Improved Diffusion-Weighted Hyperpolarized 129Xe Lung MRI with Patch-Based Higher-Order, Singular Value Decomposition Denoising.

RATIONALE AND OBJECTIVES: Hyperpolarized xenon (129Xe) MRI is a noninvasive method to assess pulmonary structure and function. To measure lung microstructure, diffusion-weighted imaging-commonly the apparent diffusion coefficient (ADC)-can be employed to map changes in alveolar-airspace size resulting from normal aging and pulmonary disease. However, low signal-to-noise ratio (SNR) decreases ADC measurement certainty, and biases ADC to spuriously low values. Further, these challenges are most severe in regions of the lung where alveolar simplification or emphysematous remodeling generate abnormally high ADCs. Here, we apply Global Local Higher Order Singular Value Decomposition (GLHOSVD) denoising to enhance image SNR, thereby reducing uncertainty and bias in diffusion measurements. MATERIALS AND METHODS: GLHOSVD denoising was employed in simulated images and gas phantoms with known diffusion coefficients to validate its effectiveness and optimize parameters for analysis of diffusion-weighted 129Xe MRI. GLHOSVD was applied to data from 120 subjects (34 control, 39 cystic fibrosis (CF), 27 lymphangioleiomyomatosis (LAM), and 20 asthma). Image SNR, ADC, and distributed diffusivity coefficient (DDC) were compared before and after denoising using Wilcoxon signed-rank analysis for all images. RESULTS: Denoising significantly increased SNR in simulated, phantom, and in-vivo images, showing a greater than 2-fold increase (p < 0.001) across diffusion-weighted images. Although mean ADC and DDC remained unchanged (p > 0.05), ADC and DDC standard deviation decreased significantly in denoised images (p < 0.001). CONCLUSION: When applied to diffusion-weighted 129Xe images, GLHOSVD improved image quality and allowed airspace size to be quantified in high-diffusion regions of the lungs that were previously inaccessible to measurement due to prohibitively low SNR, thus providing insights into disease pathology.

Detection of Bronchiolitis Obliterans Syndrome Following Pediatric Hematopoietic Stem Cell Transplantation. An Official American Thoracic Society Clinical Practice Guideline.

BACKGROUND: Many children undergo allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for the treatment of malignant and non-malignant conditions. Unfortunately, pulmonary complications occur frequently post-HSCT, with bronchiolitis obliterans syndrome (BOS) being the most common non-infectious pulmonary complication. Current international guidelines contain conflicting recommendations regarding post-HSCT surveillance for BOS, and a recent National Institutes of Health workshop highlighted the need for a standardized approach to post-HSCT monitoring. As such, this guideline provides an evidence-based approach to detection of post-HSCT BOS in children. METHODS: A multinational, multidisciplinary panel of experts identified six questions regarding surveillance for, and evaluation of post-HSCT BOS in children. Systematic review of the literature was undertaken to answer each question. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of recommendations. RESULTS: The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations addressing the role of screening pulmonary function testing and diagnostic tests in children with suspected post-HSCT BOS were made. Following a Delphi process, new diagnostic criteria for pediatric post-HSCT BOS were also proposed. CONCLUSIONS: This document provides an evidence-based approach to detection of post-HSCT BOS in children, while also highlighting considerations for implementation of each recommendation. Further, the document describes important areas for future research.

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.

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.

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.

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.

Hyperpolarized 129Xenon MRI Ventilation Defect Quantification via Thresholding and Linear Binning in Multiple Pulmonary Diseases.

RATIONALE: There is no agreed upon method for quantifying ventilation defect percentage (VDP) with high sensitivity and specificity from hyperpolarized (HP) gas ventilation MR images in multiple pulmonary diseases for both pediatrics and adults, yet identifying such methods will be necessary for future multi-site trials. Most HP gas MRI ventilation research focuses on a specific pulmonary disease and utilizes one quantification scheme for determining VDP. Here we sought to determine the potential of different methods for quantifying VDP from HP 129Xe images in multiple pulmonary diseases through comparison of the most utilized quantification schemes: linear binning and thresholding. MATERIALS AND METHODS: HP 129Xe MRI was performed in a total of 176 subjects (125 pediatrics and 51 adults, age 20.98±16.48 years) who were either healthy controls (n = 23) or clinically diagnosed with cystic fibrosis (CF) (n = 37), lymphangioleiomyomatosis (LAM) (n = 29), asthma (n = 22), systemic juvenile idiopathic arthritis (sJIA) (n = 11), interstitial lung disease (ILD) (n = 7), or were bone marrow transplant (BMT) recipients (n = 47). HP 129Xe ventilation images were acquired during a ≤16 second breath-hold using a 2D multi-slice gradient echo sequence on a 3T Philips scanner (TR/TE 8.0/4.0ms, FA 10-12°, FOV 300 × 300mm, voxel size≈3 × 3 × 15mm). Images were analyzed using 5 different methods to quantify VDPs: linear binning (histogram normalization with binning into 6 clusters) following either linear or a variant of a nonparametric nonuniform intensity normalization algorithm (N4ITK) bias-field correction, thresholding ≤60% of the mean signal intensity with linear bias-field correction, and thresholding ≤60% and ≤75% of the mean signal intensity following N4ITK bias-field correction. Spirometry was successfully obtained in 84% of subjects. RESULTS: All quantification schemes were able to label visually identifiable ventilation defects in similar regions within all subjects. The VDPs of control subjects were significantly lower (p<0.05) compared to BMT, CF, LAM, and ILD subjects for most of the quantification methods. No one quantification scheme was better able to differentiate individual disease groups from the control group. Advanced statistical modeling of the VDP quantification schemes revealed that in comparing controls to the combined disease group, N4ITK bias-field corrected 60% thresholding had the highest predictive efficacy, sensitivity, and specificity at the VDP cut-point of 2.3%. However, compared to the thresholding quantification schemes, linear binning was able to capture and label subtle low-ventilation regions in subjects with milder obstruction, such as subjects with asthma. CONCLUSION: The difference in VDP between healthy controls and patients varied between the different disease states for all quantification methods. Although N4ITK bias-field corrected 60% thresholding was superior in separating the combined diseased group from controls, linear binning is able to better label low-ventilation regions unlike the current, 60% thresholding scheme. For future clinical trials, a consensus will need to be reached on which VDP scheme to utilize, as there are subtle advantages for each for specific disease.

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.

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.

Effects of neonatal lung abnormalities on parenchymal R2 * estimates.

Infants admitted to the neonatal intensive care unit (NICU) often suffer from multifaceted pulmonary morbidities that are not well understood. Ultrashort echo time (UTE) magnetic resonance imaging (MRI) is a promising technique for pulmonary imaging in this population without requiring exposure to ionizing radiation. The aims of this study were to investigate the effect of neonatal pulmonary disease on R2 * and tissue density and to utilize numerical simulations to evaluate the effect of different alveolar structures on predicted R2 *.This was a prospective study, in which 17 neonatal human subjects (five control, seven with bronchopulmonary dysplasia [BPD], five with congenital diaphragmatic hernia [CDH]) were enrolled. Twelve subjects were male and five were female, with postmenstrual age (PMA) at MRI of 39.7 ± 4.7 weeks. A 1.5T/multiecho three-dimensional UTE MRI was used. Pulmonary R2 * and tissue density were compared across disease groups over the whole lung and regionally. A spherical shell alveolar model was used to predict the expected R2 * over a range of tissue densities and tissue susceptibilities. Tests for significantly different mean R2 * and tissue densities across disease groups were evaluated using analysis of variance, with subsequent pairwise group comparisons performed using t tests. Lung tissue density was lower in the ipsilateral lung in CDH compared to both controls and BPD patients (both p < 0.05), while only the contralateral lung in CDH (CDHc) had higher whole-lung R2 * than both controls and BPD (both p < 0.05). R2 * differences were significant between controls and CDHc within all tissue density ranges (all p < 0.05) with the exception of the 80%-90% range (p = 0.17). Simulations predicted an inverse relationship between alveolar tissue density and R2 * that matches empirical human data. Alveolar wall thickness had no effect on R2 * independent of density (p = 1). The inverse relationship between R2 * and tissue density is influenced by the presence of disease globally and regionally in neonates with BPD and CDH in the NICU. LEVEL OF EVIDENCE: 2. TECHNICAL EFFICACY STAGE: 2.

Quantitative inspiratory-expiratory chest CT to evaluate pulmonary involvement in pediatric hematopoietic stem-cell transplantation patients.

Pulmonary complications following allogeneic hematopoietic stem-cell transplantation (HSCT) are a significant source of morbidity and complications may arise from a myriad of infectious and noninfectious sources. These complications may occur soon or many months post-transplantation and can have a broad range of outcomes. Surveillance for pulmonary involvement in the pediatric HSCT population can be challenging due to poor compliance with clinical pulmonary function testing, primarily spirometry, and there may be a role for clinical imaging to provide an additional means of monitoring, particularly in the era of clinical low-dose computed tomography (CT) protocols. In this single-site, retrospective study, a review of our institution's radiological and HSCT databases was conducted to assess the utility of a quantitative CT algorithm to describe ventilation abnormalities on high-resolution chest CT scans of pediatric HSCT patients. Thirteen non-contrast enhanced chest CT examinations acquired both in inspiration and expiration, from 12 deceased HSCT patients (median age at HSCT 10.4 years, median days of CT 162) were selected for the analysis. Also, seven age-matched healthy controls (median age 15.5) with non-contrast-enhanced inspiration-expiration chest CT were selected for comparison. We report that, compared to healthy age-matched controls, HSCT patients had larger percentages of poorly ventilated (median, 13.5% vs. 2.3%, p < .001) and air trapped (median 12.3% vs. 0%, p < .001) regions of lung tissue, suggesting its utility as a potential screening tool. Furthermore, there was wide variation within individual HSCT patients, supporting the use of multivolume CT and quantitative analysis to describe and phenotype post-transplantation lung involvement.

The Clinical Use of Lung MRI in Cystic Fibrosis: What, Now, How?

To assess airway and lung parenchymal damage noninvasively in cystic fibrosis (CF), chest MRI has been historically out of the scope of routine clinical imaging because of technical difficulties such as low proton density and respiratory and cardiac motion. However, technological breakthroughs have emerged that dramatically improve lung MRI quality (including signal-to-noise ratio, resolution, speed, and contrast). At the same time, novel treatments have changed the landscape of CF clinical care. In this contemporary context, there is now consensus that lung MRI can be used clinically to assess CF in a radiation-free manner and to enable quantification of lung disease severity. MRI can now achieve three-dimensional, high-resolution morphologic imaging, and beyond this morphologic information, MRI may offer the ability to sensitively differentiate active inflammation vs scarring tissue. MRI could also characterize various forms of inflammation for early guidance of treatment. Moreover, functional information from MRI can be used to assess regional, small-airway disease with sensitivity to detect small changes even in patients with mild CF. Finally, automated quantification methods have emerged to support conventional visual analyses for more objective and reproducible assessment of disease severity. This article aims to review the most recent developments of lung MRI, with a focus on practical application and clinical value in CF, and the perspectives on how these modern techniques may converge and impact patient care soon.

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.

Sensitive structural and functional measurements and 1-year pulmonary outcomes in pediatric cystic fibrosis.

BACKGROUND: Two functional measurements (multiple breath washout [MBW] and hyperpolarized 129Xe ventilation magnetic resonance imaging [129Xe MRI]) have been shown to be more sensitive to cystic fibrosis (CF) lung obstruction than traditional spirometry. However, functional techniques may be sensitive to different underlying structural abnormalities. The purpose of this study was to determine relationships between these functional markers, their pathophysiology, and 1-year clinical outcomes. METHODS: Spirometry, MBW, 129Xe MRI, and ultrashort echo-time (UTE) MRI were obtained in a same-day assessment of 27 pediatric CF patients (ages 11.5±5.0) who had not begun CFTR modulator therapies. UTE MRI was scored for structural abnormalities and functional metrics obtained via spirometry, MBW and 129Xe MRI. 1-year outcomes (ΔFEV1 and pulmonary exacerbations), during which ≈50% initiated modulator therapy, were obtained from the electronic medical record. RESULTS: MBW, 129Xe MRI, and UTE MRI detected clinically significant disease in more subjects (>78%) compared to spirometry (<30%). UTE MRI suggests increased odds of bronchial changes when mucus plugging is present in the same lobe. MBW and 129Xe MRI correlated best with mucus plugging, while spirometry correlated best with consolidations. Bronchial abnormalities were associated with future pulmonary exacerbations. CONCLUSIONS: MBW, 129Xe MRI, and UTE MRI are more sensitive for detection of pediatric CF lung disease when compared to spirometry. MBW and 129Xe MRI correlated with structural abnormalities which occur in early CF disease, suggesting MBW and 129Xe MRI are valuable tools in mild CF lung disease that can guide clinical decision making.

A semi-empirical model to optimize continuous-flow hyperpolarized 129Xe production under practical cryogenic-accumulation conditions.

Continuous-flow spin exchange optical pumping (SEOP) with cryogenic accumulation is a powerful technique to generate multiple, large volumes of hyperpolarized (HP) 129Xe in rapid succession. It enables a range of studies, from dark matter tracking to preclinical and clinical MRI. Multiple analytical models based on first principles atomic physics and device-specific design features have been proposed for individual processes within HP 129Xe production. However, the modeling efforts have not yet integrated all the steps involved in practical, large volume HP 129Xe production process (e.g., alkali vapor generation, continuous-flow SEOP, and cryogenic accumulation). Here, we use a simplified analytical model that couples both SEOP and cryogenic accumulation, incorporating only two system-specific empirical parameters: the longitudinal relaxation time of the polycrystalline 129Xe "snow', T1snow, generated during cryogenic accumulation, and 2) the average Rb density during active, continuous-flow polarization. By fitting the model to polarization data collected from >140 L of 129Xe polarized across a range of flow and volume conditions, the estimates for Rb density and T1snow were 1.6 ± 0.1 × 1013 cm-3 and 84 ± 5 min, respectively - each notably less than expected based on previous literature. Together, these findings indicate that 1) earlier polarization predictions were hindered by miscalculated Rb densities, and 2) polarization is not optimized by maximizing SEOP efficiency with a low concentration 129Xe, but rather by using richer 129Xe-buffer gas blends that enable faster accumulation. Accordingly, modeling and experimentation revealed the optimal fraction of 129Xe, f, in the 129Xe-buffer gas blend was ~2%. Further, if coupled with modest increases in laser power, the model predicts liter volumes of HP 129Xe with polarizations exceeding 60% could be generated routinely in only tens of minutes.

Lung microstructure in adolescent idiopathic scoliosis before and after posterior spinal fusion.

Adolescent idiopathic scoliosis (AIS) is associated with decreased respiratory quality of life and impaired diaphragm function. Recent hyperpolarized helium (HHe) MRI studies show alveolarization continues throughout adolescence, and mechanical forces are known to impact alveolarization. We therefore hypothesized that patients with AIS would have alterations in alveolar size, alveolar number, or alveolar septal dimensions compared to adolescents without AIS, and that posterior spinal fusion (PSF) might reverse these differences. We conducted a prospective observational trial using HHe MRI to test for changes in alveolar microstructure in control and AIS subjects at baseline and one year. After obtaining written informed consent from subjects' legal guardians and assent from the subjects, we performed HHe and proton MRI in 14 AIS and 16 control subjects aged 8-21 years. The mean age of control subjects (12.9 years) was significantly less than AIS (14.9 years, p = 0.003). At baseline, there were no significant differences in alveolar size, number, or alveolar duct morphometry between AIS and control subjects or between the concave (compressed) and convex (expanded) lungs of AIS subjects. At one year after PSF AIS subjects had an increase in alveolar density in the formerly convex lung (p = 0.05), likely reflecting a change in thoracic anatomy, but there were no other significant changes in lung microstructure. Modeling of alveolar size over time demonstrated similar rates of alveolar growth in control and AIS subjects in both right and left lungs pre- and post-PSF. Although this study suffered from poor age-matching, we found no evidence that AIS or PSF impacts lung microstructure. Trial registration: Clinical trial registration number NCT03539770.

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.

Cyst Ventilation Heterogeneity and Alveolar Airspace Dilation as Early Disease Markers in Lymphangioleiomyomatosis.

Rationale: Lymphangioleiomyomatosis (LAM) is a rare disease associated with cystic destruction of the pulmonary parenchyma and chronic respiratory failure, and there are trials underway to determine if early intervention can prevent disease progression. An imaging technique that is sensitive to early regional disease would therefore be valuable for patient care and clinical trials.Objectives: We postulated that hyperpolarized 129Xe MRI would be sensitive to ventilation abnormalities and alveolar airspace dilation in patients with mild LAM disease and normal pulmonary function and that 129Xe MRI would reveal important features of cyst ventilation.Methods:129Xe ventilation and diffusion-weighted MR images were acquired in 22 patients with LAM during two breath-holds of hyperpolarized 129Xe. 129Xe ventilation defect percentage (VDP; percentage of voxels <60% of the mean whole-lung 129Xe MRI signal) and apparent diffusion coefficient (ADC), a measure of alveolar airspace size, were quantified and compared with pulmonary function test parameters with Spearman statistics. Sixteen patients with LAM had a recent, clinical chest computed tomography (CT) scan available, and cyst ventilation was assessed by thresholding cysts on the CT images and registration to the 129Xe ventilation images.Results: Ventilation deficits were observed in all patients with LAM, including those with normal pulmonary function and few cysts, and the mean VDP was 19.2% (95% confidence interval [CI], 14.8-23.5%). 129Xe VDP was strongly correlated with forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio (r = -0.51, P = 0.02) and diffusing capacity of the lung for carbon monoxide (DlCO) (r = -0.60, P = 0.009) but not with FEV1 (r = -0.33, P = 0.13), likely because of the sensitivity of 129Xe MRI to mild LAM disease in patients with normal FEV1. The mean ADC was 0.048 cm2/s (95% CI, 0.042-0.053 cm2/s). In many cases, ADC was elevated relative to previously reported values in adults, and ADC was correlated with FEV1, FEV1/FVC ratio, and DlCO (P ≤ 0.02 for all). Co-registered 129Xe MRI and CT imaging revealed considerable ventilation heterogeneity within individual patients with LAM and across patients with similarly sized cysts.Conclusions:129Xe MRI provides a means to assess the complex regional ventilation and alveolar airspace size changes of LAM with high sensitivity and may be a clinically useful future tool for screening, managing patients, and measuring treatment efficacy.