MRI Ventilation Defect Research Articles

129Xe MRI Ventilation Defects in Asthma: What is the Upper Limit of Normal and Minimal Clinically Important Difference?

The minimal clinically important difference (MCID) and upper limit of normal (ULN) for MRI ventilation defect percent (VDP) were previously reported for hyperpolarized 3He gas MRI. Hyperpolarized 129Xe VDP is more sensitive to airway dysfunction than 3He, therefore the objective of this study was to determine the ULN and MCID for 129Xe MRI VDP in healthy and asthma participants. We retrospectively evaluated healthy and asthma participants who underwent spirometry and 129XeMRI on a single visit; participants with asthma completed the asthma control questionnaire (ACQ-7). The MCID was estimated using distribution- (smallest detectable difference [SDD]) and anchor-based (ACQ-7) methods. Two observers measured VDP (semiautomated k-means-cluster segmentation algorithm) in 10 participants with asthma, five-times each in random order, to determine SDD. The ULN was estimated based on the 95% confidence interval of the relationships between VDP and age. Mean VDP was 1.6 ± 1.2% for healthy (n=27) and 13.7 ± 12.9% for asthma participants (n=55). ACQ-7 and VDP were correlated (r=.37, p=.006; VDP=3.5·ACQ+4.9). The anchor-based MCID was 1.75% while the mean SDD and distribution-based MCID was 2.25%. VDP was correlated with age for healthy participants (p=.56, p =.003; VDP=.04·Age-.01). The ULN for all healthy participants was 2.0%. By age tertiles, the ULN was 1.3% ages 18-39 years, 2.5% for 40-59 years and 3.8% for 60-79 years. The 129Xe MRI VDP MCID was estimated in participants with asthma; the ULN was estimated in healthy participants across a range of ages, both of which provide a way to interpret VDP measurements in clinical investigations.

CT Mucus Score and 129Xe MRI Ventilation Defects After 2.5 Years’ Anti-IL-5Rα in Eosinophilic Asthma

We previously showed in patients with poorly controlled eosinophilic asthma that a single dose of benralizumab resulted in significantly improved Asthma Control Questionnaire (ACQ-6) score and 129Xe MRI ventilation defect percent (VDP) 28days postinjection, and 129Xe MRI VDP and CT airway mucus occlusions were shown to independently predict this early ACQ-6 response to benralizumab. Do early VDP responses at 28days persist, and do FEV1, fractional exhaled nitric oxide, and mucus plug score improve during a 2.5 year treatment period? Participants with poorly controlled eosinophilic asthma completed spirometry, ACQ-6, and MRI, 28days, 1 year, and 2.5 years after initiation of treatment with benralizumab; chest CT was acquired at enrollment and 2.5 years later. Of 29 participants evaluated at 28days post-benralizumab, 16 participants returned for follow-up while on therapy at 1 year, and 13 participants were evaluable while on therapy at 2.5 years post-benralizumab initiation. As compared with 28days post-benralizumab, ACQ-6 score (2.0 ± 1.4) significantly improved after 1 year (0.5 ± 0.6, P= .02; 95%CI, 0.1-1.1) and 2.5 years (0.5 ± 0.5, P= .03; 95%CI, 0.1-1.1). The mean VDP change at 2.5 years (-4%± 3%) was greater than the minimal clinically important difference, but not significantly different from VDP measured 28days post-benralizumab. Mucus score (3 ± 4) was significantly improved at 2.5 years (1 ± 1, P= .03; 95%CI, 0.3-5.5). In six of eight participants with previous occlusions, mucus plugs vanished or substantially diminished 2.5 years later. VDP (P< .001) and mucus score (P< .001) measured at baseline, but not fractional exhaled nitric oxide or FEV1, independently predicted ACQ-6 score after 2.5 years. In poorly controlled eosinophilic asthma, early MRI VDP responses at 28days post-benralizumab persisted 2.5 years later, alongside significantly improved mucus scores and asthma control.

Postacute COVID-19 Syndrome: 129Xe MRI Ventilation Defects and Respiratory Outcomes 1 Year Later.

Background In individuals with postacute COVID-19 syndrome (PACS) and normal pulmonary function, xenon 129 (129Xe) MRI ventilation defects, abnormal quality-of-life scores, and exercise limitation were reported 3 months after infection; the longitudinal trajectory remains unclear. Purpose To measure and compare pulmonary function, exercise capacity, quality of life, and 129Xe MRI ventilation defect percent (VDP) in individuals with PACS evaluated 3 and 15 months after COVID-19 infection. Materials and Methods In this prospective study, participants with PACS aged 18-80 years were enrolled between July 2020 and August 2021 from two quaternary care centers. 129Xe MRI VDP, diffusing capacity of lung for carbon monoxide (Dlco), spirometry, oscillometry, 6-minute walk distance (6MWD), and St George Respiratory Questionnaire (SGRQ) scores were evaluated 3 months and 15 months after COVID-19 infection. Differences between time points were evaluated using the paired t test. Multivariable models were generated to explain exercise capacity and quality-of-life improvement. Odds ratios (ORs) were used to evaluate potential treatment influences. Results Overall, 53 participants (mean age, 55 years ± 18 [SD]; 27 women) attended both 3- and 15-month visits and were included in the analysis. The mean values for 129Xe MRI VDP (5.8% and 4.2%; P = .003), forced expiratory volume in the 1st second of expiration percent predicted (84% and 90%; P = .001), Dlco percent predicted (86% and 99%; P = .002), and SGRQ score (35 and 25; P < .001) improved between the 3- and 15-month visit. VDP measured 3 months after COVID-19 infection predicted the change in 6MWD (β = -0.643, P = .006), while treatment with respiratory medication at 3 months predicted an improved quality-of-life score at 15 months (OR, 4.0; 95% CI: 1.2, 13.8; P = .03). Conclusion Pulmonary function, gas exchange, exercise capacity, quality of life, and 129Xe MRI ventilation defect percent (VDP) improved in participants with postacute COVID-19 syndrome at 15 months compared with 3 months after infection. VDP measured at 3 months after infection correlated with improved exercise capacity, while treatment with respiratory medication was associated with an improved quality-of-life score 15 months after infection. ClinicalTrials.gov registration no. NCT05014516 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Vogel-Claussen in this issue.

129Xe MRI ventilation defects in ever-hospitalised and never-hospitalised people with post-acute COVID-19 syndrome

BackgroundPatients often report persistent symptoms beyond the acute infectious phase of COVID-19. Hyperpolarised 129Xe MRI provides a way to directly measure airway functional abnormalities; the clinical relevance of 129Xe MRI...

Pulmonary MRI and Cluster Analysis Help Identify Novel Asthma Phenotypes.

Outside eosinophilia, current clinical asthma phenotypes do not show strong relationships with disease pathogenesis or treatment responses. While chest x-ray computed tomography (CT) phenotypes have previously been explored, functional MRI measurements provide complementary phenotypic information. To derive novel data-driven asthma phenotypic clusters using functional MRI airway biomarkers that better describe airway pathologies in patients. Retrospective. A total of 45 patients with asthma who underwent post-bronchodilator 129 Xe MRI, volume-matched CT, spirometry and plethysmography within a 90-minute visit. Three-dimensional gradient-recalled echo 129 Xe ventilation sequence at 3T. We measured MRI ventilation defect percent (VDP), CT airway wall-area percent (WA%), wall-thickness (WT, WT* [*normalized for age/sex/height]), lumen-area (LA), lumen-diameter (D, D*) and total airway count (TAC). Univariate relationships were utilized to select variables for k-means cluster analysis and phenotypic subgroup generation. Spirometry and plethysmography measurements were compared across imaging-based clusters. Spearman correlation (ρ), one-way analysis of variance (ANOVA) or Kruskal-Wallis tests with post hoc Bonferroni correction for multiple comparisons, significance level 0.05. Based on limited common variance (Kaiser-Meyer-Olkin-measure=0.44), four unique clusters were generated using MRI VDP, TAC, WT* and D* (52 ± 14 years, 27 female). Imaging measurements were significantly different across clusters as was the forced expiratory volume in 1-second (FEV1 %pred ), residual volume/total lung capacity and airways resistance. Asthma-control (P=0.9), quality-of-life scores (P=0.7) and the proportions of severe-asthma (P=0.4) were not significantly different. Cluster1 (n=15/8 female) reflected mildly abnormal CT airway measurements and FEV1 with moderately abnormal VDP. Cluster2 (n=12/12 female) reflected moderately abnormal TAC, WT and FEV1 . In Cluster3 and Cluster4 (n=14/6 female, n=4/1 female, respectively), there was severely reduced TAC, D and FEV1 , but Cluster4 also had significantly worse, severely abnormal VDP (7 ± 5% vs. 41 ± 12%). We generated four proof-of-concept MRI-derived clusters of asthma with distinct structure-function pathologies. Cluster analysis of asthma using 129 Xe MRI in combination with CT biomarkers is feasible and may challenge currently used paradigms for asthma phenotyping and treatment decisions. 3 TECHNICAL EFFICACY: Stage.

Asthma Control, Airway Mucus, and 129Xe MRI Ventilation After a Single Benralizumab Dose

Patients with eosinophilic asthma often report poor symptomatic control and quality of life. Anti-IL-5 therapy, including anti-IL-5Rα (benralizumab), rapidly depletes eosinophils in the blood and airways and also reduces asthma exacerbations and improves quality of life scores. In patients with severe asthma, eosinophilic inflammation-driven airway mucus occlusions have been measured using thoracic x-ray CT imaging. Pulmonary 129Xe MRI ventilation defect percentage (VDP) also sensitively measures asthma airway dysfunction caused by airway hyperresponsiveness, remodeling, and luminal mucus occlusions. Using 129Xe MRI and CT imaging together, it is feasible to measure both airway luminal occlusions and airway ventilation in relationship to anti-IL-5 therapy to ascertain the direct impact of therapy-induced eosinophil depletion on airway function. Does 129Xe MRI detect airway functional responses to eosinophil depletion after a single benralizumab dose and do airway mucus occlusions mediate this response? MRI, eosinophil count, spirometry, oscillometry, Asthma Control Questionnaire (ACQ), Asthma Quality of Life Questionnaire (AQLQ), and St. George's Respiratory Questionnaire were completed on day 0 and 28days after a single 30-mg subcutaneous benralizumab dose. CT scan mucus plugs were scored on day 0, and MRI VDP was quantified on days 0 and28. Twenty-nine participants (27 with baseline CT imaging) completed day 0 and day 28 visits. On day 28 after a single benralizumab dose, significantly improved blood eosinophil counts, VDP, ACQ 6 scores, AQLQ scores (all P< .001), and peripheral airway resistance (P= .04) were found in all participants. On day 28, significantly improved VDP and ACQ 6 scores also were found in the subgroup of nine participants with five or more mucus plugs, but not in the subgroup (n= 18) with fewer than five mucus plugs. Based on univariate relationships for change in ACQ 6 score, multivariate models were generated and showed that day 0 VDP (P< .001) and day 0 CT scan mucus score (P< .001) were significant variables for change in ACQ 6 score on day 28 after benralizumab injection. 129Xe ventilation significantly improved in participants with uncontrolled asthma and in those with significant mucus plugging after a single dose of benralizumab. ClinicalTrials.gov; No.: NCT03733535; URL: www. gov.

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

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. 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. 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. 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.

Pulmonary Ventilation Maps Generated with Free-breathing Proton MRI and a Deep Convolutional Neural Network.

Background Hyperpolarized noble gas MRI helps measure lung ventilation, but clinical translation remains limited. Free-breathing proton MRI may help quantify lung function using existing MRI systems without contrast material and may assist in providing information about ventilation not visible to the eye or easily extracted with segmentation methods. Purpose To explore the use of deep convolutional neural networks (DCNNs) to generate synthetic MRI ventilation scans from free-breathing MRI (deep learning [DL] ventilation MRI)-derived specific ventilation maps as a surrogate of noble gas MRI and to validate this approach across a wide range of lung diseases. Materials and Methods In this secondary analysis of prospective trials, 114 paired noble gas MRI and two-dimensional free-breathing MRI scans were obtained in healthy volunteers with no history of chronic or acute respiratory disease and in study participants with a range of different obstructive lung diseases, including asthma, bronchiectasis, chronic obstructive pulmonary disease, and non-small-cell lung cancer between September 2013 and April 2018 (ClinicalTrials.gov identifiers: NCT03169673, NCT02351141, NCT02263794, NCT02282202, NCT02279329, and NCT02002052). A U-Net-based DCNN model was trained to map free-breathing proton MRI to hyperpolarized helium 3 (3He) MRI ventilation and validated using a sixfold validation. During training, the DCNN ventilation maps were compared with noble gas MRI scans using the Pearson correlation coefficient (r) and mean absolute error. DCNN ventilation images were segmented for ventilation and ventilation defects and were compared with noble gas MRI scans using the Dice similarity coefficient (DSC). Relationships were evaluated with the Spearman correlation coefficient (rS). Results One hundred fourteen study participants (mean age, 56 years ± 15 [standard deviation]; 66 women) were evaluated. As compared with 3He MRI, DCNN model ventilation maps had a mean r value of 0.87 ± 0.08. The mean DSC for DL ventilation MRI and 3He MRI ventilation was 0.91 ± 0.07. The ventilation defect percentage for DL ventilation MRI was highly correlated with 3He MRI ventilation defect percentage (rS = 0.83, P < .001, mean bias = -2.0% ± 5). Both DL ventilation MRI (rS = -0.51, P < .001) and 3He MRI (rS = -0.61, P < .001) ventilation defect percentage were correlated with the forced expiratory volume in 1 second. The DCNN model required approximately 2 hours for training and approximately 1 second to generate a ventilation map. Conclusion In participants with diverse pulmonary pathologic findings, deep convolutional neural networks generated ventilation maps from free-breathing proton MRI trained with a hyperpolarized noble-gas MRI ventilation map data set. The maps showed correlation with noble gas MRI ventilation and pulmonary function measurements. © RSNA, 2020 See also the editorial by Vogel-Claussen in this issue.

Reproducibility of Hyperpolarized 129Xe MRI Ventilation Defect Percent in Severe Asthma to Evaluate Clinical Trial Feasibility

129Xe MRI has been developed to noninvasively visualize and quantify the functional consequence of airway obstruction in asthma. Its widespread application requires evidence of intersite reproducibility and agreement. Our objective was to evaluate reproducibility and agreement of 129Xe ventilation MRI measurements in severe asthmatics at two sites. In seven adults with severe asthma, 129Xe ventilation MRI was acquired pre- and post-bronchodilator at two geographic sites within 24-hours. 129Xe MRI signal-to-noise ratio (SNR) was calculated and ventilation abnormalities were quantified as the whole-lung and slice-by-slice ventilation defect percent (VDP). Intraclass correlation coefficients (ICC) and Bland-Altman analysis were used to determine intersite 129Xe VDP reproducibility and agreement. Whole-lung and slice-by-slice 129Xe VDP measured at both sites were correlated and reproducible (pre-bronchodilator: whole-lung ICC = 0.90, p = 0.005, slice-by-slice ICC = 0.78, p < 0.0001; post-bronchodilator: whole-lung ICC = 0.94, p < 0.0001, slice-by-slice ICC = 0.83, p < 0.0001) notwithstanding intersite differences in the 129Xe-dose-equivalent-volume (101 ± 15 mL site 1, 49 ± 6 mL site 2, p < 0.0001), gas-mixture (129Xe/4He site 1; 129Xe/N2 site 2) and SNR (40 ± 19 site 1, 23 ± 5 site 2, p = 0.02). Qualitative 129Xe gas distribution differences were observed between sites and slice-by-slice 129Xe VDP, but not whole-lung 129Xe VDP, was significantly lower at site 1 (pre-bronchodilator VDP: whole-lung bias = -3%, p > 0.99, slice-by-slice bias = -3%, p = 0.0001; post-bronchodilator VDP: whole-lung bias = -2%, p = 0.59, slice-by-slice-bias = -2%, p = 0.0003). 129Xe MRI VDP at two different sites measured within 24-hours in the same severe asthmatics were correlated. Qualitative and quantitative intersite differences in 129Xe regional gas distribution and VDP point to site-specific variability that may be due to differences in gas-mixture composition or SNR.

Investigating the Effects of QVM149 on MRI Ventilation Defects

Investigating the Effects of QVM149 on MRI Ventilation Defects

Hyperpolarized Helium 3 MRI in Mild-to-Moderate Asthma: Prediction of Postbronchodilator Reversibility.

Background Longitudinal progression to irreversible airflow limitation occurs in approximately 10% of patients with asthma, but it is difficult to identify patients who are at risk for this transition. Purpose To investigate 6-year longitudinal changes in hyperpolarized helium 3 (3He) MRI ventilation defects in study participants with mild-to-moderate asthma and identify predictors of longitudinal changes in postbronchodilator forced expiratory volume in 1 second (FEV1) reversibility Materials and Methods Spirometry and hyperpolarized 3He MRI were evaluated in participants with mild-to-moderate asthma in two prospectively planned visits approximately 6 years apart. Participants underwent methacholine challenge at baseline (January 2010 to April 2011) and pre- and postbronchodilator evaluations at follow-up (November 2016 to June 2017). FEV1 and MRI ventilation defects, quantified as ventilation defect volume (VDV), were compared between visits by using paired t tests. Participants were dichotomized by postbronchodilator change in FEV1 at follow-up, and differences between reversible and not-reversible groups were determined by using unpaired t tests. Multivariable models were generated to explain postbronchodilator FEV1 reversibility at follow-up. Results Eleven participants with asthma (mean age, 42 years ± 9 [standard deviation]; seven men) were evaluated at baseline and after mean 78 months ± 7. Medications, exacerbations, FEV1 (76% predicted vs 76% predicted; P = .91), and VDV (240 mL vs 250 mL; P = .92) were not different between visits. In eight of 11 participants (73%), MRI ventilation defects at baseline were at the same location in the lung at follow-up MRI. In the remaining three participants (27%), MRI ventilation defects worsened at the same lung locations as depicted at baseline methacholine-induced ventilation. At follow-up, postbronchodilator FEV1 was not reversible in six of 11 participants; the concentration of methacholine to decrease FEV1 by 20% (PC20) was greater in FEV1-irreversible participants at follow-up (P = .01). In a multivariable model, baseline MRI VDV helped to predict postbronchodilator reversibility at follow-up (R 2 = 0.80; P < .01), but PC20, age, and FEV1 did not (R 2 = 0.63; P = .15). Conclusion MRI-derived, spatially persistent ventilation defects predict postbronchodilator reversibility 78 months ± 7 later for participants with mild-to-moderate asthma in whom there were no changes in lung function, medication, or exacerbations. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Stojanovska in this issue.

CT and Functional MRI to Evaluate Airway Mucus in Severe Asthma

Intraluminal contributor(s) to airflow obstruction in severe asthma are patient-specific and must be evaluated to personalize treatment. The occurrence and functional consequence of airway mucus in the presence or absence of airway eosinophils remain undetermined. The objective of this study was to understand the functional consequence of airway mucus in the presence or absence of eosinophils and to identify biomarkers of mucus-related airflow obstruction. Mucus plugs were quantified on CT scans, and their contribution to ventilation heterogeneity (using MRI ventilation defect percent [VDP]) was evaluated in 27 patients with severe asthma. Patients were dichotomized based on sputum eosinophilia such that the relationship between mucus, eosinophilia, and ventilation heterogeneity could be investigated. Fractional exhaled nitric oxide (Feno) and related cytokines in sputum were measured. Mucus plugging was present in 100%of asthma patients with sputum eosinophils and 36%of those without sputum eosinophils (P= .0006) and was correlated with MRI VDP prebronchodilator (r= 0.68; P= .0001) and postbronchodilator (r= 0.72; P< .0001). In a multivariable regression, both mucus and eosinophils contributed to the prediction of postbronchodilator MRI VDP (R2= 0.75; P< .0001). Patients with asthma in whom the mucus score was high had raised Feno (P= .03) and IL-4 (P= .02) values. Mucus plugging correlated with Feno (r= 0.63; P= .005). Both airway eosinophils and mucus can contribute to ventilation heterogeneity in patients with severe asthma. Patients in whom mucus is the dominant cause of airway obstruction have evidence of an upregulated IL-4/IL-13 pathway that could be identified according to increased Feno level.

Patient-Specific Computational Simulations of Hyperpolarized 3He MRI Ventilation Defects in Healthy and Asthmatic Subjects.

This study combines medical image data with patient-specific computational models to predict gas distributions and airway mechanics in healthy and asthmatic subjects. We achieve this by integrating segmental volume defect percent (SVDP), measured from hyperpolarized 3He MRI and CT images, to create models of patient-specific gas flow within the conducting airways. Predicted and measured SVDP distributions are achieved when the prescribed resistances are increased systematically. Because of differences in airway morphology and regional function, airway resistances and flow structures varied between the asthmatic subjects. Specifically, while mean SVDP was similar between the severe asthmatics (4.30±5.22 versus 3.54±5.98%), one subject exhibited abnormal flow structures, high near wall flow gradients, and enhanced conducting airway resistances (17.3E-3versus 1.1E-3 cmH2O-s/mL) in comparison to the other severe asthmatic subject. By coupling medical imaging data with computer simulations, we provide detailed insight into pathological flow characteristics and airway mechanics in asthmatics, beyond what could be inferred independently.

Free-breathing Functional Pulmonary MRI: Response to Bronchodilator and Bronchoprovocation in Severe Asthma

Ventilation heterogeneity is a hallmark feature of asthma. Our objective was to evaluate ventilation heterogeneity in patients with severe asthma, both pre- and post-salbutamol, as well as post-methacholine (MCh) challenge using the lung clearance index, free-breathing pulmonary 1H magnetic resonance imaging (FDMRI), and inhaled-gas MRI ventilation defect percent (VDP). Sixteen severe asthmatics (49 ± 10 years) provided written informed consent to an ethics board-approved protocol. Spirometry, plethysmography, and multiple breath nitrogen washout to measure the lung clearance index were performed during a single visit within 15 minutes of MRI. Inhaled-gas MRI and FDMRI were performed pre- and post-bronchodilator to generate VDP. For asthmatics with forced expiratory volume in 1 second (FEV1) >70%predicted, MRI was also performed before and after MCh challenge. Wilcoxon signed-rank tests, Spearman correlations, and a repeated-measures analysis of variance were performed. Hyperpolarized 3He (P = .02) and FDMRI (P = .02) VDP significantly improved post-salbutamol and for four asthmatics who could perform MCh (n = 4). 3He and FDMRI VDP significantly increased at the provocative concentration of MCh, resulting in a 20% decrease in FEV1 (PC20) and decreased post-bronchodilator (P = .02), with a significant difference between methods (P = .01). FDMRI VDP was moderately correlated with 3He VDP (ρ = .61, P = .01), but underestimated VDP relative to 3He VDP (-6 ± 9%). Whereas 3He MRI VDP was significantly correlated with the lung clearance index, FDMRI was not (ρ = .49, P = .06). FDMRI VDP generated in free-breathing asthmatic patients was correlated with static inspiratory breath-hold 3He MRI VDP but underestimated VDP relative to 3He MRI VDP. Although less sensitive to salbutamol and MCh, FDMRI VDP may be considered for asthma patient evaluations at centers without inhaled-gas MRI.

TH-CD-202-09: Free-Breathing Proton MRI Functional Lung Avoidance Maps to Guide Radiation Therapy

Purpose: Pulmonary functional MRI using inhaled gas contrast agents was previously investigated as a way to identify well-functioning lung in patients with NSCLC who are clinical candidates for radiotherapy. Hyperpolarized noble-gas (3He and 129Xe) MRI has also been optimized to measure functional lung information, but for a number of reasons, the clinical translation of this approach to guide radiotherapy planning has been limited. As an alternative, free-breathing pulmonary 1H MRI using clinically available MRI systems and pulse sequences provides a non-contrast-enhanced method to generate both ventilation and perfusion maps. Free-breathing 1H MRI exploits non-rigid registration and Fourier decomposition of MRI signal intensity differences (Bauman et al., MRM, 2009) that may be generated during normal tidal breathing. Here, our objective was to generate free-breathing 1H MRI ventilation and lung function avoidance maps in patients with NSCLC as a way to guide radiation therapy planning. Methods: Stage IIIA/IIIB NSCLC patients (n=8, 68±9yr) provided written informed consent to a randomized controlled clinical trial (https://clinicaltrials.gov/ct2/show/NCT02002052) that aimed to compare outcomes related to image-guided versus conventional radiation therapy planning. Hyperpolarized 3He/129Xe and dynamic free tidal-breathing 1H MRI were acquired as previously described (Capaldi et al., Acad Radiol, 2015). Non-rigid registration was performed using the modality-independent-neighbourhood-descriptor (MIND) deformable approach (Heinrich et al., Med Image Anal, 2012). Ventilation-defect-percent (3He:VDPHe, 129Xe:VDPXe, Free-breathing-1H:VDPFB) and the corresponding ventilation maps were compared using Pearson correlation coefficients (r) and the Dice similarity coefficient (DSC). Results: VDPFB was significantly related to VDPHe (r=.71; p=.04) and VDPXe (r=.80; p=.01) and there were also strong spatial relationships (DSCHe/DSCXe=89±3%/77±11%). Conclusion: In this proof of concept study in NSCLC patients, free-breathing 1H MRI ventilation defects were quantitatively and spatially related to inhaled-noble-gas MRI ventilation defects. Free-breathing 1H MRI measures lung function/ventilation that can be used to optimize radiotherapy planning in NSCLC patients.

Free-breathing Pulmonary 1H and Hyperpolarized 3He MRI: Comparison in COPD and Bronchiectasis

In this proof-of-concept demonstration, we aimed to quantitatively and qualitatively compare pulmonary ventilation abnormalities derived from Fourier decomposition of free-breathing (1)H magnetic resonance imaging (FDMRI) to hyperpolarized (3)He MRI in subjects with chronic obstructive pulmonary disease (COPD) and bronchiectasis. All subjects provided written informed consent to a protocol approved by a local research ethics board and Health, Canada, and they underwent MRI, computed tomography (CT), spirometry, and plethysmography during a single 2-hour visit. Semiautomated segmentation was used to generate ventilation defect measurements derived from FDMRI and (3)He MRI, and these were compared using analysis of variance and Pearson correlations. Twenty-six subjects were evaluated including 12 COPD subjects (67 ± 9years) and 14 bronchiectasis subjects (70±11years). For COPD subjects, FDMRI and (3)He MRI ventilation defect percent (VDP) was 7±6% and 24±14%, respectively (P<.001; bias=-16±9%). In COPD subjects, FDMRI was significantly correlated with (3)He MRI VDP (r=.88; P=.0001), (3)He MRI apparent diffusion coefficient (r=.71; P<.05), airways resistance (r=.60; P<.05), and RA950 (r=.80; P<.01). In subjects with bronchiectasis, FDMRI VDP (5±3%) and (3)He MRI VDP (18±9%) were significantly different (P<.001) and not correlated (P>.05). The Dice similarity coefficient (DSC) for FDMRI and (3)He MRI ventilation was 86±7% for COPD and 86±4% for bronchiectasis subjects (P>.05); the DSC for FDMRI ventilation defects and CT RA950 was 19±20% in COPD and 2±3% in bronchiectasis subjects (P<.01). FDMRI and (3)He MRI VDP were strongly related in COPD but not in bronchiectasis subjects. In COPD only, FDMRI ventilation defects were spatially related with (3)He ventilation defects and emphysema.

Pulmonary ventilation defects in older never-smokers.

Hyperpolarized (3)He MRI previously revealed spatially persistent ventilation defects in healthy, older compared with healthy, younger never-smokers. To understand better the physiological consequences and potential relevance of (3)He MRI ventilation defects, we evaluated (3)He-MRI ventilation-defect percent (VDP) and the effect of deep inspiration (DI) and salbutamol on VDP in older never-smokers. To identify the potential determinants of ventilation defects in these subjects, we evaluated dyspnea, pulmonary function, and cardiopulmonary exercise test (CPET) measurements, as well as occupational and second-hand smoke exposure. Fifty-two never-smokers (71 ± 6 yr) with no history of chronic respiratory disease were evaluated. During a single visit, pulmonary function tests, CPET, and (3)He MRI were performed and the Burden of Obstructive Lung Disease questionnaire administered. For eight of 52 subjects, there was spirometry evidence of airflow limitation (Global Initiative for Chronic Obstructive Lung Disease-Unclassified, I, and II), and occupational exposure was reported in 13 of 52 subjects. In 13 of 52 (25%) subjects, there were no ventilation defects and in 39 of 52 (75%) subjects, ventilation defects were observed. For those subjects with ventilation defects, six of 39 showed a VDP response to DI/salbutamol. Ventilation heterogeneity and VDP were significantly greater, and forced expiratory volume in 1 s (FEV1)/forced vital capacity was significantly lower (P < 0.05) for subjects with ventilation defects with a response to DI/salbutamol than subjects with ventilation defects without a response to DI/salbutamol and subjects without ventilation defects. In a step-wise, forward multivariate model, FEV1, inspiratory capacity, and airway resistance significantly predicted VDP (R(2) = 0.45, P < 0.001). In conclusion, most never-smokers had normal spirometry and peripheral ventilation defects not reversed by DI/salbutamol; such ventilation defects were likely related to irreversible airway narrowing/collapse but not to dyspnea and decreased exercise capacity.

Hyperpolarized 3He and 129Xe MRI: Differences in asthma before bronchodilation

To compare hyperpolarized helium-3 ((3) He) and xenon-129 ((129) Xe) MRI in asthmatics before and after salbutamol inhalation. Seven asthmatics provided written informed consent and underwent spirometry, plethysmography, and MRI before and after salbutamol inhalation. (3) He and (129) Xe ventilation defect percent (VDP) and ventilation coefficient of variation (COV) were measured. To characterize the airways spatially related to ventilation defects, wall area percent (WA%) and lumen area (LA) were evaluated for two subjects who had thoracic x-ray computed tomography (CT) acquired 1 year before MRI. Before salbutamol inhalation, (129) Xe VDP (8 ± 5%) was significantly greater than (3) He VDP (6 ± 5%, P = 0.003). Post-salbutamol, there was a significant improvement in both (129) Xe (5 ± 4%, P < 0.0001) and (3) He (4 ± 3%, P = 0.001) VDP, and the improvement in (129) Xe VDP was significantly greater (P = 0.008). (129) Xe MRI COV (Pre: 0.309 ± 0.028, Post: 0.296 ± 0.036) was significantly greater than (3) He MRI COV (Pre: 0.282 ± 0.018, Post: 0.269 ± 0.024), pre- (P < 0.0001) and post-salbutamol (P < 0.0001) and the decrease in COV post-salbutamol was significant ((129) Xe, P = 0.002; (3) He, P < 0.0001). For a single asthmatic, a sub-segmental (129) Xe MRI ventilation defect that was visible only before salbutamol inhalation but not visible using (3) He MRI was spatially related to a remodeled fourth generation sub-segmental airway (WA% = 78%, LA = 2.9 mm(2) ). In asthma, hyperpolarized (129) Xe MRI may help reveal ventilation abnormalities before bronchodilation that are not observed using hyperpolarized (3) He MRI.