A decay-modeled compressed sensing reconstruction approach for non-Cartesian hyperpolarized 129Xe MRI.

PURPOSE: Hyperpolarized 129Xe MRI benefits from non-Cartesian acquisitions that sample k-space efficiently and rapidly. However, their reconstructions are complex and burdened by decay processes unique to hyperpolarized gas. Currently used gridded reconstructions are prone to artifacts caused by magnetization decay and are ill-suited for undersampling. We present a compressed sensing (CS) reconstruction approach that incorporates magnetization decay in the forward model, thereby producing images with increased sharpness and contrast, even in undersampled data. METHODS: Radio-frequency, T1, and T 2 * $$ {\mathrm{T}}_2^{\ast } $$ decay processes were incorporated into the forward model and solved using iterative methods including CS. The decay-modeled reconstruction was validated in simulations and then tested in 2D/3D-spiral ventilation and 3D-radial gas-exchange MRI. Quantitative metrics including apparent-SNR and sharpness were compared between gridded, CS, and twofold undersampled CS reconstructions. Observations were validated in gas-exchange data collected from 15 healthy and 25 post-hematopoietic-stem-cell-transplant participants. RESULTS: CS reconstructions in simulations yielded images with threefold increases in accuracy. CS increased sharpness and contrast for ventilation in vivo imaging and showed greater accuracy for undersampled acquisitions. CS improved gas-exchange imaging, particularly in the dissolved-phase where apparent-SNR improved, and structure was made discernable. Finally, CS showed repeatability in important global gas-exchange metrics including median dissolved-gas signal ratio and median angle between real/imaginary components. CONCLUSION: A non-Cartesian CS reconstruction approach that incorporates hyperpolarized 129Xe decay processes is presented. This approach enables improved image sharpness, contrast, and overall image quality in addition to up-to threefold undersampling. This contribution benefits all hyperpolarized gas MRI through improved accuracy and decreased scan durations.

Diffusion weighted hyperpolarized 129 Xe MRI of the lung with 2D and 3D (FLORET) spiral.

PURPOSE: To enable efficient hyperpolarized 129 Xe diffusion imaging using 2D and 3D (Fermat Looped, ORthogonally Encoded Trajectories, FLORET) spiral sequences and demonstrate that 129 Xe ADCs obtained using these sequences are comparable to those obtained using a conventional, 2D gradient-recalled echo (GRE) sequence. THEORY AND METHODS: Diffusion-weighted 129 Xe MRI (b-values = 0, 7.5, 15 s/cm2 ) was performed in four healthy volunteers and one subject with lymphangioleiomyomatosis using slice-selective 2D-GRE (scan time = 15 s), slice-selective 2D-Spiral (4 s), and 3D-FLORET (16 s) sequences. Experimental SNRs from b-value = 0 images ( SNR 0 EX $$ SNR{0}_{EX} $$ ) and mean ADC values were compared across sequences. In two healthy subjects, a second b = 0 image was acquired using the 2D-Spiral sequence to map flip angle and correct RF-induced, hyperpolarized signal decay at the voxel level, thus improving regional ADC estimates. RESULTS: Diffusion-weighted images from spiral sequences displayed image quality comparable to 2D-GRE and produced sufficient SNR 0 EX $$ SNR{0}_{EX} $$ (16.8 ± 3.8 for 2D-GRE, 21.2 ± 3.5 for 2D-Spiral, 20.4 ± 3.5 for FLORET) to accurately calculate ADC. Whole-lung means and SDs of ADC obtained via spiral were not significantly different (P > 0.54) from those obtained via 2D-GRE. Finally, 2D-Spiral images were corrected for signal decay, which resulted in a whole-lung mean ADC decrease of ˜15%, relative to uncorrected images. CONCLUSIONS: Relative to GRE, efficient spiral sequences allow 129 Xe diffusion images to be acquired with isotropic lung coverage (3D), higher SNR $$ SNR $$ (2D and 3D), and three-fold faster (2D) within a single breath-hold. In turn, shortened breath-holds enable flip-angle mapping, and thus, allow RF-induced signal decay to be corrected, increasing ADC accuracy.

Childhood to adulthood: Accounting for age dependence in healthy-reference distributions in 129 Xe gas-exchange MRI.

PURPOSE: Xenon-129 (129 Xe) gas-exchange MRI is a pulmonary-imaging technique that provides quantitative metrics for lung structure and function and is often compared to pulmonary-function tests. Unlike such tests, it does not normalize to predictive values based on demographic variables such as age. Many sites have alluded to an age dependence in gas-exchange metrics; however, a procedure for normalizing metrics has not yet been introduced. THEORY: We model healthy reference values for 129 Xe gas-exchange MRI against age using generalized additive models for location, scale, and shape (GAMLSS). GAMLSS takes signal data from an aggregated heathy-reference cohort and fits a distribution with flexible median, variation, skewness, and kurtosis to predict age-dependent centiles. This approach mirrors methods by the Global Lung Function Initiative for modeling pulmonary-function test data and applies it to binning methods widely used by the 129 Xe MRI community to interpret and quantify gas-exchange data. METHODS: Ventilation, membrane-uptake, red blood cell transfer, and red blood cell:membrane gas-exchange metrics were collected on 30 healthy subjects over an age range of 5 to 68 years. A GAMLSS model was fit against age and compared against widely used linear and generalized-linear binning 129 Xe MRI analysis schemes. RESULTS: All 4 gas-exchange metrics had significant skewness, and membrane-uptake had significant kurtosis compared to a normal distribution. Age has significant impact on distribution parameters. GAMLSS-binning produced narrower bins compared to the linear and generalized-linear binning schemes and distributed signal data closer to a normal distribution. CONCLUSION: The proposed "proof-of-concept" GAMLSS-binning approach can improve diagnostic accuracy of 129 Xe gas-exchange MRI by providing a means of modeling voxel distribution data against age.

B1 and magnetization decay correction for hyperpolarized 129 Xe lung imaging using sequential 2D spiral acquisitions.

PURPOSE: To mitigate signal variations caused by inhomogeneous RF and magnetization decay in hyperpolarized 129 Xe ventilation images using flip-angle maps generated from sequential 2D spiral ventilation images acquired in a breath-hold. Images and correction maps were compared with those obtained using conventional, 2D gradient-recalled echo. THEORY AND METHODS: Analytical expressions to predict signal intensity and uncertainty in flip-angle measurements were derived from the Bloch equations and validated by simulations and phantom experiments. Imaging in 129 Xe phantoms and human subjects (1 healthy, 1 cystic fibrosis) was performed using 2D gradient-recalled echo and spiral. For both sequences, consecutive images were acquired with the same slice position during a breath-hold (Cartesian scan time = 15 s; spiral scan time = 5 s). The ratio of these images was used to calculate flip-angle maps and correct intensity inhomogeneities in ventilation images. RESULTS: Mean measured flip angle showed excellent agreement with the applied flip angle in simulations (R2 = 0.99) for both sequences. Mean measured flip angle agreed well with the globally applied flip angle (∼15% difference) in 129 Xe phantoms and in vivo imaging using both sequences. Corrected images displayed reduced coil-dependent signal nonuniformity relative to uncorrected images. CONCLUSIONS: Flip-angle maps were obtained using sequentially acquired, 2D spiral, 129 Xe ventilation images. Signal intensity variations caused by RF-coil inhomogeneity can be corrected by acquiring sequential single-breath ventilation images in less than 5-s scan time. Thus, this method can be used to remove undesirable heterogeneity while preserving physiological effects on the signal distribution.

Improving hyperpolarized 129 Xe ADC mapping in pediatric and adult lungs with uncertainty propagation.

RATIONALE: Hyperpolarized (HP) 129 Xe-MRI provides non-invasive methods to quantify lung function and structure, with the 129 Xe apparent diffusion coefficient (ADC) being a well validated measure of alveolar airspace size. However, the experimental factors that impact the precision and accuracy of HP 129 Xe ADC measurements have not been rigorously investigated. Here, we introduce an analytical model to predict the experimental uncertainty of 129 Xe ADC estimates. Additionally, we report ADC dependence on age in healthy pediatric volunteers. METHODS: An analytical expression for ADC uncertainty was derived from the Stejskal-Tanner equation and simplified Bloch equations appropriate for HP media. Parameters in the model were maximum b-value (bmax ), number of b-values (Nb ), number of phase encoding lines (Nph ), flip angle and the ADC itself. This model was validated by simulations and phantom experiments, and five fitting methods for calculating ADC were investigated. To examine the lower range for 129 Xe ADC, 32 healthy subjects (age 6-40 years) underwent diffusion-weighted 129 Xe MRI. RESULTS: The analytical model provides a lower bound on ADC uncertainty and predicts that decreased signal-to-noise ratio yields increases in relative uncertainty (ϵADC) . As such, experimental parameters that impact non-equilibrium 129 Xe magnetization necessarily impact the resulting ϵADC . The values of diffusion encoding parameters (Nb and bmax ) that minimize ϵADC strongly depend on the underlying ADC value, resulting in a global minimum for ϵADC . Bayesian fitting outperformed other methods (error < 5%) for estimating ADC. The whole-lung mean 129 Xe ADC of healthy subjects increased with age at a rate of 1.75 × 10-4  cm2 /s/yr (p = 0.001). CONCLUSIONS: HP 129 Xe diffusion MRI can be improved by minimizing the uncertainty of ADC measurements via uncertainty propagation. Doing so will improve experimental accuracy when measuring lung microstructure in vivo and should allow improved monitoring of regional disease progression and assessment of therapy response in a range of lung diseases.

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.

129Xe MRI as a measure of clinical disease severity for pediatric asthma.

BACKGROUND: Measurement of regional lung ventilation with hyperpolarized 129Xe magnetic resonance imaging (129Xe MRI) in pediatric asthma is poised to advance our understanding of disease mechanisms and pathophysiology in a disorder with diverse clinical phenotypes. 129Xe MRI has not been investigated in a pediatric asthma cohort. OBJECTIVE: We hypothesized that 129Xe MRI is feasible and can demonstrate ventilation defects that relate to and predict clinical severity in a pediatric asthma cohort. METHODS: Thirty-seven children (13 with severe asthma, 8 with mild/moderate asthma, 16 age-matched healthy controls) aged 6 to 17 years old were imaged with 129Xe MRI. Ventilation defect percentage (VDP) and image reader score were calculated and compared with clinical measures at baseline and at follow-up. RESULTS: Children with asthma had higher VDP (P = .002) and number of defects per image slice (defects/slice) (P = .0001) than children without asthma. Children with clinically severe asthma had significantly higher VDP and number of defects/slice than healthy controls. Children with asthma who had a higher number of defects/slice had a higher rate of health care utilization (r = 0.48; P = .03) and oral corticosteroid use (r = 0.43; P = .05) at baseline. Receiver-operating characteristic analysis demonstrated that the VDP and number of defects/slice were predictive of increased health care utilization, asthma, and severe asthma. VDP correlated with FEV1 (r = -0.35; P = .04) and FEV1/forced vital capacity ratio (r = -0.41; P = .01). CONCLUSIONS: 129Xe MRI correlates with asthma severity, health care utilization, and oral corticosteroid use. Because delineation of clinical severity is often difficult in children, 129Xe MRI may be an important biomarker for severity, with potential to identify children at higher risk for exacerbations and improve outcomes.

Removal of off-resonance xenon gas artifacts in pulmonary gas-transfer MRI.

PURPOSE: Hyperpolarized xenon (129 Xe) gas-transfer imaging allows different components of pulmonary gas transfer-alveolar air space, lung interstitium/blood plasma (barrier), and red blood cells (RBCs)-to be assessed separately in a single breath. However, quantitative analysis is challenging because dissolved-phase 129 Xe images are often contaminated by off-resonant gas-phase signal generated via imperfectly selective excitation. Although previous methods required additional data for gas-phase removal, the method reported here requires no/minimal sequence modifications/data acquisitions, allowing many previously acquired images to be corrected retroactively. METHODS: 129 Xe imaging was implemented at 3.0T via an interleaved three-dimensional radial acquisition of the gaseous and dissolved phases (using one-point Dixon reconstruction for the dissolved phase) in 46 human subjects and a phantom. Gas-phase contamination (9.5% ± 4.8%) was removed from gas-transfer data using a modified gas-phase image. The signal-to-noise ratio (SNR) and signal distributions were compared before and after contamination removal. Additionally, theoretical gaseous contaminations were simulated at different magnetic field strengths for comparison. RESULTS: Gas-phase contamination at 3.0T was more diffuse and located predominantly outside the lungs, relative to simulated 1.5T contamination caused by the larger frequency offset. Phantom experiments illustrated a 91% removal efficiency. In human subjects, contamination removal produced significant changes in dissolved signal SNR (+7.8%), mean (-1.4%), and standard deviation (-2.3%) despite low contamination. Repeat measurements showed reduced variance (dissolved mean, -1.0%; standard deviation, -8.4%). CONCLUSION: Off-resonance gas-phase contamination can be removed robustly with no/minimal sequence modifications. Contamination removal permits more accurate quantification, reduces radiofrequency stringency requirements, and increases data consistency, providing improved sensitivity needed for multicenter trials.

Validating in vivo hyperpolarized 129 Xe diffusion MRI and diffusion morphometry in the mouse lung.

PURPOSE: Diffusion and lung morphometry imaging using hyperpolarized gases are promising tools to quantify pulmonary microstructure noninvasively in humans and in animal models. These techniques assume the motion encoded is exclusively diffusive gas displacement, but the impact of cardiac motion on measurements has never been explored. Furthermore, although diffusion morphometry has been validated against histology in humans and mice using 3 He, it has never been validated in mice for 129 Xe. Here, we examine the effect of cardiac motion on diffusion imaging and validate 129 Xe diffusion morphometry in mice. THEORY AND METHODS: Mice were imaged using gradient-echo-based diffusion imaging, and apparent diffusion-coefficient (ADC) maps were generated with and without cardiac gating. Diffusion-weighted images were fit to a previously developed theoretical model using Bayesian probability theory, producing morphometric parameters that were compared with conventional histology. RESULTS: Cardiac gating had no significant impact on ADC measurements (dual-gating: ADC = 0.020 cm2 /s, single-gating: ADC = 0.020 cm2 /s; P = .38). Diffusion-morphometry-generated maps of ADC (mean, 0.0165 ± 0.0001 cm2 /s) and acinar dimensions (alveolar sleeve depth [h] = 44 µm, acinar duct radii [R] = 99 µm, mean linear intercept [Lm ] = 74 µm) that agreed well with conventional histology (h = 45 µm, R = 108 µm, Lm = 63 µm). CONCLUSION: Cardiac motion has negligible impact on 129 Xe ADC measurements in mice, arguing its impact will be similarly minimal in humans, where relative cardiac motion is reduced. Hyperpolarized 129 Xe diffusion morphometry accurately and noninvasively maps the dimensions of lung microstructure, suggesting it can quantify the pulmonary microstructure in mouse models of lung disease.

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.

Improved preclinical hyperpolarized 129 Xe ventilation imaging with constant flip angle 3D radial golden means acquisition and keyhole reconstruction.

Hyperpolarized (HP) 129 Xe MRI is increasingly used to noninvasively probe regional lung structure and function in the preclinical setting. As in human imaging, the primary barrier to quantitative imaging with HP gases is nonequilibrium magnetization, which is depleted by T1 relaxation and radio frequency excitation. Preclinical HP gas imaging commonly involves mechanically ventilating small animals and encoding k-space over tens or hundreds of breaths, with small subsets of k-space data collected within each breath. Breath-to-breath magnetization renewal enables the use of large flip angles, but the resulting magnetization decay generates large view-to-view differences in within-breath signal intensity, leading to artifacts and degraded image quality. This deleterious signal decay has motivated the use of variable flip angle (VFA) sampling schemes, in which the flip angle is progressively increased to maintain constant view-to-view signal intensity. However, VFA imaging complicates data acquisition and provides only a global correction that fails to compensate for regional differences in signal dynamics. When constant flip angle (CFA) imaging is used alongside 3D radial golden means acquisition, the center of k-space is sampled with every excitation, thereby encoding signal dynamics alongside imaging data. Here, keyhole reconstruction is used to generate multiple images to capture in-breath HP 129 Xe signal dynamics in mice and thus provide flip angle maps to quantitatively correct images without extra data collection. These CFA images display SNR that is not significantly different from VFA images, and further, high frequency k-space scaling can be used to mitigate decay-induced image artifacts. Results are supported by point spread function calculations and simulations of radial imaging with preclinical signal dynamics. Together, these results show that CFA 3D radial golden means ventilation imaging provides comparable image quality with VFA in small animals and allows for keyhole reconstruction, which can be used to generate flip angle maps and correct images for signal depletion.

Improved pulmonary 129 Xe ventilation imaging via 3D-spiral UTE MRI.

PURPOSE: Hyperpolarized 129 Xe MRI characterizes regional lung ventilation in a variety of disease populations, with high sensitivity to airway obstruction in early disease. However, ventilation images are usually limited to a single breath-hold and most-often acquired using gradient-recalled echo sequences with thick slices (~10-15 mm), which increases partial-volume effects, limits ability to observe small defects, and suffers from imperfect slice selection. We demonstrate higher-resolution ventilation images, in shorter breath-holds, using FLORET (Fermat Looped ORthogonally Encoded Trajectories), a center-out 3D-spiral UTE sequence. METHODS: In vivo human adult (N = 4; 2 healthy, 2 with cystic fibrosis) 129 Xe images were acquired using 2D gradient-recalled echo, 3D radial, and FLORET. Each sequence was acquired at its highest possible resolution within a 16-second breath-hold with a minimum voxel dimension of 3 mm. Images were compared using 129 Xe ventilation defect percentage, SNR, similarity coefficients, and vasculature cross-sections. RESULTS: The FLORET sequence obtained relative normalized SNR, 40% greater than 2D gradient-recalled echo (P = .012) and 26% greater than 3D radial (P = .067). Moreover, the FLORET images were acquired with 3-fold-higher nominal resolution in a 15% shorter breath-hold. Finally, vasculature was less prominent in FLORET, likely due to diminished susceptibility-induced dephasing at shorter TEs afforded by UTE sequences. CONCLUSION: The FLORET sequence yields higher SNR for a given resolution with a shorter breath-hold than traditional ventilation imaging techniques. This sequence more accurately measures ventilation abnormalities and enables reduced scan times in patients with poor compliance and severe lung disease.

Preclinical hyperpolarized 129 Xe MRI: ventilation and T2 * mapping in mouse lungs at 7 T using multi-echo flyback UTE.

Fast apparent transverse relaxation (short T2 *) is a common obstacle when attempting to perform quantitative 1 H MRI of the lungs. While T2 * times are longer for pulmonary hyperpolarized (HP) gas functional imaging (in particular for gaseous 129 Xe), T2 * can still lead to quantitative inaccuracies for sequences requiring longer echo times (such as diffusion weighted images) or longer readout duration (such as spiral sequences). This is especially true in preclinical studies, where high magnetic fields lead to shorter relaxation times than are typically seen in human studies. However, the T2 * of HP 129 Xe in the most common animal model of human disease (mice) has not been reported. Herein, we present a multi-echo radial flyback imaging sequence and use it to measure HP 129 Xe T2 * at 7 T under a variety of respiratory conditions. This sequence mitigates the impact of T1 relaxation outside the animal by using multiple gradient-refocused echoes to acquire images at a number of effective echo times for each RF excitation. After validating the sequence using a phantom containing water doped with superparamagnetic iron oxide nanoparticles, we measured the 129 Xe T2 * in vivo for 10 healthy C57Bl/6 J mice and found T2 * ~ 5 ms in the lung airspaces. Interestingly, T2 * was relatively constant over all experimental conditions, and varied significantly with sex, but not age, mass, or the O2 content of the inhaled gas mixture. These results are discussed in the context of T2 * relaxation within porous media.

Mapping and correcting hyperpolarized magnetization decay with radial keyhole imaging.

PURPOSE: Hyperpolarized (HP) media enable biomedical imaging applications that cannot be achieved with conventional MRI contrast agents. Unfortunately, quantifying HP images is challenging, because relaxation and radio-frequency pulsing generate spatially varying signal decay during acquisition. We demonstrate that, by combining center-out k-space sampling with postacquisition keyhole reconstruction, voxel-by-voxel maps of regional HP magnetization decay can be generated with no additional data collection. THEORY AND METHODS: Digital phantom, HP 129 Xe phantom, and in vivo 129 Xe human (N = 4 healthy; N = 2 with cystic fibrosis) imaging was performed using radial sampling. Datasets were reconstructed using a postacquisition keyhole approach in which 2 temporally resolved images were created and used to generate maps of regional magnetization decay following a simple analytical model. RESULTS: Mean, keyhole-derived decay terms showed excellent agreement with the decay used in simulations (R2 = 0.996) and with global attenuation terms in HP 129 Xe phantom imaging (R2 > 0.97). Mean regional decay from in vivo imaging agreed well with global decay values and displayed spatial heterogeneity that matched expected variations in flip angle and oxygen partial pressure. Moreover, these maps could be used to correct variable signal decay across the image volume. CONCLUSIONS: We have demonstrated that center-out trajectories combined with keyhole reconstruction can be used to map regional HP signal decay and to quantitatively correct images. This approach may be used to improve the accuracy of quantitative measures obtained from hyperpolarized media. Although validated with gaseous HP 129 Xe in this work, this technique can be generalized to any hyperpolarized agent.

Murine pulmonary imaging at 7T: T2* and T1 with anisotropic UTE.

PURPOSE: To measure the T2* and T1 of mouse lung at 7T via anisotropic-resolution radial ultrashort echo-time imaging with ellipsoidal k-space coverage. METHODS: Ellipsoidal field-of-view was created by expanding uniform spherical k-space coverage. The effects of T2* and ellipsoidal sampling on image resolution were investigated by using point-spread-function analysis and resolution phantoms. Finally, this ellipsoidal sampling approach was used to measure the lung T2* and T1 of healthy C57BL/6 mice at the increasingly common preclinical field strength of 7T. RESULTS: Lung parenchyma T2* of 17- to 23-week-old mice at 7T was 0.395 ± 0.033 ms. T1 of lung and left- and right-heart ventricles was 1452.5 ± 87.0 ms, 1810.5 ± 54.6 ms, and 1602.6 ± 120.9 ms, respectively. Ellipsoidal k-space sampling provides enhanced resolution for a fixed scanning time or provides equivalent (although anisotropic) spatial resolution with reduced scanning times, while simultaneously avoiding fold-in artifacts. CONCLUSION: Using these techniques, the first T2* and T1 measures of mouse lung at 7T are reported. Ultrashort echo-time imaging with ellipsoidal k-space coverage significantly increases in-plane resolution without increasing scanning time, or equivalently, decreases scanning time while maintaining equivalent in-plane resolution. Magn Reson Med 79:2254-2264, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Magnetic resonance imaging of disease progression and resolution in a transgenic mouse model of pulmonary fibrosis.

Pulmonary fibrosis contributes to morbidity and mortality in a range of diseases, and there are no approved therapies for reversing its progression. To understand the mechanisms underlying pulmonary fibrosis and assess potential therapies, mouse models are central to basic and translational research. Unfortunately, metrics commonly used to assess murine pulmonary fibrosis require animals to be grouped and euthanized, increasing experimental difficulty and cost. We examined the ability of magnetic resonance imaging (MRI) to noninvasively assess lung fibrosis progression and resolution in a doxycycline (Dox) regulatable, transgenic mouse model that overexpresses transforming growth factor-α (TGF-α) under control of a lung-epithelial-specific promoter. During 7 wk of Dox treatment, fibrotic lesions were readily observed as high-signal tissue. Mean weighted signal and percent signal volume were found to be the most robust MRI-derived measures of fibrosis, and these metrics correlated significantly with pleural thickness, histology scores, and hydroxyproline content (R = 0.75-0.89). When applied longitudinally, percent high signal volume increased by 1.5% wk-1 (P < 0.001) and mean weighted signal increased at a rate of 0.0065 wk-1 (P = 0.0062). Following Dox treatment, lesions partially resolved, with percent high signal volume decreasing by -3.2% wk-1 (P = 0.0034) and weighted mean signal decreasing at -0.015 wk-1 (P = 0.0028). Additionally, longitudinal MRI revealed dynamic remodeling in a subset of lesions, a previously unobserved behavior in this model. These results demonstrate MRI can noninvasively assess experimental lung fibrosis progression and resolution and provide unique insights into its pathobiology.

Feasibility, tolerability and safety of pediatric hyperpolarized 129Xe magnetic resonance imaging in healthy volunteers and children with cystic fibrosis.

BACKGROUND: Hyperpolarized 129Xe is a promising contrast agent for MRI of pediatric lung function, but its safety and tolerability in children have not been rigorously assessed. OBJECTIVE: To assess the feasibility, safety and tolerability of hyperpolarized 129Xe gas as an inhaled contrast agent for pediatric pulmonary MRI in healthy control subjects and in children with cystic fibrosis. MATERIALS AND METHODS: Seventeen healthy control subjects (ages 6-15 years, 11 boys) and 11 children with cystic fibrosis (ages 8-16 years, 4 boys) underwent 129Xe MRI, receiving up to three doses of 129Xe gas prepared by either a commercially available or a homebuilt 129Xe polarizer. Subject heart rate and SpO2 were monitored for 2 min post inhalation and compared to resting baseline values. Adverse events were reported via follow-up phone call at days 1 and 30 (range ±7 days) post-MRI. RESULTS: All children tolerated multiple doses of 129Xe, and no children withdrew from the study. Relative to baseline, most children who received a full dose of gas for imaging (10 of 12 controls and 8 of 11 children with cystic fibrosis) experienced a nadir in SpO2 (mean -6.0 ± standard deviation 7.2%, P≤0.001); however within 2 min post inhalation SpO2 values showed no significant difference from baseline (P=0.11). There was a slight elevation in heart rate (mean +6.6 ± 13.9 beats per minute [bpm], P=0.021), which returned from baseline within 2 min post inhalation (P=0.35). Brief side effects related to the anesthetic properties of xenon were mild and quickly resolved without intervention. No serious or severe adverse events were observed; in total, four minor adverse events (14.3%) were reported following 129Xe MRI, but all were deemed unrelated to the study. CONCLUSION: The feasibility, safety and tolerability of 129Xe MRI has been assessed in a small group of children as young as 6 years. SpO2 changes were consistent with the expected physiological effects of a short anoxic breath-hold, and other mild side effects were consistent with the known anesthetic properties of xenon and with previous safety assessments of 129Xe MRI in adults. Hyperpolarized 129Xe is a safe and well-tolerated inhaled contrast agent for pulmonary MR imaging in healthy children and in children with cystic fibrosis who have mild to moderate lung disease.

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

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