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Purpose To demonstrate the feasibility of 129 Xe chemical shift saturation recovery (CSSR) combined with spiral-IDEAL imaging for simultaneous measurement of the time-course of red blood cell (RBC) and brain tissue signals in the rat brain. Methods Images of both the RBC and brain tissue 129 Xe signals from the brains of five rats were obtained using interleaved spiral-IDEAL imaging following chemical shift saturation pulses applied at multiple CSSR delay times, τ. A linear fit of the signals to τ was used to calculate the slope of the signal for both RBC and brain tissue compartments on a voxel-by-voxel basis. Gas transfer was evaluated by measuring the ratio of the whole brain tissue-to-RBC signal intensities as a function of τ. To investigate the relationship between the CSSR images and gas transfer in the brain, the experiments were repeated during hypercapnic ventilation. Results Hypercapnia, affected the ratio of the tissue-to-RBC signal intensity (p = 0.026), consistent with an increase in gas transfer. Conclusion CSSR with spiral-IDEAL imaging is feasible for acquisition of 129 Xe RBC and brain tissue time-course images in the rat brain. Differences in the time-course of the signal intensity ratios are consistent with gas transfer changes expected under hypercapnic conditions.

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.

Premature infants often require mechanical ventilation and oxygen therapy, which can result in bronchopulmonary dysplasia (BPD), characterized by developmental arrest and impaired lung function. Conventional clinical methods for assessing the prenatal lung are not adequate for the detection and assessment of long-term health risks in infants with BPD, highlighting the need for a noninvasive tool for the characterization of lung microstructure and function. Theoretical diffusion models, like the model of xenon exchange (MOXE), interrogate alveolar gas exchange by predicting the uptake of inert hyperpolarized (HP) 129Xe gas measured with HP 129Xe magnetic resonance spectroscopy (MRS). To investigate HP 129Xe MRS as a tool for noninvasive characterization of pulmonary microstructural and functional changes in vivo, HP 129Xe gas exchange data were acquired in an oxygen exposure rat model of BPD that recapitulates the fewer and larger distal airways and pulmonary vascular stunting characteristics of BPD. Gas exchange parameters from MOXE, including airspace mean chord length ( Lm), apparent hematocrit in the pulmonary capillaries (HCT), and pulmonary capillary transit time ( tx), were compared with airspace mean axis length and area density (MAL and ρA) and percentage area of tissue and air (PTA and PAA) from histology. Lm was significantly larger in the exposed rats ( P = 0.003) and correlated with MAL, ρA, PTA, and PAA (0.59x are also discussed. These findings support the use of HP 129Xe MRS for detecting fewer, enlarged distal airways in this rat model of BPD, and potentially in humans.

Rationale and Objectives Phase resolved functional lung (PREFUL) magnetic resonance imaging (MRI) is a free-breathing 1H-based technique that produces maps of fractional ventilation (FV). This study compared ventilation defect percent (VDP) calculated using PREFUL to hyperpolarized (HP) 129Xe MRI and pulmonary function tests in pediatric cystic fibrosis (CF). Materials and Methods 27 pediatric participants were recruited (mean age 13.0 ± 2.7), including 6 with clinically stable CF, 11 CF patients undergoing a pulmonary exacerbation (PEx), and 10 healthy controls. Spirometry was performed to measure forced expiratory volume in 1 second (FEV1), along with nitrogen multiple breath washout to measure lung clearance index (LCI). VDP was calculated from single central coronal slice PREFUL FV maps and the corresponding HP 129Xe slice. Results The stable CF group had a normal FEV1 (p = 0.41) and elevated LCI (p = 0.007). The CF PEx group had a decreased FEV1 (p Conclusion PREFUL MRI is feasible in pediatric CF, distinguishes patients undergoing pulmonary exacerbations compared to healthy subjects, and correlates with HP 129Xe MRI as well as functional measures of disease severity. PREFUL MRI does not require breath-holds and is straight forward to implement on any MRI scanner.

Purpose To investigate the dependence of dissolved 129 Xe chemical shift on the fraction of inhaled oxygen, Fi O2 , in the lungs of healthy rats. Methods The chemical shifts of 129 Xe dissolved in red blood cells, δRBC , and blood plasma and/or tissue, δPlasma , were measured using MRS in 12 Sprague Dawley rats mechanically ventilated at Fi O2 values of 0.14, 0.19, and 0.22. Regional effects on the chemical shifts were controlled using a chemical shift saturation recovery sequence with a fixed delay time. MRS was also performed at an Fi CO2 value of 0.085 to investigate the potential effect of the vascular response on δRBC and δPlasma . Results δRBC increased with decreasing Fi O2 (P = .0002), and δPlasma showed no dependence on Fi O2 (P = .23). δRBC at Fi CO2 = 0 (210.7 ppm ± 0.1) and at Fi CO2 = 0.085 (210.6 ppm ± 0.2) were not significantly different (P = .67). δPlasma at Fi CO2 = 0 (196.9 ppm ± 0.3) and at Fi CO2 = 0.085 (197.0 ppm ± 0.1) were also not significantly different (P = .81). Conclusion Rat lung δRBC showed an inverse relationship to Fi O2 , opposite to the relationship previously demonstrated for in vitro human blood. Rat lung δRBC did not depend on Fi CO2 .

Diffusion-weighted, hyperpolarized 129Xe MRI is useful for the characterization of microstructural changes in the lung. A stretched exponential model was proposed for morphometric extraction of the mean chord length (Lm) from diffusion-weighted data. The stretched exponential model enables accelerated mapping of Lm in a single-breathhold using compressed sensing. Our purpose was to compare Lm maps obtained from stretched-exponential model analysis of accelerated versus unaccelerated diffusion-weighted 129Xe MRI data obtained from healthy/injured rat lungs. Lm maps were generated using a stretched-exponential model analysis of previously acquired fully sampled diffusion-weighted 129Xe rat data (b values = 0 … 110 s/cm2) and compared to Lm maps generated from retrospectively undersampled data simulating acceleration factors of 7/10. The data included four control rats and five rats receiving whole-lung irradiation to mimic radiation-induced lung injury. Mean Lm obtained from the accelerated/unaccelerated maps were compared to histological mean linear intercept. Accelerated Lm estimates were similar to unaccelerated Lm estimates in all rats, and similar to those previously reported (

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.To determine the relationship of persistent symptoms and exercise limitation with xenon 129 (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),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. TheXenon 129 (

PURPOSE To assess the feasibility of hyperpolarized 129 Xe multiple-breath washout MRI in pediatric cystic fibrosis (CF) participants with preserved lung function. Fractional ventilation (r), defined as the fractional gas replacement per breath, was mapped using 2 signal models: (1) constant T1 and (2) variable T1 as a function of the hyperpolarized gas washout. METHODS A total of 17 pediatric participants were recruited (mean age 11.7 ± 2.8 years), including 7 children with clinically stable CF and 10 aged-matched healthy controls. Pulmonary function tests were performed, including spirometry, to measure the forced expiratory volume in 1 second and nitrogen multiple-breath washout to measure the lung clearance index. Hyperpolarized 129 Xe MRI was performed during consecutive breaths of air following a single 129 Xe inhalation, and fractional ventilation maps were calculated. RESULTS The forced expiratory volume in 1 second was similar in both groups (P = .32), but there was a statistically significant difference in lung clearance index between healthy and CF participants (P = .001). With variable T1 modeling, CF participants had a mean r of 0.44 ± 0.08 and healthy participants had a mean r of 0.37 ± 0.12 (P = .20). With constant T1 modeling, CF participants had a mean r' of 0.48 ± 0.08, and healthy participants had a mean r' of 0.43 ± 0.12 (P = .32). Therefore, assuming a constant T1 leads to a relative bias in r of 15.1% ± 6.4% and 20.8% ± 7.4% for CF and healthy participants, respectively (P = .12). CONCLUSION This study demonstrates that hyperpolarized 129 Xe multiple-breath washout imaging is feasible in pediatric participants with CF, and inclusion of variable T1 modeling reduces bias in the fractional ventilation measurements.

Purpose To measure regional changes in hyperpolarized 129 Xe MRI signal and apparent transverse relaxation ( T 2 ∗ ) because of instillation of SPION-labeled alveolar-like macrophages (ALMs) in the lungs of rats and compare to histology. Methods MRI was performed in 6 healthy mechanically ventilated rats before instillation, as well as 5 min and 1 h after instillation of 4 million SPION-labeled ALMs into either the left or right lung. T 2 ∗ maps were calculated from 2D multi-echo data at each time point and changes in T 2 ∗ were measured and compared to control rats receiving 4 million unlabeled ALMs. Histology of the ex vivo lungs was used to compare the regional MRI findings with the locations of the SPION-labeled ALMs. Results Regions of signal loss were observed immediately after instillation of unlabeled and SPION-labeled ALMs and persisted at least 1 h in the case of the SPION-labeled ALMs. This was reflected in the measurements of T 2 ∗ . One hour after the instillation of SPION-labeled ALMs, the T 2 ∗ decreased to 54.0 ± 7.0% of the baseline, compared to a full recovery to baseline after the instillation of unlabeled ALMs. Histology confirmed the co-localization of SPION-labeled ALMs with regions of signal loss and T 2 ∗ decreases for each rat. Conclusion Hyperpolarized 129 Xe MRI can detect the presence of SPION-labeled ALMs in the airways 1 h after instillation. This approach is promising for targeting and tracking of stem cells for the treatment of lung disease.

Background The ventilation defect percent (VDP), measured from hyperpolarized (HP) 129Xe magnetic resonance imaging (MRI), is sensitive to functional changes in cystic fibrosis (CF) lung disease. The purpose of this study was to measure and compare VDP from HP 129Xe MRI acquired at two institutions in stable pediatric CF subjects with preserved lung function. Methods This retrospective analysis included 26 participants from two institutions (18 CF, 8 healthy, age range 10–17). Pulmonary function tests, N2 multiple breath washout (to measure lung clearance index, LCI), and HP 129Xe MRI were performed. VDP measurements were compared between two trained analysts using mean-anchored linear binning. Correlations were investigated for VDP compared to the forced expiratory volume in one second (FEV1) and LCI. Results VDP measurements agreed for the two analysts with an intraclass correlation coefficient of 0.99. In the combined dataset, VDP measured by Analyst 1 was 5.96 ± 1.82% and 15.96 ± 6.76% for the healthy and CF groups, respectively (p = .0004). Analyst 2 showed similar differences between healthy and CF (p = .0003). VDP measured by either analyst was shown to correlate with FEV1 (R2 = 0.33, p = .003; and R2 = 0.26, p = .009 for Analysts 1 and 2, respectively) and LCI (R2 = 0.76, p Conclusion HP 129Xe MRI provides a robust measurement of ventilation heterogeneity in stable pediatric CF subjects at two sites. Since measurements performed at two sites yielded similar VDP values with near-identical values between different analysts, implementation of the technique in multi-center trials in CF appears feasible.

Introduction Newer proton MRI methods may be complementary to conventional respiratory diagnostics like computed tomography (CT) and spirometry. Non-contrast Ultrashort Echo Time (UTE) MRI acquires high resolution structural images, comparable to CT, and gradient-echo combined with phase-resolved functional lung (PREFUL) processing methods can produce spatial assessments of lung function. The need for such MRI methods is exemplified by cystic fibrosis (CF), where rapid development of novel therapeutics demands an equivalent change in our ability to monitor lung disease. Aim To evaluate lung structure and function using UTE and PREFUL MRI methods in people with CF with at least one F508-del mutation pre-Trikafta therapy. Methods 5 people with CF (12–21 years; n=4 homozygous F508-del; n=3 on Symkevi) underwent a single MRI scanning session performed on a 3T Philips Ingenia scanner. UTE-MRI was collected during a 10-second breath-hold (n=2) or free breathing with a respiratory-gated acquisition (n=3). PREFUL-MRI was performed using a continuous single coronal slice Fast Field Echo acquisition during 2 minutes of free breathing (n=5). PREFUL analysis was performed using a semiautomated k-means segmentation algorithm in MATLAB. 1 A region of interest (ROI) at the diaphragm was defined, images with extremes of signal intensity were removed and those remaining sorted into a sinusoidal pattern of signal intensity within the ROI. Thoracic masking and a pulmonary vessel filter were applied followed by k-means clustering analysis to demonstrate normal ventilation and ventilation defect. Ventilation defect percentage (VDP) was calculated by dividing the ventilation defect volume by the lung mask volume. Results MRI scanning was well-tolerated and both UTE and PREFUL acquisitions were completed in all participants. VDP values ranged from 8.09–36.65%, with the individual with the lowest FEV1 having the highest VDP (figure 1). Discussion Our findings demonstrate the feasibility of combined structural and functional lung MRI assessment in people with CF. These non-contrast approaches do not require additional specialised equipment, such as hyperpolarised gas, and could be obtained using standard clinical MRI scanners. In the future, functional lung MRI may facilitate longitudinal assessment of response to disease modifying therapies, such as CFTR modulators. Reference Couch, et al. Academic Radiology 2020. doi:10.1016/j.acra.2020.05.008.

Treatment response in Cystic Fibrosis (CF) is traditionally monitored using pulmonary function tests (PFTs), such as spirometry. However, PFTs can be insensitive to treatment, particularly in early CF lung disease [1]. Hyperpolarized (HP) 129Xe MRI (Xe-MRI) has been shown to be feasible in children [2], more sensitive to early CF lung disease compared to PFTs [3 and captures improvements in ventilation inhomogeneity in pediatric CF patients receiving intravenous antibiotic treatment for a PEx [4]. However, access to hyperpolarized 129Xe gas is not widely available and Xe-MRI requires subjects to perform an extended breath-hold (10–15 s), which is challenging for very sick children. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Munidasa reports grants from Cystic Fibrosis Centre, grants from Natural Sciences and Engineering Research Council of Canada, grants from Canadian Institutes of Health Research, during the conduct of the study. Conflict of interest: Dr. Couch reports that he was supported by a MITACS Elevate Postdoctoral Fellowship, which was funded in part by Siemens Healthcare Limited. Dr. Couch is currently an employee of Siemens Healthcare Limited. This employment began after the conclusion of the study. Conflict of interest: Dr. Rayment reports other from Polarean Inc, outside the submitted work. Conflict of interest: Dr. Voskrebenzev reports In addition, Dr. Voskrebenzev has a patent Method of quantitative magnetic resonance lung imaging Conflict of interest: Dr. Seethamraju reports personal fees from Siemens Medical Solutions, USA Inc., outside the submitted work. Conflict of interest: Dr. Vogel-Claussen reports grants from Siemens Healthineers, during the conduct of the study; grants and personal fees from Boehringer Ingelheim, grants from GSK, grants and personal fees from Astra Zeneca, outside the submitted work; In addition, Dr. Vogel-Claussen has a patent Voskrebenzev, Gutberlet, Vogel-Claussen „Method of quantitative magnetic resonance lung imaging“Nr. EP3107066, US-2016-0367200-A1 22.12.2016 licensed to Siemens Healthineers. Conflict of interest: Dr. Ratjen has nothing to disclose. Conflict of interest: Dr. Santyr reports grants and non-financial support from Siemens Healthineers, grants from Canadian Institutes of Health Research, during the conduct of the study; grants and non-financial support from Siemens Healthineers, outside the submitted work.

Conventional pulmonary function tests appear normal in early cystic fibrosis (CF) lung disease. Therefore, new diagnostic approaches are required that can detect CF lung disease in children and monitor treatment response. Hyperpolarized (HP) gas (129Xe and 3He) magnetic resonance imaging (MRI) is a powerful, emergent tool for mapping regional lung function and may be well suited for studying pediatric CF. HP gas MRI is well tolerated, reproducible, and it can be performed longitudinally without the need for ionizing radiation. In particular, quantification of the distribution of ventilation, or ventilation defect percent (VDP), has been shown to be a sensitive indicator of CF lung disease and correlates well with pulmonary function tests. This article presents the current state of CF diagnosis and treatment and describes the potential role of HP gas MRI for detection of early CF lung disease and following the effects of interventions. The typical HP gas imaging workflow is described, along with a discussion of image analysis to calculate VDP, dosing considerations, and the reproducibility of VDP. The potential use of VDP as an outcome measure in CF is discussed, by considering the correlation with pulmonary function measures, preliminary interventional studies, and case studies involving longitudinal imaging and pulmonary exacerbations. Finally, emerging HP gas imaging techniques such as multiple breath washout imaging are introduced, followed by a discussion of future directions. Overall, HP gas MRI biomarkers are expected to provide sensitive outcome measures that can be used in disease surveillance as well as interventional studies involving novel CF therapies.

PURPOSE To investigate the effect of incorporating T1 as a function of wash-out breath number (T1 (n)) on estimation of fractional ventilation (r) using hyperpolarized 129 Xe multiple breath wash-out (MBWO) imaging in rats. METHODS MBWO imaging was performed in 8 healthy mechanically ventilated rats at several inter-image delay times (τ) and tidal volumes (TV). r maps were calculated from the imaging data using a model of T1 (n) (assuming that the longitudinal relaxation rate of 129 Xe in the lung is directly proportional to pA O2 ) and compared to r maps obtained by assuming a fixed T1 measured before wash-out breaths (r'). RESULTS Fractional ventilation was overestimated by up to 19.3% when T1 was fixed. An inverse relationship between bias (Δr) and ventilation was observed at all τ and TV. Additionally, Δr significantly increased when TV was decreased (F statistic F(2,7) = 48.97, P

PURPOSE To map physiological gas exchange parameters using dissolved hyperpolarized (HP) 129 Xe in a rat model of regional radiation-induced lung injury (RILI) with spiral-IDEAL and the model of xenon exchange (MOXE). Results are compared to quantitative histology of pulmonary tissue and red blood cell (RBC) distribution. METHODS Two cohorts (n = 6 each) of age-matched rats were used. One was irradiated in the right-medial lung, producing regional injury. Gas exchange was mapped 4 weeks postirradiation by imaging dissolved-phase HP 129 Xe using spiral-IDEAL at five gas exchange timepoints using a clinical 1.5 T scanner. Physiological lung parameters were extracted regionally on a voxel-wise basis using MOXE. Mean gas exchange parameters, specifically air-capillary barrier thickness (δ) and hematocrit (HCT) in the right-medial lung were compared to the contralateral lung as well as nonirradiated control animals. Whole-lung spectroscopic analysis of gas exchange was also performed. RESULTS δ was significantly increased (1.43 ± 0.12 μm from 1.07 ± 0.09 μm) and HCT was significantly decreased (17.2 ± 1.2% from 23.6 ± 1.9%) in the right-medial lung (i.e., irradiated region) compared to the contralateral lung of the irradiated rats. These changes were not observed in healthy controls. δ and HCT correlated with histologically measured increases in pulmonary tissue heterogeneity (r = 0.77) and decreases in RBC distribution (r = 0.91), respectively. No changes were observed using whole-lung analysis. CONCLUSION This work demonstrates the feasibility of mapping gas exchange using HP 129 Xe in an animal model of RILI 4 weeks postirradiation. Spatially resolved gas exchange mapping is sensitive to regional injury between cohorts that was undetected with whole-lung gas exchange analysis, in agreement with histology. Gas exchange mapping holds promise for assessing regional lung function in RILI and other pulmonary diseases.

Purpose The purpose of this work was to use magnetic resonance imaging (MRI) of hyperpolarized (HP) 129 Xe dissolved in pulmonary tissue (PT) and red blood cells (RBCs) to detect regional changes to PT structure and perfusion in a partial-lung rat model of radiation-induced lung injury and compare with histology. Methods and materials The right medial region of the lungs of 6 Sprague-Dawley rats was irradiated (20 Gy, single-fraction). A second nonirradiated cohort served as the control group. Imaging was performed 4 weeks after irradiation to quantify intensity and heterogeneity of PT and RBC 129 Xe signals. Imaging findings were correlated with measures of PT and RBC distribution. Results Asymmetric (right vs left) changes in 129 Xe signal intensity and heterogeneity were observed in the irradiated cohort but were not seen in the control group. PT signal was observed to increase in intensity and heterogeneity and RBC signal was observed to increase in heterogeneity in the irradiated right lungs, consistent with histology. Conclusion Regional changes to PT and RBC 129 Xe signals are detectable 4 weeks following partial-lung irradiation in rats.

Purpose To demonstrate the feasibility of mapping gas exchange with single breath-hold hyperpolarized (HP) 129 Xe in humans, acquiring parametric maps of lung physiology. The potential benefit of acceleration using parallel imaging for this application is also explored. Methods Six healthy volunteers were scanned with a modified spiral-IDEAL sequence to acquire gas exchange-weighted images using a single dose of 129 Xe. These images were fit with the model of xenon exchange (MOXE) on a voxel-wise basis calculating parametric maps of lung physiology, specifically: air-capillary barrier thickness (δ), alveolar septal thickness (d), capillary transit time (tx ), pulmonary hematocrit (HCT), and alveolar surface area-to-volume ratio (SVR). An accelerated version of the sequence was also tested in subset of 4 volunteers and compared to the fully sampled (FS) results. Results Mean image-wide values calculated from MOXE parametric maps derived from FS dissolved 129 Xe spiral-IDEAL images were: δ = 0.89 ± 0.17 μm, d = 7.5 ± 0.5 μm, tx = 1.1 ± 0.2s, HCT = 28.8 ± 2.3%, and SVR = 140 ± 16 cm-1 , in good agreement with previously published values based on whole-lung spectroscopy of healthy human subjects. Parallel imaging sufficiently reduces artifacting in accelerated images, but increases disagreement with MOXE parameters derived from FS data with mean voxel-wise unsigned relative differences of: δ = 39 ± 9%, d = 22 ± 3%, tx = 117 ± 43%, HCT = 11 ± 2%, and SVR = 31 ± 12%. Conclusion Dissolved HP 129 Xe spiral-IDEAL imaging for gas exchange mapping is feasible in humans using a single breath-hold. Accelerated gas exchange mapping is also shown to be feasible but requires further improvements to increase quantitative accuracy.

Purpose Hyperpolarized (HP) gas MRI of the rodent lung is of great interest because of the increasing need for novel biomarkers with which to develop new therapies for respiratory diseases. The use of fast gradient-recalled echo (FGRE) for high-resolution HP gas rodent lung MRI is challenging as a result of signal loss caused by significant diffusion weighting, particularly in the larger airways. In this work, a modified FGRE approach is described for HP 3He rodent lung MRI using a centric-out readout scheme (ie, x-centric), allowing high-resolution, density-weighted imaging. Methods HP 3He x-centric imaging was performed in a phantom and compared with a conventional partial-echo FGRE acquisition for in-plane spatial resolutions varying between 39 and 312 µm. Partial-echo and x-centric acquisitions were also compared for high spatial-resolution breath-hold (1 s) imaging of rodent lungs. Results X-centric provided improved signal-to-noise ratio efficiency by a factor of up to 13/1.7 and 6.7/1.8, compared with the partial-echo FGRE for the airways/parenchyma of mouse and rat, respectively, at high spatial resolutions in vivo (

Purpose: To assess the feasibility of hyperpolarized (HP) 129Xe MRI for detection of early stage radiation-induced lung injury (RILI) in a rat model involving unilateral irradiation by assessing differences in gas exchange dynamics between irradiated and unirradiated lungs. Methods: The dynamics of gas exchange between alveolar air space and pulmonary tissue (PT), PT and red blood cells (RBCs) was measured using single-shot spiral iterative decomposition of water and fat with echo asymmetry and least-squares estimation images of the right and left lungs of two age-matched cohorts of Sprague Dawley rats. The first cohort (n = 5) received 18 Gy irradiation to the right lung using a 60Co source and the second cohort (n = 5) was not irradiated and served as the healthy control. Both groups were imaged two weeks following irradiation when radiation pneumonitis (RP) was expected to be present. The gas exchange data were fit to a theoretical gas exchange model to extract measurements of pulmonary tissue thickness (LPT) and relative blood volume (VRBC) from each of the right and left lungs of both cohorts. Following imaging,lung specimens were retrieved and percent tissue area (PTA) was assessed histologically to confirm RP and correlate with MRI measurements. Results: Statistically significant differences in LPT and VRBC were observed between the irradiated and non-irradiated cohorts. In particular, LPT of the right and left lungs was increased approximately 8.2% and 5.0% respectively in the irradiated cohort. Additionally, VRBC of the right and left lungs was decreased approximately 36.1% and 11.7% respectively for the irradiated cohort compared to the non-irradiated cohort. PTA measurements in both right and left lungs were increased in the irradiated group compared to the non-irradiated cohort for both the left (P < 0.05) and right lungs (P < 0.01) confirming the presence of RP. PTA measurements also correlated with the MRI measurements for both the non-irradiated (r = 0.79, P < 0.01) and irradiated groups (r = 0.91, P < 0.01). Conclusions: Regional RILI can be detected two weeks post-irradiation using HP 129Xe MRI and analysis of gas exchange curves. This approach correlates well with histology and can potentially be used clinically to assess radiation pneumonitis associated with early RILI to improve radiation therapy outcomes.

To measure regional changes in hyperpolarizedMRI was performed in 6 healthy mechanically ventilated rats before instillation, as well as 5 min and 1 h after instillation of 4 million SPION-labeled ALMs into either the left or right lung.Regions of signal loss were observed immediately after instillation of unlabeled and SPION-labeled ALMs and persisted at least 1 h in the case of the SPION-labeled ALMs. This was reflected in the measurements ofHyperpolarized

Purpose To implement and optimize a single-shot spiral encoding strategy for rapid 2D IDEAL projection imaging of hyperpolarized (Hp) 129Xe in the gas phase, and in the pulmonary tissue (PT) and red blood cells (RBCs) compartments of the rat lung, respectively. Theory and Methods A theoretical and experimental point spread function analysis was used to optimize the spiral k-space read-out time in a phantom. Hp 129Xe IDEAL images from five healthy rats were used to: (i) optimize flip angles by a Bloch equation analysis using measured kinetics of gas exchange and (ii) investigate the feasibility of the approach to characterize the exchange of Hp 129Xe. Results A read-out time equal to approximately 1.8 × was found to provide the best trade-off between spatial resolution and signal-to-noise ratio (SNR). Spiral IDEAL approaches that use the entire dissolved phase magnetization should give an SNR improvement of a factor of approximately three compared with Cartesian approaches with similar spatial resolution. The IDEAL strategy allowed imaging of gas, PT, and RBC compartments with sufficient SNR and temporal resolution to permit regional gas exchange measurements in healthy rats. Conclusion Single-shot spiral IDEAL imaging of gas, PT and RBC compartments and gas exchange is feasible in rat lung using Hp 129Xe. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

Purpose Radiation-induced lung injury (RILI) is still the major dose-limiting toxicity related to lung cancer radiation therapy, and it is difficult to predict and detect patients who are at early risk of severe pneumonitis and fibrosis. The goal of this proof-of-concept preclinical demonstration was to investigate the potential of hyperpolarized 129Xe diffusion-weighted MRI to detect the lung morphological changes associated with early stage RILI. Methods Hyperpolarized 129Xe MRI was performed using eight different diffusion sensitizations (0.0–115 s/cm2) in a small group of control rats (n = 4) and rats 2 wk after radiation exposure (n = 5). The diffusion-weighted images were used to obtain morphological estimates of the pulmonary parenchyma including external radius (R), internal radius (r), alveolar sleeve depth (h), and mean airspace chord length (Lm). The histological mean linear intercept (MLI) were obtained for five control and five irradiated animals. Results Mean R, r, and Lm were both significantly different (P

We report a novel radiofrequency (RF) transmit-only/receive-only (TO/RO) coil configuration providing excellent transmit B1+ field uniformity as well as high sensitivity for hyperpolarized 129Xe MR lung imaging of rats at 3T (35.34 MHz). The TO/RO coil configuration consisted of two separate components: (i) a high-pass birdcage transmit coil which produces a homogeneous B1+ magnetic field, (ii) a saddle-shaped single-turn receive-only surface coil that couples closely to the rat lung. On transmit, the receive-only coil is decoupled from the transmit coil using a detuning circuit. On receive, the bird-cage coil is deactivated through the use of PIN diodes. The sensitivity and uniformity of the saddle-shaped receive coil were optimized solving the Biot-Savart equation using 3D finite element modeling. The electrical performance of the new TO/RO configuration in transmit/receive (T/R) mode was compared with a commercial T/R birdcage coil of similar diameter, which was considering to be the gold standard for conventional T/R mode imaging. Experimental results in phantoms confirm that our novel TO/RO coil configuration provides a factor of three increase in SNR without compromising B1 transmit uniformity compared with the commercial T/R birdcage coil configuration. The novel TO/RO coil was successfully tested for in vivo rat lung imaging. © 2015 Wiley Periodicals, Inc. Concepts Magn Reson Part B (Magn Reson Engineering) 45B: 115–124, 2015

phometry magnetic resonance imaging (MRI) can be used to map regional differences in lung tissue micro-structure. We aimed to generate absolute xenon concentration ([Xe]) and alveolar oxygen partial pressure (pAO2) maps by extracting the unrestricted diffusion coefficient (D0) of xenon as a morphometric parameter. Methods: In this proof-of-concept demonstration, morphometry was performed using multi b-value (0, 12, 20, 30 s/cm 2 ) DW hyperpolarized 129 Xe images obtained in four neversmokers and four COPD ex-smokers. Morphometric parameters and D0 maps were computed and the latter used to generate [Xe] and pAO2 maps. Xenon concentration phantoms estimating a range of values mimicking those observed in vivo were also investigated. Results: Xenon D0 was significantly increased (P ¼0.035) in COPD (0.14 60.03 cm 2 /s) compared with never-smokers (0.12 60.02 cm 2 /s). COPD ex-smokers also had significantly decreased [Xe] (COPD ¼8 67% versus never-smokers ¼ 13 68%, P ¼0.012) and increased pAO2 (COPD ¼18 63% versus never-smokers ¼15 63%, P ¼0.009) compared with never-smokers. Phantom measurements showed the expected dependence of D0 on [Xe] over the range of concentrations anticipated in vivo. Conclusion: DW hyperpolarized 129 Xe MRI morphometry can be used to simultaneously map [Xe] and pAO2 in addition to providing micro-structural biomarkers of emphysematous destruction in COPD. Phantom measurements of D0([Xe]) supported the hypotheses that differences in subjects may reflect differences in functional residual capacity. Magn Reson Med 000:000–000, 2014. V C 2014 Wiley Periodicals, Inc.

MRI of hyperpolarized 129Xe gas and 13C-enriched substrates (e.g. pyruvate) presents an unprecedented opportunity to map anatomical, functional and metabolic changes associated with lung injury. In particular, inhaled hyperpolarized 129Xe gas is exquisitely sensitive to changes in alveolar microanatomy and function accompanying lung inflammation through decreases in the apparent diffusion coefficient (ADC) of alveolar gas and increases in the transfer time (Ttr) of xenon exchange from the gas and into the dissolved phase in the lung. Furthermore, metabolic changes associated with hypoxia arising from lung injury may be reflected by increases in lactate-to-pyruvate signal ratio obtained by magnetic resonance spectroscopic imaging following injection of hyperpolarized [1-13C]pyruvate. In this work, the application of hyperpolarized 129Xe and 13C MRI to radiation-induced lung injury (RILI) is reviewed and results of ADC, Ttr and lactate-to-pyruvate signal ratio changes in a rat model of RILI are summarized. These results are consistent with conventional functional (i.e. blood gases) and histological (i.e. tissue density) changes, and correlate significantly with inflammatory cell counts (i.e. macrophages). Hyperpolarized MRI may provide an earlier indication of lung injury associated with radiotherapy of thoracic tumors, potentially allowing adjustment of treatment before the onset of severe complications and irreversible fibrosis. Copyright © 2014 John Wiley & Sons, Ltd.

Purpose Radiation Pneumonitis (RP) limits radiotherapy. Detection of early metabolic changes in the lungs associated with RP may provide an opportunity to adjust treatment before substantial toxicities occur. In this work, regional lactate-to-pyruvate signal ratio (lac/pyr) was quantified in rat lungs and heart following administration of hyperpolarized 13 C-pyruvate magnetic resonance imaging (MRI) at day 5, 10, 15 and 25-post conformal radiotherapy. These results were also compared to histology and blood analyses. Methods The lower right lungs of 12 Sprague Dawley rats were irradiated in 2 fractions with a total dose of 18.5Gy using a modified micro-CT system. Regional lactate and pyruvate data were acquired from three irradiated and three age-matched healthy rats at each time point on days 5, 10, 15 and 25-post radiotherapy. Arterial blood was collected from each animal prior to the 13 C-pyruvate injection and was analyzed for blood lactate concentration and arterial oxygen concentration (p a O 2 ). Macrophage count was computed from the histology of all rat lungs. Results A significant increase in lac/pyr was observed in both right and left lungs of the irradiated cohort compared to the healthy cohort for all time points. No increase in lac/pyr was observed in the hearts of the irradiated cohort compared to the hearts of the healthy cohorts. Blood lactate concentration and p a O 2 did not show a significant change between the irradiated and the healthy cohorts. Macrophage count in both right and left lungs was elevated for the irradiated cohort compared to the healthy cohort. Conclusions Metabolic changes associated with RP may be mapped as early as five days post conformal radiotherapy. Over the small sample size in each cohort, elevated macrophage count, consistent with early phase of inflammation was highly correlated to increases in lac/pyr in both the irradiated and unirradiated lungs. Further experiments with larger sample size may improve the confidence of this finding.

Purpose MRI using hyperpolarized noble gases, 3He and 129Xe, provides noninvasive assessments of lung structure and function. Previous work demonstrated that absolute ventilated lung volumes (aVLV) measured in rats using hyperpolarized 3He agree well with micro-CT. Methods In this work, aVLV measurements were performed in rats using hyperpolarized 129Xe MRI and compared with hyperpolarized 3He measurements of aVLV under matched ventilation conditions. Whole-lung compliance was also determined. Partial volume, apparent diffusion coefficient, and effective transverse relaxation time corrections were applied during postprocessing to reduce bias between methods. Results Mean apparent diffusion coefficient of the trachea was 0.83 ± 0.09 cm2/s and 0.067 ± 0.011 cm2/s for 3He and 129Xe, respectively. Mean apparent diffusion coefficient of parenchyma was 0.21 ± 0.07 cm2/s and 0.027 ± 0.008 cm2/s for 3He and 129Xe, respectively. Mean transverse relaxation time values were 1.57 ± 0.25 ms and 2.80 ± 0.25 ms for 3He and 129Xe, respectively, in a model trachea and 3.18 ± 1.00 ms and 4.88 ± 0.60 ms for 3He and 129Xe, respectively, for lung parenchyma. Mean aVLV values were 7.07 ± 0.67 mL and 6.99 ± 1.00 mL at 14 cmH2O and 4.88 ± 0.71 mL and 5.36 ± 0.76 mL at 10 cmH2O obtained with 3He and 129Xe, respectively, demonstrating good agreement between 129Xe and 3He. Conclusions 129Xe offers an important alternative to 3He for hyperpolarized gas MRI of aVLV in rats. Magn Reson Med 71:1130–1136, 2014. © 2013 Wiley Periodicals, Inc.

Purpose The goal of this work was to investigate lung morphological changes associated with chronic obstructive pulmonary disease (COPD) using hyperpolarized 129Xe diffusion-weighted MRI. Methods Hyperpolarized 129Xe MRI was performed at three different nonzero diffusion sensitizations (b-value = 12, 20, and 30 s/cm2) in the lungs of four subjects with COPD and four healthy volunteers. The image signal intensities were fit as a function of b-value to obtain anisotropic diffusion coefficient maps for all subjects. The image signal intensities were also fit to a morphological model allowing extraction of length scales associated with the terminal airways: external radius (R), internal radius (r), mean airspace chord length (Lm), and depth of alveolar sleeve (h). Results Longitudinal (DL) and transverse (DT) anisotropic diffusion coefficients were both significantly increased (both P= 0.004) in the COPD subjects (0.102 ± 0.02 cm2/s and 0.072 ± 0.02 cm2/s, respectively) compared with the healthy subjects (0.083 ± 0.011 cm2/s and 0.046 ± 0.017 cm2/s, respectively). Significant morphological differences were observed between the COPD subjects and healthy volunteers, specifically decreases in h (68 ± 36 µm vs. 95 ± 710 µm, respectively, P = 0.019) and increases in Lm (352 ± 57 µm vs. 253 ± 37 µm, respectively, P = 0.002) consistent with values obtained previously using hyperpolarized 3He MRI in similar subjects. Conclusions Diffusion-weighted hyperpolarized 129Xe MRI is a promising technique for mapping changes in human lung morphology and may be useful for early detection of emphysema associated with COPD. Magn Reson Med 70:1699–1706, 2013. © 2013 Wiley Periodicals, Inc.

Hyperpolarized (HP) gas MRI of the rodent lung is of great interest because of the increasing need for novel biomarkers with which to develop new therapies for respiratory diseases. The use of fast gradient-recalled echo (FGRE) for high-resolution HP gas rodent lung MRI is challenging as a result of signal loss caused by significant diffusion weighting, particularly in the larger airways. In this work, a modified FGRE approach is described for HPHPX-centric provided improved signal-to-noise ratio efficiency by a factor of up to 13/1.7 and 6.7/1.8, compared with the partial-echo FGRE for the airways/parenchyma of mouse and rat, respectively, at high spatial resolutions in vivo (78 µm). In particular, rodent major airways with less restricted diffusion ofThe x-centric method significantly reduces diffusion weighting, allowing high spatial and temporal resolution HP

A novel imaging method is presented, Flip Angle Variation for Offset of RF and Relaxation (FAVOR), for rapid and efficient measurement of rat lung ventilation using hyperpolarized helium-3 (3He) gas. The FAVOR technique utilizes variable flip angles to remove the cumulative effect of RF pulses and T1 relaxation on the hyperpolarized gas signal and thereby eliminates the need for intervening air wash-out breaths and multiple cycles of 3He wash-in breaths before each image. The former allows an improvement in speed (by a factor of ≈30) while the latter reduces the cost of each measurement (by a factor of ≈5). The FAVOR and conventional ventilation methods were performed on six healthy male Brown Norway rats (190–270 g). Lobar measurements of ventilation, r, obtained with the FAVOR method were not significantly different from those obtained with the conventional method for the right middle and caudal and left lobes (P > 0.05 by a Wilcoxon matched pairs test). A methacholine challenge test was also administered to an animal and reduction and recovery of r was detected by the FAVOR method. The reduced 3He consumption and the improvement in speed provided by FAVOR suggest that it may allow measurement of ventilation in human subjects not previously possible. Magn Reson Med 59:1304–1310, 2008. © 2008 Wiley-Liss, Inc.

To assess the feasibility of hyperpolarized (HP) (129)Xe MRI for detection of early stage radiation-induced lung injury (RILI) in a rat model involving unilateral irradiation by assessing differences in gas exchange dynamics between irradiated and unirradiated lungs.The dynamics of gas exchange between alveolar air space and pulmonary tissue (PT), PT and red blood cells (RBCs) was measured using single-shot spiral iterative decomposition of water and fat with echo asymmetry and least-squares estimation images of the right and left lungs of two age-matched cohorts of Sprague Dawley rats. The first cohort (n = 5) received 18 Gy irradiation to the right lung using a (60)Co source and the second cohort (n = 5) was not irradiated and served as the healthy control. Both groups were imaged two weeks following irradiation when radiation pneumonitis (RP) was expected to be present. The gas exchange data were fit to a theoretical gas exchange model to extract measurements of pulmonary tissue thickness (LPT) and relative blood volume (VRBC) from each of the right and left lungs of both cohorts. Following imaging, lung specimens were retrieved and percent tissue area (PTA) was assessed histologically to confirm RP and correlate with MRI measurements.Statistically significant differences in LPT and VRBC were observed between the irradiated and non-irradiated cohorts. In particular, LPT of the right and left lungs was increased approximately 8.2% and 5.0% respectively in the irradiated cohort. Additionally, VRBC of the right and left lungs was decreased approximately 36.1% and 11.7% respectively for the irradiated cohort compared to the non-irradiated cohort. PTA measurements in both right and left lungs were increased in the irradiated group compared to the non-irradiated cohort for both the left (P0.05) and right lungs (P0.01) confirming the presence of RP. PTA measurements also correlated with the MRI measurements for both the non-irradiated (r = 0.79, P0.01) and irradiated groups (r = 0.91, P0.01).Regional RILI can be detected two weeks post-irradiation using HP (129)Xe MRI and analysis of gas exchange curves. This approach correlates well with histology and can potentially be used clinically to assess radiation pneumonitis associated with early RILI to improve radiation therapy outcomes.

Radiation-induced lung injury limits radiotherapy of thoracic cancers. Detection of radiation pneumonitis associated with early radiation-induced lung injury (2-4 weeks postirradiation) may provide an opportunity to adjust treatment, before the onset of acute pneumonitis and/or irreversible fibrosis. In this study, localized magnetic resonance (MR) spectroscopy and imaging of hyperpolarized (13)C-pyruvate (pyruvate) and (13)C-lactate (lactate) were performed in the thorax and kidney regions of rats 2 weeks following whole-thorax irradiation (14 Gy). Lactate-to-pyruvate signal ratio was observed to increase by 110% (P < 0.01), 57% (P < 0.02), and 107% (P < 0.01), respectively, in the thorax, lung, and heart tissues of the radiated rats compared with healthy age-matched rats. This was consistent with lung inflammation confirmed using cell micrographs of bronchioalveolar lavage specimens and decreases in arterial oxygen partial pressure (paO2), indicative of hypoxia. No statistically significant difference was observed in either lactate-to-pyruvate signal ratios in the kidney region (P = 0.50) between the healthy (0.215 ± 0.100) and radiated cohorts (0.215 ± 0.054) or in blood lactate levels (P = 0.69) in the healthy (1.255 ± 0.247 mmol/L) and the radiated cohorts (1.325 ± 0.214 mmol/L), confirming that the injury is localized to the thorax. This work demonstrates the feasibility of hyperpolarized (13)C metabolic MR spectroscopy and imaging for detection of early radiation-induced lung injury.

Rationale and Objectives The objective of this study was to evaluate the tolerability of hyperpolarized 129 Xe gas inhaled from functional residual capacity and magnetic resonance imaging in healthy subjects and those with pulmonary disease. Materials and Methods Twelve healthy volunteers (mean age, 59 ± 17 years), seven subjects with asthma (mean age, 47 ± 7 years), 10 subjects with chronic obstructive pulmonary disease (mean age, 74 ± 4 years), three subjects with cystic fibrosis (mean age, 27 ± 10 years), and a single subject with radiation-induced lung injury (age, 66 years) were enrolled and evaluated over 43 visits with 136 anoxic inhalations of 500 mL 129 Xe gas mixed with 500 mL 4 He gas. Oxygen saturation and heart rate were monitored during the breath-hold and imaging; subjects were queried for adverse events (AEs) before and immediately following gas inhalation and for 24 hours after the last dose. Results No subjects withdrew from the study or reported serious, hypoxic, or severe AEs. Over the course of 136 dose administrations, two mild AEs (1%) were reported in two different subjects (two of 33 [6%]). One of these AEs (light-headedness) was temporally related and judged as possibly related to 129 Xe administration and resolved without treatment within 2 minutes. Statistically significant but clinically insignificant changes in oxygen saturation and heart rate were observed after inhalation ( P Conclusions Inhalation of hyperpolarized 129 Xe gas and subsequent magnetic resonance imaging were well tolerated in healthy subjects and ambulatory subjects with obstructive and restrictive pulmonary disease.

Hyperpolarized noble gas (3He and 129Xe) apparent diffusion coefficient (ADC) measurements have shown remarkable sensitivity to microstructural (i.e., alveolar) changes in the lung, particularly emphysema. The ADC of hyperpolarized noble gases depends strongly on the diffusion time (Δ), and 3He ADC has been shown to be anisotropic for Δ ranging from a few milliseconds down to a few hundred microseconds. In this study, the anisotropic nature of 129Xe diffusion and its dependence on Δ were investigated both numerically, in a budded cylinder model, and in vivo, in an elastase-instilled rat model of emphysema. Whole lung longitudinal ADC (DL) and transverse ADC (DT) were measured for Δ = 6, 50, and 100 ms at 73.5 mT, and correlated with measurements of the mean linear intercept (Lm) obtained from lung histology. A significant increase (P = 0.0021) in DT was measured for Δ = 6 ms between the sham (0.0021 ± 0.0005 cm2/s) and elastase-instilled (0.005 ± 0.001 cm2/s) cohorts, and a strong correlation was measured between DT (Δ = 6 ms) and Lm, with a Pearson's correlation coefficient of 0.90. This study confirms that 129Xe DT increases correlate with alveolar space enlargement due to elastase instillation in rats. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.