Cluster Analysis to Identify Long COVID Phenotypes Using 129Xe Magnetic Resonance Imaging: A Multi-centre Evaluation.

BACKGROUND: Long COVID impacts ∼10% of people diagnosed with COVID-19, yet the pathophysiology driving ongoing symptoms is poorly understood. We hypothesised that 129Xe magnetic resonance imaging (MRI) could identify unique pulmonary phenotypic subgroups of long COVID, therefore we evaluated ventilation and gas exchange measurements with cluster analysis to generate imaging-based phenotypes. METHODS: COVID-negative controls and participants who previously tested positive for COVID-19 underwent 129XeMRI ∼14-months post-acute infection across three centres. Long COVID was defined as persistent dyspnea, chest tightness, cough, fatigue, nausea and/or loss of taste/smell at MRI; participants reporting no symptoms were considered fully-recovered. 129XeMRI ventilation defect percent (VDP) and membrane (Mem)/Gas, red blood cell (RBC)/Mem and RBC/Gas ratios were used in k-means clustering for long COVID, and measurements were compared using ANOVA with post-hoc Bonferroni correction. RESULTS: We evaluated 135 participants across three centres: 28 COVID-negative (40±16yrs), 34 fully-recovered (42±14yrs) and 73 long COVID (49±13yrs). RBC/Mem (p=0.03) and FEV1 (p=0.04) were different between long- and COVID-negative; FEV1 and all other pulmonary function tests (PFTs) were within normal ranges. Four unique long COVID clusters were identified compared with recovered and COVID-negative. Cluster1 was the youngest with normal MRI and mild gas-trapping; Cluster2 was the oldest, characterised by reduced RBC/Mem but normal PFTs; Cluster3 had mildly increased Mem/Gas with normal PFTs; and Cluster4 had markedly increased Mem/Gas with concomitant reduction in RBC/Mem and restrictive PFT pattern. CONCLUSION: We identified four 129XeMRI long COVID phenotypes with distinct characteristics. 129XeMRI can dissect pathophysiologic heterogeneity of long COVID to enable personalised patient care.

Optimized quantitative mapping of cardiopulmonary oscillations using hyperpolarized 129 Xe gas exchange MRI: Digital phantoms and clinical evaluation in CTEPH.

PURPOSE: The interaction between 129 Xe atoms and pulmonary capillary red blood cells provides cardiogenic signal oscillations that display sensitivity to precapillary and postcapillary pulmonary hypertension. Recently, such oscillations have been spatially mapped, but little is known about optimal reconstruction or sensitivity to artifacts. In this study, we use digital phantom simulations to specifically optimize keyhole reconstruction for oscillation imaging. We then use this optimized method to re-establish healthy reference values and quantitatively evaluate microvascular flow changes in patients with chronic thromboembolic pulmonary hypertension (CTEPH) before and after pulmonary thromboendarterectomy (PTE). METHODS: A six-zone digital lung phantom was designed to investigate the effects of radial views, key radius, and SNR. One-point Dixon 129 Xe gas exchange MRI images were acquired in a healthy cohort (n = 17) to generate a reference distribution and thresholds for mapping red blood cell oscillations. These thresholds were applied to 10 CTEPH participants, with 6 rescanned following PTE. RESULTS: For undersampled acquisitions, a key radius of 0.14 k max $$ 0.14{k}_{\mathrm{max}} $$ was found to optimally resolve oscillation defects while minimizing excessive heterogeneity. CTEPH participants at baseline showed higher oscillation defect + low (32 ± 14%) compared with healthy volunteers (18 ± 12%, p < 0.001). For those scanned both before and after PTE, oscillation defect + low decreased from 37 ± 13% to 23 ± 14% (p = 0.03). CONCLUSIONS: Digital phantom simulations have informed an optimized keyhole reconstruction technique for gas exchange images acquired with standard 1-point Dixon parameters. Our proposed methodology enables more robust quantitative mapping of cardiogenic oscillations, potentially facilitating effective regional quantification of microvascular flow impairment in patients with pulmonary vascular diseases such as CTEPH.

Establishing a hemoglobin adjustment for 129 Xe gas exchange MRI and MRS.

PURPOSE: 129 Xe MRI and MRS signals from airspaces, membrane tissues (M), and red blood cells (RBCs) provide measurements of pulmonary gas exchange. However, 129 Xe MRI/MRS studies have yet to account for hemoglobin concentration (Hb), which is expected to affect the uptake of 129 Xe in the membrane and RBC compartments. We propose a framework to adjust the membrane and RBC signals for Hb and use this to assess sex-specific differences in RBC/M and establish a Hb-adjusted healthy reference range for the RBC/M ratio. METHODS: We combined the 1D model of xenon gas exchange (MOXE) with the principle of TR-flip angle equivalence to establish scaling factors that normalize the dissolved-phase signals with respect to a standard H b 0 $$ H{b}^0 $$ (14 g/dL). 129 Xe MRI/MRS data from a healthy, young cohort (n = 18, age = 25.0 ± $$ \pm $$ 3.4 years) were used to validate this model and assess the impact of Hb adjustment on M/gas and RBC/gas images and RBC/M. RESULTS: Adjusting for Hb caused RBC/M to change by up to 20% in healthy individuals with normal Hb and had marked impacts on M/gas and RBC/gas distributions in 3D gas-exchange maps. RBC/M was higher in males than females both before and after Hb adjustment (p < 0.001). After Hb adjustment, the healthy reference value for RBC/M for a consortium-recommended acquisition of TR = 15 ms and flip = 20° was 0.589 ± $$ \pm $$ 0.083 (mean ± $$ \pm $$ SD). CONCLUSION: MOXE provides a useful framework for evaluating the Hb dependence of the membrane and RBC signals. This work indicates that adjusting for Hb is essential for accurately assessing 129 Xe gas-exchange MRI/MRS metrics.

Persistent 129Xe MRI Pulmonary and CT Vascular Abnormalities in Symptomatic Individuals with Post-acute COVID-19 Syndrome.

BACKGROUND: In patients with post-acute COVID-19 syndrome (PACS), abnormal gas-transfer and pulmonary vascular density have been reported, but such findings have not been related to each other or to symptoms and exercise limitation. The pathophysiologic drivers of PACS in patients previously infected with COVID-19 who were admitted to in-patient treatment in hospital (or ever-hospitalized patients) and never-hospitalized patients are not well understood. PURPOSE: To determine the relationship of persistent symptoms and exercise limitation with xenon 129 (129Xe) MRI and CT pulmonary vascular measurements in individuals with PACS. MATERIALS AND METHODS: In this prospective study, patients with PACS aged 18-80 years with a positive polymerase chain reaction COVID-19 test were recruited from a quaternary-care COVID-19 clinic between April and October 2021. Participants with PACS underwent spirometry, diffusing capacity of the lung for carbon monoxide (DLco), 129Xe MRI, and chest CT. Healthy controls had no prior history of COVID-19 and underwent spirometry, DLco, and 129Xe MRI. The 129Xe MRI red blood cell (RBC) to alveolar-barrier signal ratio, RBC area under the receiver operating characteristic curve (AUC), CT volume of pulmonary vessels with cross-sectional area 5 mm2 or smaller (BV5), and total blood volume were quantified. St George's Respiratory Questionnaire, International Physical Activity Questionnaire, and modified Borg Dyspnea Scale measured quality of life, exercise limitation, and dyspnea. Differences between groups were compared with use of Welch t-tests or Welch analysis of variance. Relationships were evaluated with use of Pearson (r) and Spearman (ρ) correlations. RESULTS: Forty participants were evaluated, including six controls (mean age ± SD, 35 years ± 15, three women) and 34 participants with PACS (mean age, 53 years ± 13, 18 women), of whom 22 were never hospitalized. The 129Xe MRI RBC:barrier ratio was lower in ever-hospitalized participants (P = .04) compared to controls. BV5 correlated with RBC AUC (ρ = .44, P = .03). The 129Xe MRI RBC:barrier ratio was related to DLco (r = .57, P = .002) and forced expiratory volume in 1 second (ρ = .35, P = .03); RBC AUC was related to dyspnea (ρ = -.35, P = .04) and International Physical Activity Questionnaire score (ρ = .45, P = .02). CONCLUSION: Xenon 129 (129Xe) MRI measurements were lower in participants previously infected with COVID-19 who were admitted to in-patient treatment in hospital with post-acute COVID-19 syndrome, 34 weeks ± 25 after infection compared to controls. The 129Xe MRI measures were associated with CT pulmonary vascular density, diffusing capacity of the lung for carbon monoxide, exercise capacity, and dyspnea. Clinical trial registration no.: NCT04584671 © RSNA, 2022 Online supplemental material is available for this article See also the editorial by Wild and Collier in this issue.

Bias field correction in hyperpolarized 129 Xe ventilation MRI using templates derived by RF-depolarization mapping.

PURPOSE: To correct for RF inhomogeneity for in vivo 129 Xe ventilation MRI using flip-angle mapping enabled by randomized 3D radial acquisitions. To extend this RF-depolarization mapping approach to create a flip-angle map template applicable to arbitrary acquisition strategies, and to compare these approaches to conventional bias field correction. METHODS: RF-depolarization mapping was evaluated first in digital simulations and then in 51 subjects who had undergone radial 129 Xe ventilation MRI in the supine position at 3T (views = 3600; samples/view = 128; TR/TE = 4.5/0.45 ms; flip angle = 1.5; FOV = 40 cm). The images were corrected using newly developed RF-depolarization and templated-based methods and the resulting quantitative ventilation metrics (mean, coefficient of variation, and gradient) were compared to those resulting from N4ITK correction. RESULTS: RF-depolarization and template-based mapping methods yielded a pattern of RF-inhomogeneity consistent with the expected variation based on coil architecture. The resulting corrected images were visually similar, but meaningfully distinct from those generated using standard N4ITK correction. The N4ITK algorithm eliminated the physiologically expected anterior-posterior gradient (-0.04 ± 1.56%/cm, P < 0.001). These 2 newly introduced methods of RF-depolarization and template correction retained the physiologically expected anterior-posterior ventilation gradient in healthy subjects (2.77 ± 2.09%/cm and 2.01 ± 2.73%/cm, respectively). CONCLUSIONS: Randomized 3D 129 Xe MRI ventilation acquisitions can inherently be corrected for bias field, and this technique can be extended to create flip angle templates capable of correcting images from a given coil regardless of acquisition strategy. These methods may be more favorable than the de facto standard N4ITK because they can remove undesirable heterogeneity caused by RF effects while retaining results from known physiology.

Utilizing flip angle/TR equivalence to reduce breath hold duration in hyperpolarized 129 Xe 1-point Dixon gas exchange imaging.

PURPOSE: To reduce scan duration in hyperpolarized 129 Xe 1-point Dixon gas exchange imaging by utilizing flip angle (FA)/TR equivalence. METHODS: Images were acquired in 12 subjects (n = 3 radiation therapy, n = 1 unexplained dyspnea, n = 8 healthy) using both standard (TR = 15 ms, FA = 20°, duration = 15 s, 998 projections) and "fast" (TR = 5.4 ms, FA = 12°, duration = 11.3 s, 2100 projections) acquisition parameters. For the fast acquisition, 3 image sets were reconstructed using subsets of 1900, 1500, and 1000 projections. From the resulting ventilation, tissue ("barrier"), and red blood cell (RBC) images, image metrics and biomarkers were compared to assess agreement between methods. RESULTS: Images acquired using both FA/TR settings had similar qualitative appearance. There were no significant differences in SNR, image mean, or image SD between images. Moreover, the percentage of the lungs in "defect", "normal", and "high" bins for each image (ventilation, RBC, barrier) was not significantly different among the acquisition types. After registration, comparison of 3D image metrics (Dice, volume similarity, average distance) agreed well between bins. Images using 1000 projections for reconstruction had no significant differences from images using all projections. CONCLUSION: Using flip angle/TR equivalence, hyperpolarized 129 Xe gas exchange images can be acquired via the 1-point Dixon technique in as little as 6 s, compared to ~15 s for previously reported parameter settings. The resulting images from this accelerated scan have no significant differences from the standard method in qualitative appearance or quantitative metrics.

Pediatric 129 Xe Gas-Transfer MRI-Feasibility and Applicability.

BACKGROUND: 129 Xe gas-transfer MRI provides regional measures of pulmonary gas exchange in adults and separates xenon in interstitial lung tissue/plasma (barrier) from xenon in red blood cells (RBCs). The technique has yet to be demonstrated in pediatric populations or conditions. PURPOSE/HYPOTHESIS: To perform an exploratory analysis of 129 Xe gas-transfer MRI in children. STUDY TYPE: Prospective. POPULATION: Seventy-seven human volunteers (38 males, age = 17.7 ± 15.1 years, range 5-68 years, 16 healthy). Four pediatric disease cohorts. FIELD STRENGTH/SEQUENCE: 3-T, three-dimensional-radial one-point Dixon Fast Field Echo (FFE) Ultrashort Echo Time (UTE). ASSESSMENT: Breath hold compliance was assessed by quantitative signal-to-noise and dynamic metrics. Whole-lung means and standard deviations were extracted from gas-transfer maps. Gas-transfer metrics were investigated with respect to age and lung disease. Clinical pulmonary function tests were retrospectively acquired for reference lung disease severity. STATISTICAL TESTS: Wilcoxon rank-sum tests to compare age and disease cohorts, Wilcoxon signed-rank tests to compare pre- and post-breath hold vitals, Pearson correlations between age and gas-transfer metrics, and limits of normal with a binomial exact test to compare fraction of subjects with abnormal gas-transfer. P ≤ 0.05 was considered significant. RESULTS: Eighty percentage of pediatric subjects successfully completed 129 Xe gas-transfer MRI. Gas-transfer parameters differed between healthy children and adults, including ventilation (0.75 and 0.67) and RBC:barrier ratio (0.31 and 0.46) which also correlated with age (ρ = -0.76, 0.57, respectively). Bone marrow transplant subjects had impaired ventilation (90% of reference) and increased dissolved 129 Xe standard deviation (242%). Bronchopulmonary dysplasia subjects had decreased barrier-uptake (69%). Cystic fibrosis subjects had impaired ventilation (91%) and increased RBC-transfer (146%). Lastly, childhood interstitial lung disease subjects had increased ventilation heterogeneity (113%). Limits of normal provided detection of abnormalities in additional gas-transfer parameters. DATA CONCLUSION: Pediatric 129 Xe gas-transfer MRI was adequately successful and gas-transfer metrics correlated with age. Exploratory analysis revealed abnormalities in a variety of pediatric obstructive and restrictive lung diseases. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

Pulmonary functional MRI: Detecting the structure-function pathologies that drive asthma symptoms and quality of life.

Pulmonary functional MRI (PfMRI) using inhaled hyperpolarized, radiation-free gases (such as 3 He and 129 Xe) provides a way to directly visualize inhaled gas distribution and ventilation defects (or ventilation heterogeneity) in real time with high spatial (~mm3 ) resolution. Both gases enable quantitative measurement of terminal airway morphology, while 129 Xe uniquely enables imaging the transfer of inhaled gas across the alveolar-capillary tissue barrier to the red blood cells. In patients with asthma, PfMRI abnormalities have been shown to reflect airway smooth muscle dysfunction, airway inflammation and remodelling, luminal occlusions and airway pruning. The method is rapid (8-15 s), cost-effective (~$300/scan) and very well tolerated in patients, even in those who are very young or very ill, because unlike computed tomography (CT), positron emission tomography and single-photon emission CT, there is no ionizing radiation and the examination takes only a few seconds. However, PfMRI is not without limitations, which include the requirement of complex image analysis, specialized equipment and additional training and quality control. We provide an overview of the three main applications of hyperpolarized noble gas MRI in asthma research including: (1) inhaled gas distribution or ventilation imaging, (2) alveolar microstructure and finally (3) gas transfer into the alveolar-capillary tissue space and from the tissue barrier into red blood cells in the pulmonary microvasculature. We highlight the evidence that supports a deeper understanding of the mechanisms of asthma worsening over time and the pathologies responsible for symptoms and disease control. We conclude with a summary of approaches that have the potential for integration into clinical workflows and that may be used to guide personalized treatment planning.

Hyperpolarized 129Xe MRI and Spectroscopy of Gas-Exchange Abnormalities in Nonspecific Interstitial Pneumonia.

Background Recent studies demonstrate that antifibrotic drugs previously reserved for idiopathic pulmonary fibrosis (IPF) may slow progression in other interstitial lung diseases (ILDs), creating an urgent need for tools that can sensitively assess disease activity, progression, and therapy response across ILDs. Hyperpolarized xenon 129 (129Xe) MRI and spectroscopy have provided noninvasive measurements of regional gas-exchange abnormalities in IPF. Purpose To assess gas exchange function using 129Xe MRI in a group of study participants with nonspecific interstitial pneumonia (NSIP) compared with healthy control participants. Materials and Methods In this prospective study, participants with NSIP and healthy control participants were enrolled between November 2017 and February 2020 and underwent 129Xe MRI and spectroscopy. Quantitative imaging provided three-dimensional maps of ventilation, interstitial barrier uptake, and transfer into the red blood cell (RBC) compartment. Spectroscopy provided parameters of the static RBC and barrier uptake compartments, as well as cardiogenic oscillations in RBC signal amplitude and chemical shift. Differences between NSIP and healthy control participants were assessed using the Wilcoxon rank-sum test. Results Thirty-six participants with NSIP (mean age, 57 years ± 11 [standard deviation]; 27 women) and 15 healthy control participants (mean age, 39 years ± 18; two women) were evaluated. Participants with NSIP had no difference in ventilation compared with healthy control participants (median, 4.4% [first quartile, 1.5%; third quartile, 8.7%] vs 6.0% [first quartile, 2.8%; third quartile, 6.9%]; P = .91), but they had a higher barrier uptake (median, 6.2% [first quartile, 1.8%; third quartile, 23.9%] vs 0.53% [first quartile, 0.33%; third quartile, 2.9%]; P = .003) and an increased RBC transfer defect (median, 20.6% [first quartile, 11.6%; third quartile, 27.8%] vs 2.8% [first quartile, 2.3%; third quartile, 4.9%]; P < .001). NSIP participants also had a reduced ratio of RBC-to-barrier peaks (median, 0.24 [first quartile, 0.19; third quartile, 0.31] vs 0.57 [first quartile, 0.52; third quartile, 0.67]; P < .001) and a reduced RBC chemical shift (median, 217.5 ppm [first quartile, 217.0 ppm; third quartile, 218.0 ppm] vs 218.2 ppm [first quartile, 217.9 ppm; third quartile, 218.6 ppm]; P = .001). Conclusion Participants with nonspecific interstitial pneumonia had increased barrier uptake and decreased red blood cell (RBC) transfer compared with healthy controls measured using xenon 129 gas-exchange MRI and reduced RBC-to-barrier ratio and RBC chemical shift measured using spectroscopy. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Wild in this issue.

Protocols for multi-site trials using hyperpolarized 129 Xe MRI for imaging of ventilation, alveolar-airspace size, and gas exchange: A position paper from the 129 Xe MRI clinical trials consortium.

Hyperpolarized (HP) 129 Xe MRI uniquely images pulmonary ventilation, gas exchange, and terminal airway morphology rapidly and safely, providing novel information not possible using conventional imaging modalities or pulmonary function tests. As such, there is mounting interest in expanding the use of biomarkers derived from HP 129 Xe MRI as outcome measures in multi-site clinical trials across a range of pulmonary disorders. Until recently, HP 129 Xe MRI techniques have been developed largely independently at a limited number of academic centers, without harmonizing acquisition strategies. To promote uniformity and adoption of HP 129 Xe MRI more widely in translational research, multi-site trials, and ultimately clinical practice, this position paper from the 129 Xe MRI Clinical Trials Consortium (https://cpir.cchmc.org/XeMRICTC) recommends standard protocols to harmonize methods for image acquisition in HP 129 Xe MRI. Recommendations are described for the most common HP gas MRI techniques-calibration, ventilation, alveolar-airspace size, and gas exchange-across MRI scanner manufacturers most used for this application. Moreover, recommendations are described for 129 Xe dose volumes and breath-hold standardization to further foster consistency of imaging studies. The intention is that sites with HP 129 Xe MRI capabilities can readily implement these methods to obtain consistent high-quality images that provide regional insight into lung structure and function. While this document represents consensus at a snapshot in time, a roadmap for technical developments is provided that will further increase image quality and efficiency. These standardized dosing and imaging protocols will facilitate the wider adoption of HP 129 Xe MRI for multi-site pulmonary research.

Regional Gas Exchange Measured by 129 Xe Magnetic Resonance Imaging Before and After Combination Bronchodilators Treatment in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Hyperpolarized 129 Xe magnetic resonance imaging (MRI) provides a non-invasive assessment of regional pulmonary gas exchange function. This technique has demonstrated that chronic obstructive pulmonary disease (COPD) patients exhibit ventilation defects, reduced interstitial barrier tissue uptake, and poor transfer to capillary red blood cells (RBCs). However, the behavior of these measurements following therapeutic intervention is unknown. PURPOSE: To characterize changes in 129 Xe gas transfer function following administration of an inhaled long-acting beta-agonist/long-acting muscarinic receptor antagonist (LABA/LAMA) bronchodilator. STUDY TYPE: Prospective. POPULATION: Seventeen COPD subjects (GOLD II/III classification per Global Initiative for Chronic Obstructive Lung Disease criteria) were imaged before and after 2 weeks of LABA/LAMA therapy. FIELD STRENGTH/SEQUENCES: Dedicated ventilation imaging used a multi-slice 2D gradient echo sequence. Three-dimensional images of ventilation, barrier uptake, and RBC transfer used an interleaved, radial, 1-point Dixon sequence. Imaging was acquired at 3 T. ASSESSMENT: 129 Xe measurements were quantified before and after LABA/LAMA treatment by ventilation defect + low percent (vendef + low ) and by barrier uptake and RBC transfer relative to a healthy reference population (bar%ref and RBC%ref ). Pulmonary function tests, including diffusing capacity of the lung for carbon monoxide (DLCO ), were also performed before and after treatment. STATISTICAL TESTS: Paired t-test, Pearson correlation coefficient (r). RESULTS: Baseline vendef + low was 57.8 ± 8.4%, bar%ref was 73.2 ± 19.6%, and RBC%ref was 36.5 ± 13.6%. Following treatment, vendef + low decreased to 52.5 ± 10.6% (P < 0.05), and improved in 14/17 (82.4%) of subjects. However, RBC%ref decreased in 10/17 (58.8%) of subjects. Baseline measurements of bar%ref and DLCO were correlated with the degree of post-treatment change in vendef + low (r = -0.49, P < 0.05 and r = -0.52, P < 0.05, respectively). CONCLUSION: LABA/LAMA therapy tended to preferentially improve ventilation in subjects whose 129 Xe barrier uptake and DLCO were relatively preserved. However, newly ventilated regions often revealed RBC transfer defects, an aspect of lung function opaque to spirometry. These microvasculature abnormalities must be accounted for when assessing the effects of LABA/LAMA therapy. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 4.

Diverse cardiopulmonary diseases are associated with distinct xenon magnetic resonance imaging signatures.

BACKGROUND: As an increasing number of patients exhibit concomitant cardiac and pulmonary disease, limitations of standard diagnostic criteria are more frequently encountered. Here, we apply noninvasive 129Xe magnetic resonance imaging (MRI) and spectroscopy to identify patterns of regional gas transfer impairment and haemodynamics that are uniquely associated with chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), left heart failure (LHF) and pulmonary arterial hypertension (PAH). METHODS: Healthy volunteers (n=23) and patients with COPD (n=8), IPF (n=12), LHF (n=6) and PAH (n=10) underwent 129Xe gas transfer imaging and dynamic spectroscopy. For each patient, three-dimensional maps were generated to depict ventilation, barrier uptake (129Xe dissolved in interstitial tissue) and red blood cell (RBC) transfer (129Xe dissolved in RBCs). Dynamic 129Xe spectroscopy was used to quantify cardiogenic oscillations in the RBC signal amplitude and frequency shift. RESULTS: Compared with healthy volunteers, all patient groups exhibited decreased ventilation and RBC transfer (both p≤0.01). Patients with COPD demonstrated more ventilation and barrier defects compared with all other groups (both p≤0.02). In contrast, IPF patients demonstrated elevated barrier uptake compared with all other groups (p≤0.007), and increased RBC amplitude and shift oscillations compared with healthy volunteers (p=0.007 and p≤0.01, respectively). Patients with COPD and PAH both exhibited decreased RBC amplitude oscillations (p=0.02 and p=0.005, respectively) compared with healthy volunteers. LHF was distinguishable from PAH by enhanced RBC amplitude oscillations (p=0.01). CONCLUSION: COPD, IPF, LHF and PAH each exhibit unique 129Xe MRI and dynamic spectroscopy signatures. These metrics may help with diagnostic challenges in cardiopulmonary disease and increase understanding of regional lung function and haemodynamics at the alveolar-capillary level.

A thermally polarized 129 Xe phantom for quality assurance in multi-center hyperpolarized gas MRI studies.

PURPOSE: Hyperpolarized 129 Xe MR is increasingly being adopted worldwide, but no standards exist for assessing or comparing performance at different 129 Xe imaging centers. Therefore, we sought to develop a thermally polarized xenon phantom assembly, approximating the size of a human torso, along with an associated imaging protocol to enable rapid quality-assurance imaging. METHODS: MR-compatible pressure vessels, with an internal volume of 5.85 L, were constructed from pressure-rated, engineering grade PE4710 high-density polyethylene. They were filled with a mixture of 61% natural xenon and 39% oxygen to approximately 11.6 bar and placed in a loader shell filled with a 0.56% saline solution to mimic the human chest. Imaging employed a 2D spoiled gradient-echo sequence using non-slice-selective excitation (TR/TE = 750/6.13 ms, flip angle = 74°, FOV = 40 × 440 mm, matrix = 64 × 32, bandwidth = 30 Hz/pixel, averages = 4), resulting in a 1.6 min acquisition. System characterization and imaging were performed at 8 different MRI centers. RESULTS: At 3 Telsa, 129 Xe in the pressure vessels was characterized by T1 = 580.5 ± 8.3 ms, linewidth = 0.21 ppm, and chemical shift = +10.2 ppm. The phantom assembly was used to obtain transmit voltage calibrations and 2D and 3D images across multiple coil and scanner configurations at 8 sites. Across the 5 sites that employed a standard flexible chest coil, the SNR was 12.4 ± 1.8. CONCLUSION: The high-density polyethylene pressure vessels filled with thermally polarized xenon and associated loader shell combine to form a phantom assembly that enables spectroscopic and imaging acquisitions that can be used for testing, quality assurance, and performance tracking-capabilities essential for standardizing hyperpolarized 129 Xe MRI within and across institutions.

A protocol for quantifying cardiogenic oscillations in dynamic 129 Xe gas exchange spectroscopy: The effects of idiopathic pulmonary fibrosis.

The spectral parameters of hyperpolarized 129 Xe exchanging between airspaces, interstitial barrier, and red blood cells (RBCs) are sensitive to pulmonary pathophysiology. This study sought to evaluate whether the dynamics of 129 Xe spectroscopy provide additional insight, with particular focus on quantifying cardiogenic oscillations in the RBC resonance. 129 Xe spectra were dynamically acquired in eight healthy volunteers and nine subjects with idiopathic pulmonary fibrosis (IPF). 129 Xe FIDs were collected every 20 ms (TE  = 0.932 ms, 512 points, dwell time = 32 µs, flip angle ≈ 20°) during a 16 s breathing maneuver. The FIDs were pre-processed using the spectral improvement by Fourier thresholding technique (SIFT) and fit in the time domain to determine the airspace, interstitial barrier, and RBC spectral parameters. The RBC and gas resonances were fit to a Lorentzian lineshape, while the barrier was fit to a Voigt lineshape to account for its greater structural heterogeneity. For each complex resonance the amplitude, chemical shift, linewidth(s), and phase were calculated. The time-averaged spectra confirmed that the RBC to barrier amplitude ratio (RBC:barrier ratio) and RBC chemical shift are both reduced in IPF subjects. Their temporal dynamics showed that all three 129 Xe resonances are affected by the breathing maneuver. Most notably, several RBC spectral parameters exhibited prominent oscillations at the cardiac frequency, and their peak-to-peak variation differed between IPF subjects and healthy volunteers. In the IPF cohort, oscillations were more prominent in the RBC amplitude (16.8 ± 5.2 versus 9.7 ± 2.9%; P = 0.008), chemical shift (0.43 ± 0.33 versus 0.083 ± 0.05 ppm; P < 0.001), and phase (7.7 ± 5.6 versus 1.4 ± 0.8°; P < 0.001). Dynamic 129 Xe spectroscopy is a simple and sensitive tool that probes the temporal variability of gas exchange and may prove useful in discerning the underlying causes of its impairment.

Multireader Determination of Clinically Significant Obstruction Using Hyperpolarized 129Xe-Ventilation MRI.

OBJECTIVE: The objective of our study was to identify the magnitude and distribution of ventilation defect scores (VDSs) derived from hyperpolarized (HP) 129Xe-MRI associated with clinically relevant airway obstruction. MATERIALS AND METHODS: From 2012 to 2015, 76 subjects underwent HP 129Xe-MRI (48 healthy volunteers [mean age ± SD, 54 ± 17 years]; 20 patients with asthma [mean age, 44 ± 20 years]; eight patients with chronic obstructive pulmonary disease [mean age, 67 ± 5 years]). All subjects underwent spirometry 1 day before MRI to establish the presence of airway obstruction (forced expiratory volume in 1 second-to-forced vital capacity ratio [FEV1/FVC] < 70%). Five blinded readers assessed the degree of ventilation impairment and assigned a VDS (range, 0-100%). Interreader agreement was assessed using the Fleiss kappa statistic. Using FEV1/FVC as the reference standard, the optimum VDS threshold for the detection of airway obstruction was estimated using ROC curve analysis with 10-fold cross-validation. RESULTS: Compared with the VDSs in healthy subjects, VDSs in patients with airway obstruction were significantly higher (p < 0.0001) and significantly correlated with disease severity (r = 0.66, p < 0.0001). Ventilation defects in subjects with airway obstruction did not show a location-specific pattern (p = 0.158); however, defects in healthy control subjects were more prevalent in the upper lungs (p = 0.014). ROC curve analysis yielded an optimal threshold of 12.4% ± 6.1% (mean ± SD) for clinically significant VDS. Interreader agreement for 129Xe-MRI was substantial (κ = 0.71). CONCLUSION: This multireader study of a diverse cohort of patients and control subjects suggests a 129Xe-ventilation MRI VDS of 12.4% or greater represents clinically significant obstruction.

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 129 Xe gas transfer MRI: the transition from 1.5T to 3T.

PURPOSE: Hyperpolarized 129 Xe MRI depicting 3D ventilation, interstitial barrier uptake, and transfer to red blood cells (RBCs) has emerged as a powerful new means of detecting pulmonary disease. However, given the challenging susceptibility environment of the lung, such gas transfer imaging has, thus far, only been implemented at 1.5T. Here, we seek to demonstrate the feasibility of Dixon-based 129 Xe gas transfer MRI at 3T. METHODS: Seven healthy subjects and six patients with pulmonary disorders were recruited to characterize 129 Xe spectral structure, optimize acquisition parameters, and acquire representative images. Imaging used randomized, gradient-spoiled 3D-radial encoding of 1000 gas (0.5° flip) and dissolved (20° flip) views, reconstructed into 3-mm isotropic voxels. The center of k-space was sampled when barrier and RBC compartments were 90° out of phase (TE90 ). A single dissolved phase spectrum was appended to the sequence to measure the global RBC-barrier ratio for Dixon-based decomposition. RESULTS: A 0.69 ms sinc was found to generate minimal off-resonance gas-phase excitation (3.0 ± 0.3% of the dissolved-phase), yielding a TE90 = 0.47 ± 0.02 ms. The RBC and barrier resonance frequencies were shifted by 217.6 ± 0.6 ppm and 197.8 ± 0.2 ppm. The RBC T 2 * was estimated to be ∼1.1 ms, and therefore each read-out was limited to 1.3 ms. 129 Xe gas and dissolved-phase images have sufficient SNR to produce gas transfer maps of similar quality and sensitivity to pathology, as previously obtained at 1.5T. CONCLUSIONS: Despite short dissolved-phase T 2 * , 129 Xe gas transfer MRI is feasible at 3T.

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 HTR4's role in pulmonary function likely relates to neural innervation and control of breathing.

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

PURPOSE: 129 Xe 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 129 Xe reference from in vivo data. METHODS: Respiratory-gated hyperpolarized 129 Xe spectra from the gas- and dissolved-phases were acquired in four mice at 2T from multiple axial slices within the thoracic cavity. Complex spectra were then fitted in the time domain to identify peaks. RESULTS: Gas-phase 129 Xe exhibited two distinct resonances corresponding to 129 Xe in conducting airways (varying from -0.6 ± 0.2 to 1.3 ± 0.3 ppm) and alveoli (relatively stable, at -2.2 ± 0.1 ppm). Dissolved-phase 129 Xe exhibited five reproducible resonances in the thorax at 198.4 ± 0.4, 195.5 ± 0.4, 193.9 ± 0.2, 191.3 ± 0.2, and 190.7 ± 0.3 ppm. CONCLUSION: The alveolar 129 Xe resonance exhibits a stable frequency across all mice. Therefore, it can provide a reliable in vivo reference frequency by which to characterize other spectroscopic shifts. Magn Reson Med 77:1438-1445, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

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

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. © 2016 International Society for Magnetic Resonance in Medicine.