated with pulmonary function in mice, although the precise mechanisms were not identified. We sought to elucidate the role of neural innervation and pulmonary architecture in the lung phenotype of Htr4-/- animals. We report here that the Htr4-/- phenotype in mouse is dependent on vagal innervation to the lung. Both ex vivo tracheal ring reactivity and in vivo flexiVent pulmonary functional analyses demonstrate that vagotomy abrogates the Htr4-/- airway hyperresponsiveness phenotype. Hyperpolarized 3He gas magnetic resonance imaging and stereological assessment of wild-type and Htr4-/- mice reveal no observable differences in lung volume, inflation characteristics, or pulmonary microarchitecture. Finally, control of breathing experiments reveal substantive differences in baseline breathing characteristics between mice with/without functional HTR4 in breathing frequency, relaxation time, flow rate, minute volume, time of inspiration and expiration and breathing pauses. These results suggest that HTR4s role in pulmonary function likely relates to neural innervation and control of breathing.