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Purpose: Our objective was to train machine-learning algorithms on hyperpolarized He 3 magnetic resonance imaging (MRI) datasets to generate models of accelerated lung function decline in participants with and without chronic-obstructive-pulmonary-disease. We hypothesized that hyperpolarized gas MRI ventilation, machine-learning, and multivariate modeling could be combined to predict clinically-relevant changes in forced expiratory volume in 1 s ( FEV 1 ) across 3 years., Approach: Hyperpolarized He 3 MRI was acquired using a coronal Cartesian fast gradient recalled echo sequence with a partial echo and segmented using a k-means clustering algorithm. A maximum entropy mask was used to generate a region-of-interest for texture feature extraction using a custom-developed algorithm and the PyRadiomics platform. The principal component and Boruta analyses were used for feature selection. Ensemble-based and single machine-learning classifiers were evaluated using area-under-the-receiver-operator-curve and sensitivity-specificity analysis., Results: We evaluated 88 ex-smoker participants with 31 ± 7 months follow-up data, 57 of whom (22 females/35 males, 70 ± 9 years) had negligible changes in FEV 1 and 31 participants (7 females/24 males, 68 ± 9 years) with worsening FEV 1 ≥ 60    mL / year . In addition, 3/88 ex-smokers reported a change in smoking status. We generated machine-learning models to predict FEV 1 decline using demographics, spirometry, and texture features, with the later yielding the highest classification accuracy of 81%. The combined model (trained on all available measurements) achieved the overall best classification accuracy of 82%; however, it was not significantly different from the model trained on MRI texture features alone., Conclusion: For the first time, we have employed hyperpolarized He 3 MRI ventilation texture features and machine-learning to identify ex-smokers with accelerated decline in FEV 1 with 82% accuracy., (© 2024 The Authors.)

Rationale and Objectives: Ex-smokers without spirometry or CT evidence of chronic obstructive pulmonary disease (COPD) but with mildly abnormal diffusing capacity of the lungs for carbon monoxide (DL CO ) are at higher risk of developing COPD. It remains difficult to make clinical management decisions for such ex-smokers without other objective assessments consistent with COPD. Hence, our objective was to develop a machine-learning and CT texture-analysis pipeline to dichotomize ex-smokers with normal and abnormal DL CO (DL CO ≥75% pred and DL CO <75% pred )., Materials and Methods: In this retrospective study, 71 ex-smokers (50-85yrs) without COPD underwent spirometry, plethysmography, thoracic CT, and 3 He MRI to generate ventilation defect percent (VDP) and apparent diffusion coefficients (ADC). PyRadiomics was utilized to extract 496 CT texture-features; Boruta and principal component analysis were used for feature selection and various models were investigated for classification. Machine-learning classifiers were evaluated using area under the receiver operator characteristic curve (AUC), sensitivity, specificity, and F1-measure., Results: Of 71 ex-smokers without COPD, 29 with mildly abnormal DL CO had significantly different MRI ADC (p < .001), residual-volume to total-lung-capacity ratio (p = .003), St. George's Respiratory Questionnaire (p = .029), and six-minute-walk distance (6MWD) (p < .001), but similar relative area of the lung < -950 Hounsfield-units (RA 950 ) (p = .9) compared to 42 ex-smokers with normal DL CO . Logistic-regression machine-learning mixed-model trained on selected texture-features achieved the best classification accuracy of 87%. All clinical and imaging measurements were outperformed by high-high-pass filter high-gray-level-run-emphasis texture-feature (AUC=0.81), which correlated with DL CO (ρ = -0.29, p = .02), MRI ADC (ρ = 0.23, p = .048), and 6MWD (ρ = -0.25, p = .02)., Conclusion: In ex-smokers with no CT evidence of emphysema, machine-learning models exclusively trained on CT texture-features accurately classified ex-smokers with abnormal diffusing capacity, outperforming conventional quantitative CT measurements., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Grace Parraga reports a relationship with Natural Sciences and Engineering Research Council of Canada that includes: funding grants. Grace Parraga reports a relationship with Canadian Institutes of Health Research that includes: funding grants. Maksym Sharma reports a relationship with Natural Sciences and Engineering Research Council of Canada that includes: funding grants. Miranda Kirby reports a relationship with Natural Sciences and Engineering Research Council of Canada that includes: funding grants., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Pulmonary imaging measurements using magnetic resonance imaging (MRI) and computed tomography (CT) have the potential to deepen our understanding of chronic obstructive pulmonary disease (COPD) by measuring airway and parenchymal pathologic information that cannot be provided by spirometry. Currently, MRI and CT measurements are not included in mortality risk predictions, diagnosis, or COPD staging. We evaluated baseline pulmonary function, MRI and CT measurements alongside imaging texture-features to predict 10-year all-cause mortality in ex-smokers with ( n  = 93; 31 females; 70 ± 9years) and without ( n  = 69; 29 females, 69 ± 9years) COPD. CT airway and vessel measurements, helium-3 ( 3 He) MRI ventilation defect percent (VDP) and apparent diffusion coefficients (ADC) were quantified. MRI and CT texture-features were extracted using PyRadiomics (version2.2.0). Associations between 10-year all-cause mortality and all clinical and imaging measurements were evaluated using multivariable regression model odds-ratios. Machine-learning predictive models for 10-year all-cause mortality were evaluated using area-under-receiver-operator-characteristic-curve (AUC), sensitivity and specificity analyses. DL CO (% pred ) (HR = 0.955, 95%CI: 0.934-0.976, p  < 0.001), MRI ADC (HR = 1.843, 95%CI: 1.260-2.871, p  < 0.001), and CT informational-measure-of-correlation (HR = 3.546, 95% CI: 1.660-7.573, p  = 0.001) were the strongest predictors of 10-year mortality. A machine-learning model trained on clinical, imaging, and imaging textures was the best predictive model (AUC = 0.82, sensitivity = 83%, specificity = 84%) and outperformed the solely clinical model (AUC = 0.76, sensitivity = 77%, specificity = 79%). In ex-smokers, regardless of COPD status, addition of CT and MR imaging texture measurements to clinical models provided unique prognostic information of mortality risk that can allow for better clinical management. Clinical Trial Registration: www.clinicaltrials.gov NCT02279329.

Computed tomography (CT) total-airway-count (TAC) and airway wall-thickness differ across chronic obstructive pulmonary disease (COPD) severities, but longitudinal insights are lacking. The aim of this study was to evaluate longitudinal CT airway measurements over three-years in ex-smokers. In this prospective convenience sample study, ex-smokers with ( n  = 50; 13 female; age = 70 ± 9 years; pack-years = 43 ± 26) and without ( n  = 40; 17 female; age = 69 ± 10 years; pack-years = 31 ± 17) COPD completed CT, 3 He magnetic resonance imaging (MRI), and pulmonary function tests at baseline and three-year follow-up. CT TAC, airway wall-area (WA), lumen-area (LA), and wall-area percent (WA%) were generated. Emphysema was quantified as the relative-area-of-the-lung with attenuation < -950 Hounsfield-units (RA 950 ). MRI ventilation-defect-percent (VDP) was also quantified. Differences over time were evaluated using paired-samples t tests. Multivariable prediction models using the backwards approach were generated. After three-years, forced-expiratory-volume in 1-second (FEV 1 ) was not different in ex-smokers with ( p  = 0.4) and without ( p  = 0.5) COPD, whereas RA 950 was ( p  < 0.001, p  = 0.02, respectively). In ex-smokers without COPD, there was no change in TAC ( p  = 0.2); however, LA ( p  = 0.009) and WA% ( p  = 0.01) were significantly different. In ex-smokers with COPD, TAC ( p  < 0.001), WA ( p  = 0.04), LA ( p  < 0.001), and WA% ( p  < 0.001) were significantly different. In all ex-smokers, TAC was related to VDP (baseline: ρ = -0.30, p  = 0.005; follow-up: ρ = -0.33, p  = 0.002). In significant multivariable models, baseline airway wall-thickness was predictive of TAC worsening. After three-years, in the absence of FEV 1 worsening, TAC diminished only in ex-smokers with COPD and airway walls were thinner in all ex-smokers. These longitudinal findings suggest that the evaluation of CT airway remodeling may be a useful clinical tool for predicting disease progression and managing COPD. Clinical trial registration: www.clinicaltrials.gov NCT02279329.

Multi-b diffusion-weighted hyperpolarized gas MRI measures pulmonary airspace enlargement using apparent diffusion coefficients (ADC) and mean linear intercepts ( L m ). Rapid single-breath acquisitions may facilitate clinical translation, and, hence, we aimed to develop single-breath three-dimensional multi-b diffusion-weighted 129 Xe MRI using k-space undersampling. We evaluated multi-b (0, 12, 20, 30 s/cm 2 ) diffusion-weighted 129 Xe ADC/morphometry estimates using a fully sampled and retrospectively undersampled k-space with two acceleration-factors (AF = 2 and 3) in never-smokers and ex-smokers with chronic obstructive pulmonary disease (COPD) or alpha-one anti-trypsin deficiency (AATD). For the three sampling cases, mean ADC/ L m values were not significantly different (all p > 0.5); ADC/ L m values were significantly different for the COPD subgroup (0.08 cm 2 s -1 /580 µm, AF = 3; all p < 0.001) as compared to never-smokers (0.05 cm 2 s -1 /300 µm, AF = 3). For never-smokers, mean differences of 7%/7% and 10%/7% were observed between fully sampled and retrospectively undersampled (AF = 2/AF = 3) ADC and L m values, respectively. For the COPD subgroup, mean differences of 3%/4% and 11%/10% were observed between fully sampled and retrospectively undersampled (AF = 2/AF = 3) ADC and L m , respectively. There was no relationship between acceleration factor with ADC or L m ( p = 0.9); voxel-wise ADC/ L m measured using AF = 2 and AF = 3 were significantly and strongly related to fully-sampled values (all p < 0.0001). Multi-b diffusion-weighted 129 Xe MRI is feasible using two different acceleration methods to measure pulmonary airspace enlargement using L m and ADC in COPD participants and never-smokers.

Background: 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., Purpose: To derive novel data-driven asthma phenotypic clusters using functional MRI airway biomarkers that better describe airway pathologies in patients., Study Type: Retrospective., Population: 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., Field Strength/sequence: Three-dimensional gradient-recalled echo 129 Xe ventilation sequence at 3 T., Assessment: 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., Statistical Tests: 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., Results: 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 (FEV 1 % 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 FEV 1 with moderately abnormal VDP. Cluster2 (n = 12/12 female) reflected moderately abnormal TAC, WT and FEV 1 . In Cluster3 and Cluster4 (n = 14/6 female, n = 4/1 female, respectively), there was severely reduced TAC, D and FEV 1 , but Cluster4 also had significantly worse, severely abnormal VDP (7 ± 5% vs. 41 ± 12%)., Data Conclusion: 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., Evidence Level: 3 TECHNICAL EFFICACY: Stage., (© 2022 International Society for Magnetic Resonance in Medicine.)

Background: Suction and capillary pull are 2 biopsy techniques used in endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). Although these techniques have been shown to perform comparably in terms of overall diagnostic yield, we hypothesized that the capillary pull technique would be associated with improved rapid on-site evaluation (ROSE) adequacy rates thus allowing for a shorter procedure time., Methods: One hundred eighteen patients undergoing EBUS-TBNA for any indication were randomized to suction or capillary pull techniques for the first biopsy pass; the technique used for all subsequent passes was based on operator preference and was not recorded. The first pass was subjected to ROSE and an adequacy assessment was given. ROSE slides were also scored for cellularity of diagnostic/lesional cells and blood contamination. The overall procedure time was also recorded., Results: There were no significant differences between suction and capillary pull techniques in terms of ROSE adequacy rates. Cellularity of diagnostic/lesional cells and blood contamination scores were also comparable. There was no significant difference in procedure time for the 2 techniques., Conclusion: This study suggests no differences in ROSE outcomes between suction and capillary pull techniques in EBUS-TBNA. The technique used should therefore be left to the discretion of the operator., Competing Interests: Disclosure: There is no conflict of interest or other disclosures., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Patient-specific localisation of ventilation defects using hyperpolarised gas magnetic resonance imaging (MRI) introduces the possibility of regionally targeted bronchial thermoplasty (BT) for the treatment of severe asthma. We aimed to demonstrate that BT guided by MRI to ventilation defects reduces the number of radiofrequency activations while resulting in improved asthma quality-of-life and control scores that are non-inferior to standard BT. In a 1-year pilot randomised controlled trial, 14 patients with severe asthma who were clinically eligible to receive BT underwent hyperpolarised gas MRI to characterise ventilation defects and were randomised to MRI-guided or standard BT. End-points were improved Asthma Quality of Life Questionnaire (AQLQ) and Asthma Control Questionnaire (ACQ) scores, the proportion of AQLQ and ACQ responders and the number of radiofrequency activations and bronchoscopy sessions. Participants who underwent MRI-guided BT received 53% fewer radiofrequency activations than those who had standard BT (p=0.003). At 12 months, the mean improvement from baseline was similar between the MRI-guided group (n=5) and the standard group (n=7) for AQLQ score (MRI-guided: 1.8, 95% CI 0.1-3.5, p=0.04; standard: 0.7, 95% CI -0.9-2.3, p=0.30) (p=0.25) and ACQ-5 score (MRI-guided: -1.4, 95% CI -2.6- -0.2, p=0.03; standard: -0.7, 95% CI -1.3-0.0, p=0.04) (p=0.17). A similar proportion of participants in both groups achieved a clinically relevant improvement in AQLQ score (MRI-guided: 80%; standard: 71%) and ACQ-5 score (MRI-guided: 80%; standard: 57%). Hyperpolarised gas MRI-guided BT reduced the number of radiofrequency activations, and resulted in asthma quality of life and control improvements at 12 months that were non-inferior to standard BT., Competing Interests: Conflict of interest: S. Svenningsen reports personal fees from AstraZeneca and Novartis, grants from Cyclomedica and personal fees from Polarean, outside the submitted work. Conflict of interest: P. Nair reports grants and personal fees from AstraZeneca, grants from Novartis, grants and personal fees from Teva, grants from Sanofi, grants and personal fees from Roche, personal fees from Novartis, Merck and Equillium, and grants from Foresee, outside the submitted work. Conflict of interest: R.L Eddy has nothing to disclose. Conflict of interest: M.J. McIntosh has nothing to disclose. Conflict of interest: M. Kjarsgaard has nothing to disclose. Conflict of interest: H.F. Lim has nothing to disclose. Conflict of interest: D.G. McCormack has nothing to disclose. Conflict of interest: G. Cox has nothing to disclose. Conflict of interest: G. Parraga reports grants from Astra Zeneca and Novartis, outside the submitted work., (Copyright ©The authors 2021.)

Ultra-short echo-time (UTE) magnetic resonance imaging (MRI) provides enhanced visualization of pulmonary structural and functional abnormalities and has shown promise in phenotyping lung disease. Here, we describe the development and evaluation of a lung segmentation approach to facilitate UTE MRI methods for patient-based imaging. The proposed approach employs a k-means algorithm in kernel space for pair-wise feature clustering and imposes image domain continuous regularization, coined as continuous kernel k-means (CKKM). The high-order CKKM algorithm was simplified through upper bound relaxation and solved within an iterative continuous max-flow framework. We combined the CKKM with U-net and atlas-based approaches and comprehensively evaluated the performance on 100 images from 25 patients with asthma and bronchial pulmonary dysplasia enrolled at Robarts Research Institute (Western University, London, Canada) and Centre Hospitalier Universitaire (Sainte-Justine, Montreal, Canada). For U-net, we trained the network five times on a mixture of five different images with under-annotations and applied the model to 64 images from the two centres. We also trained a U-net on five images with full and brush annotations from one centre, and tested the model on 32 images from the other centre. For an atlas-based approach, we employed three atlas images to segment 64 target images from the two centres through straightforward atlas registration and label fusion. We applied the CKKM algorithm to the baseline U-net and atlas outputs and refined the initial segmentation through multi-volume image fusion. The integration of CKKM substantially improved baseline results and yielded, with minimal computational cost, segmentation accuracy, and precision that were greater than some state-of-the-art deep learning models and similar to experienced observer manual segmentation. This suggests that deep learning and atlas-based approaches may be utilized to segment UTE MRI datasets using relatively small training datasets with under-annotations., Competing Interests: Declaration of Competing Interest No conflicts of interest, financial or otherwise, are declared by F Guo, D Capaldi, DG McCormack, A Fenster, and G Parraga., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Rationale and Objectives: 129 Xe 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 129 Xe ventilation MRI measurements in severe asthmatics at two sites., Materials and Methods: In seven adults with severe asthma, 129 Xe ventilation MRI was acquired pre- and post-bronchodilator at two geographic sites within 24-hours. 129 Xe 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 129 Xe VDP reproducibility and agreement., Results: Whole-lung and slice-by-slice 129 Xe 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 129 Xe-dose-equivalent-volume (101 ± 15 mL site 1, 49 ± 6 mL site 2, p < 0.0001), gas-mixture ( 129 Xe/ 4 He site 1; 129 Xe/N 2 site 2) and SNR (40 ± 19 site 1, 23 ± 5 site 2, p = 0.02). Qualitative 129 Xe gas distribution differences were observed between sites and slice-by-slice 129 Xe VDP, but not whole-lung 129 Xe 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)., Conclusion: 129 Xe MRI VDP at two different sites measured within 24-hours in the same severe asthmatics were correlated. Qualitative and quantitative intersite differences in 129 Xe regional gas distribution and VDP point to site-specific variability that may be due to differences in gas-mixture composition or SNR., (Copyright © 2020 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Rationale and Objectives: The relationships between computed tomography (CT) pulmonary vascularity and MRI ventilation is not well-understood in chronic obstructive pulmonary disease (COPD) patients. Our objective was to evaluate CT pulmonary vascular and MRI ventilation measurements in ex-smokers and to investigate their associations and how such measurements change over time., Materials and Methods: Ninety ex-smokers (n = 41 without COPD 71 ± 10 years and n = 49 COPD 71 ± 8 years) provided written informed-consent to an ethics-board approved protocol and underwent imaging and pulmonary-function-tests twice, 31 ± 7 months apart. 3 He MRI was acquired to generate ventilation-defect-percent (VDP). CT measurements of the relative area-of-the-lung with attenuation <-950 Hounsfield units (RA 950 ), pulmonary vascular total-blood-volume (TBV) and percent of vessels with radius < one voxel (PV 1 ) were evaluated., Results: At baseline, there were significant differences in RA 950 (p = 0.0001), VDP (p = 0.0001), total-blood-volume (p = 0.0001) and PV 1 (p = 0.01) between ex-smokers and COPD participants as well as for VDP (p = 0.0001) in COPD participants with and without emphysema. The annual FEV 1 change (-40 ± 93 mL/year) was not different among participant subgroups (p = 0.87), but the annual RA 950 (p = 0.01) and PV 1 (p = 0.007) changes were significantly different in participants with an accelerated annual FEV 1 decline as compared to participants with a diminished annual FEV 1 decline. There were significant but weak relationships for PV 1 with FEV 1%pred (p = 0.02), FEV 1 /FVC (p = 0.001), and log RA 950 (p = 0.0001), but not VDP (p=0.20). The mean change in PV 1 was also weakly but significantly related to the change in RA 950 (p = 0.02)., Conclusion: CT pulmonary vascular measurements were significantly different in ex-smokers and participants with COPD and related to RA 950 but not VDP worsening over 2.5 years., (Copyright © 2020 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Purpose: Multi-b diffusion-weighted hyperpolarized inhaled-gas MRI provides imaging biomarkers of terminal airspace enlargement including ADC and mean linear intercept (L m ), but clinical translation has been limited because image acquisition requires relatively long or multiple breath-holds that are not well-tolerated by patients. Therefore, we aimed to accelerate single breath-hold 3D multi-b diffusion-weighted 129 Xe MRI, using k-space undersampling in imaging direction using a different undersampling pattern for different b-values combined with the stretched exponential model to generate maps of ventilation, apparent transverse relaxation time constant ( T 2 ∗ ), ADC, and L m values in a single, short breath-hold; accelerated and non-accelerated measurements were directly compared., Methods: We evaluated multi-b (0, 12, 20, 30, and 45.5 s/cm 2 ) diffusion-weighted 129 Xe T 2 ∗ /ADC/morphometry estimates using acceleration factor (AF = 1 and 7) and multi-breath sampling in 3 volunteers (HV), and 6 participants with alpha-1 antitrypsin deficiency (AATD)., Results: For the HV subgroup, mean differences of 5%, 2%, and 8% were observed between fully sampled and undersampled k-space for ADC, L m , and T 2 ∗ values, respectively. For the AATD subgroup, mean differences were 9%, 6%, and 12% between fully sampled and undersampled k-space for ADC, L m and T 2 ∗ values, respectively. Although mean differences of 1% and 4.5% were observed between accelerated and multi-breath sampled ADC and L m values, respectively, mean ADC/L m estimates were not significantly different from corresponding mean ADC M /L m M or mean ADC A /L m A estimates (all P > 0.60 , A = undersampled and M = multi-breath sampled)., Conclusions: Accelerated multi-b diffusion-weighted 129 Xe MRI is feasible at AF = 7 for generating pulmonary ADC and L m in AATD and normal lung., (© 2019 International Society for Magnetic Resonance in Medicine.)

Rationale: In patients with asthma, X-ray computed tomography (CT) has provided evidence of thickened airway walls and airway occlusions, but the total number of CT-visible airways and its relationship with disease severity is unknown. Objectives: To measure CT total airway count (TAC) in asthma and evaluate relationships with asthma severity, airway morphology, pulmonary function, and magnetic resonance imaging (MRI) ventilation. Methods: Participants underwent post-bronchodilator inspiratory CT, and prebronchodilator and post-bronchodilator spirometry and hyperpolarized 3 He MRI. CT TAC was quantified as the sum of airways in the segmented airway tree, and airway wall area percent (WA%) and lumen area were measured. MRI ventilation abnormalities were quantified as the ventilation defect percent. Measurements and Main Results: We evaluated 70 participants, including 15 Global Initiative for Asthma (GINA) steps 1 to 3, 19 GINA 4, and 36 GINA 5 participants with asthma. As compared with GINA 1 to 3, TAC was significantly diminished in GINA 4 ( P  = 0.03) and GINA 5 ( P  = 0.045). Terminal airway intraluminal occlusion was present in 5 (2 GINA 4 and 3 GINA 5) of 70 participants. Sub-subsegmental airways were CT-invisible or missing in 69 out of 70 participants; the most common number of missing sub-subsegments was 10. Participants with ≥10 missing subsegments had worse WA% ( P  < 0.0001), lumen area ( P  < 0.0001), and ventilation defect percent ( P  = 0.03) than those with <10 missing subsegments. In a multivariable model, TAC (standardized regression coefficient = 0.50; P  = 0.001) independently predicted FEV 1 ( R 2  = 0.27; P  = 0.003) and, in a separate model, TAC (standardized regression coefficient = -0.53; P  < 0.0001) independently predicted airway WA% ( R 2  = 0.32; P  = 0.0001). Conclusions: TAC was significantly diminished in participants with greater asthma severity and was related to airway wall thickness and ventilation defects. Fewer airways in severe than in mild asthma challenges our understanding of airway disease in asthma.Clinical trial registered with www.clinicaltrials.gov (NCT02351141).

Background Pulmonary imaging of chronic obstructive pulmonary disease (COPD) has focused on CT or MRI measurements, but these have not been evaluated in combination. Purpose To generate multiparametric response map (mPRM) measurements in ex-smokers with or without COPD by using volume-matched CT and hyperpolarized helium 3 ( 3 He) MRI. Materials and Methods In this prospective study ( https://clinicaltrials.gov , NCT02279329), participants underwent MRI and CT and completed pulmonary function tests, questionnaires, and the 6-minute walk test between December 2010 and January 2019. Disease status was determined by using Global initiative for chronic Obstructive Lung Disease (GOLD) criteria. The mPRM voxel values were generated by using co-registered MRI and CT labels. Kruskal-Wallis and Bonferroni tests were used to determine differences across disease severity, and correlations were determined by using Spearman coefficients. Results A total of 175 ex-smokers (mean age, 69 years ± 9 [standard deviation], 108 men) with or without COPD were evaluated. Ex-smokers without COPD had a larger fraction of normal mPRM voxels (60% vs 37%, 20%, and 7% for GOLD I, II, and III/IV disease, respectively; all P ≤ .001) and a smaller fraction of abnormal voxels, including small airways disease (normal CT, not ventilated: 5% vs 6% [not significant], 11%, and 19% [ P ≤ .001 for both] for GOLD I, II, and III/IV disease, respectively) and mild emphysema (normal CT, abnormal apparent diffusion coefficient [ADC]: 33% vs 54%, 56%, and 54% for GOLD I, II, and III/IV disease respectively; all P ≤ .001). Normal mPRM measurements were positively correlated with forced expiratory volume in 1 second (FEV 1 ) ( r = 0.65, P < .001), the FEV 1 -to-forced vital capacity ratio ( r = 0.81, P < .001), and diffusing capacity ( r = 0.75, P < .001) and were negatively correlated with worse quality of life ( r = -0.48, P < .001). Abnormal mPRM measurements of small airways disease (normal CT, not ventilated) and mild emphysema (normal CT, abnormal ADC) were negatively correlated with FEV 1 ( r = -0.65 and -0.42, respectively; P < .001) and diffusing capacity ( r = -0.53 and -0.60, respectively; P < .001) and were positively correlated with worse quality of life ( r = 0.45 and r = 0.33, respectively; P < .001), both of which were present in ex-smokers without COPD. Conclusion Multiparametric response maps revealed two abnormal structure-function results related to emphysema and small airways disease, both of which were unexpectedly present in ex-smokers with normal spirometry and CT findings. © RSNA, 2020 Online supplemental material is available for this article.

Background Fixed airflow limitation and ventilation heterogeneity are common in chronic obstructive pulmonary disease (COPD). Conventional noncontrast CT provides airway and parenchymal measurements but cannot be used to directly determine lung function. Purpose To develop, train, and test a CT texture analysis and machine-learning algorithm to predict lung ventilation heterogeneity in participants with COPD. Materials and Methods In this prospective study ( ClinicalTrials.gov : NCT02723474; conducted from January 2010 to February 2017), participants were randomized to optimization ( n = 1), training ( n = 67), and testing ( n = 27) data sets. Hyperpolarized (HP) helium 3 ( 3 He) MRI ventilation maps were co-registered with thoracic CT to provide ground truth labels, and 87 quantitative imaging features were extracted and normalized to lung averages to generate 174 features. The volume-of-interest dimension and the training data sampling method were optimized to maximize the area under the receiver operating characteristic curve (AUC). Forward feature selection was performed to reduce the number of features; logistic regression, linear support vector machine, and quadratic support vector machine classifiers were trained through fivefold cross validation. The highest-performing classification model was applied to the test data set. Pearson coefficients were used to determine the relationships between the model, MRI, and pulmonary function measurements. Results The quadratic support vector machine performed best in training and was applied to the test data set. Model-predicted ventilation maps had an accuracy of 88% (95% confidence interval [CI]: 88%, 88%) and an AUC of 0.82 (95% CI: 0.82, 0.83) when the HP 3 He MRI ventilation maps were used as the reference standard. Model-predicted ventilation defect percentage (VDP) was correlated with VDP at HP 3 He MRI ( r = 0.90, P < .001). Both model-predicted and HP 3 He MRI VDP were correlated with forced expiratory volume in 1 second (FEV 1 ) (model: r = -0.65, P < .001; MRI: r = -0.70, P < .001), ratio of FEV 1 to forced vital capacity (model: r = -0.73, P < .001; MRI: r = -0.75, P < .001), diffusing capacity (model: r = -0.69, P < .001; MRI: r = -0.65, P < .001), and quality-of-life score (model: r = 0.59, P = .001; MRI: r = 0.65, P < .001). Conclusion Model-predicted ventilation maps generated by using CT textures and machine learning were correlated with MRI ventilation maps ( r = 0.90, P < .001). © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Fain in this issue.

Recent pulmonary functional MRI findings of spatially and temporally persistent ventilation abnormalities in patients with asthma contrast with previous in silico modeling studies that suggest that in asthma, ventilation defects may be randomly distributed. In a case study that used pulmonary MRI, CT imaging, and pulmonary function tests, we prospectively evaluated over the course of 7 years, nonidentical female adult twins, each with a lifelong history of asthma. We evaluated pulmonary function and MRI ventilation heterogeneity at baseline and follow-up after 7 years. In both twins, there was a spatially identical MRI ventilation defect and an abnormal subsegmental left-sided upper lobe airway that persisted in the same spatial location after 7 years. If ventilation defects are randomly distributed, this bears a probability of approximately one per 130,000 people. Our MRI observations in related patients with asthma suggest that ventilation abnormalities may not be randomly distributed in patients with asthma and persist distal to airway abnormalities for long periods of time., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

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 ( 3 He) 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 (FEV 1 ) reversibility Materials and Methods Spirometry and hyperpolarized 3 He 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). FEV 1 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 FEV 1 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 FEV 1 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, FEV 1 (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 FEV 1 was not reversible in six of 11 participants; the concentration of methacholine to decrease FEV 1 by 20% (PC 20 ) was greater in FEV 1 -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 PC 20 , age, and FEV 1 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.

There are serious clinical gaps in our understanding of chronic lung disease that require novel, sensitive, and noninvasive in vivo measurements of the lung parenchyma to measure disease pathogenesis and progressive changes over time as well as response to treatment. Until recently, our knowledge and appreciation of the tissue changes that accompany lung disease has depended on ex vivo biopsy and concomitant histological and stereological measurements. These measurements have revealed the underlying pathologies that drive lung disease and have provided important observations about airway occlusion, obliteration of the terminal bronchioles and airspace enlargement, or fibrosis and their roles in disease initiation and progression. ex vivo tissue stereology and histology are the established gold standards and, more recently, micro-computed tomography (CT) measurements of ex vivo tissue samples has also been employed to reveal new mechanistic findings about the progression of obstructive lung disease in patients. While these approaches have provided important understandings using ex vivo analysis of excised samples, recently developed hyperpolarized noble gas MRI methods provide an opportunity to noninvasively measure acinar duct and terminal airway dimensions and geometry in vivo, and, without radiation burden. Therefore, in this review we summarize emerging pulmonary MRI morphometry methods that provide noninvasive in vivo measurements of the lung in patients with bronchopulmonary dysplasia and chronic obstructive pulmonary disease, among others. We discuss new findings, future research directions, as well as clinical opportunities to address current gaps in patient care and for testing of new therapies. Level of Evidence: 5 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2019;50:28-40., (© 2019 International Society for Magnetic Resonance in Medicine.)

Purpose: To develop a rapid Fourier decomposition (FD) free-breathing pulmonary 1 H MRI (FDMRI) image processing and biomarker pipeline for research use., Methods: We acquired MRI in 20 asthmatic subjects using a balanced steady-state free precession (bSSFP) sequence optimized for ventilation imaging. 2D 1 H MRI series were segmented by enforcing the spatial similarity between adjacent images and the right-to-left lung volume-ratio. The segmented lung series were co-registered using a coarse-to-fine deformable registration framework that used dual optimization techniques. All pairwise registrations were implemented in parallel and FD was performed to generate 2D ventilation-weighted maps and ventilation-defect-percent (VDP). Lung segmentation and registration accuracy were evaluated by comparing algorithm and manual lung-masks, deformed manual lung-masks, and fiducials in the moving and fixed images using Dice-similarity-coefficient (DSC), mean-absolute-distance (MAD), and target-registration-error (TRE). The relationship of FD-VDP and 3 He-VDP was evaluated using the Pearson-correlation-coefficient (r) and Bland Altman analysis. Algorithm reproducibility was evaluated using the coefficient-of-variation (CoV) and intra-class-correlation-coefficient (ICC) for segmentation, registration, and FD-VDP components., Results: For lung segmentation, there was a DSC of 95 ± 1.5% and MAD of 2.3 ± 0.5 mm, and for registration there was a DSC of 97 ± 0.8%, MAD of 1.6 ± 0.4 mm and TRE of 3.6 ± 1.2 mm. Reproducibility for segmentation DSC (CoV/ICC = 0.5%/0.92), registration TRE (CoV/ICC = 0.4%/0.98), and FD-VDP (Cov/ICC = 3.9%/0.97) was high. The pipeline required 10 min/subject. FD-VDP was correlated with 3 He-VDP (r = 0.69, P < 0.001) although there was a bias toward lower FD-VDP (bias = -4.9%)., Conclusions: We developed and evaluated a pipeline that provides a rapid and precise method for FDMRI ventilation maps., (© 2018 International Society for Magnetic Resonance in Medicine.)

Purpose To measure regional specific ventilation with free-breathing hydrogen 1 ( 1 H) magnetic resonance (MR) imaging without exogenous contrast material and to investigate correlations with hyperpolarized helium 3 ( 3 He) MR imaging and pulmonary function test measurements in healthy volunteers and patients with asthma. Materials and Methods Subjects underwent free-breathing 1 H and static breath-hold hyperpolarized 3 He MR imaging as well as spirometry and plethysmography; participants were consecutively recruited between January and June 2017. Free-breathing 1 H MR imaging was performed with an optimized balanced steady-state free-precession sequence; images were retrospectively grouped into tidal inspiration or tidal expiration volumes with exponentially weighted phase interpolation. MR imaging volumes were coregistered by using optical flow deformable registration to generate 1 H MR imaging-derived specific ventilation maps. Hyperpolarized 3 He MR imaging- and 1 H MR imaging-derived specific ventilation maps were coregistered to quantify regional specific ventilation within hyperpolarized 3 He MR imaging ventilation masks. Differences between groups were determined with the Mann-Whitney test and relationships were determined with Spearman (ρ) correlation coefficients. Statistical analyses were performed with software. Results Thirty subjects (median age: 50 years; interquartile range [IQR]: 30 years), including 23 with asthma and seven healthy volunteers, were evaluated. Both 1 H MR imaging-derived specific ventilation and hyperpolarized 3 He MR imaging-derived ventilation percentage were significantly greater in healthy volunteers than in patients with asthma (specific ventilation: 0.14 [IQR: 0.05] vs 0.08 [IQR: 0.06], respectively, P < .0001; ventilation percentage: 99% [IQR: 1%] vs 94% [IQR: 5%], P < .0001). For all subjects, 1 H MR imaging-derived specific ventilation correlated with plethysmography-derived specific ventilation (ρ = 0.54, P = .002) and hyperpolarized 3 He MR imaging-derived ventilation percentage (ρ = 0.67, P < .0001) as well as with forced expiratory volume in 1 second (FEV 1 ) (ρ = 0.65, P = .0001), ratio of FEV 1 to forced vital capacity (ρ = 0.75, P < .0001), ratio of residual volume to total lung capacity (ρ = -0.68, P < .0001), and airway resistance (ρ = -0.51, P = .004). 1 H MR imaging-derived specific ventilation was significantly greater in the gravitational-dependent versus nondependent lung in healthy subjects (P = .02) but not in patients with asthma (P = .1). In patients with asthma, coregistered 1 H MR imaging specific ventilation and hyperpolarized 3 He MR imaging maps showed that specific ventilation was diminished in corresponding 3 He MR imaging ventilation defects (0.05 ± 0.04) compared with well-ventilated regions (0.09 ± 0.05) (P < .0001). Conclusion 1 H MR imaging-derived specific ventilation correlated with plethysmography-derived specific ventilation and ventilation defects seen by using hyperpolarized 3 He MR imaging. © RSNA, 2018 Online supplemental material is available for this article.

We designed and generated pulmonary imaging biomarker pipelines to facilitate high-throughput research and point-of-care use in patients with chronic lung disease. Image processing modules and algorithm pipelines were embedded within a graphical user interface (based on the .NET framework) for pulmonary magnetic resonance imaging (MRI) and x-ray computed-tomography (CT) datasets. The software pipelines were generated using C++ and included: (1) inhaled He 3 / Xe 129   MRI ventilation and apparent diffusion coefficients, (2) CT-MRI coregistration for lobar and segmental ventilation and perfusion measurements, (3) ultrashort echo-time H 1   MRI proton density measurements, (4) free-breathing Fourier-decomposition H 1   MRI ventilation/perfusion and free-breathing H 1   MRI specific ventilation, (5) multivolume CT and MRI parametric response maps, and (6) MRI and CT texture analysis and radiomics. The image analysis framework was implemented on a desktop workstation/tablet to generate biomarkers of regional lung structure and function related to ventilation, perfusion, lung tissue texture, and integrity as well as multiparametric measures of gas trapping and airspace enlargement. All biomarkers were generated within 10 min with measurement reproducibility consistent with clinical and research requirements. The resultant pulmonary imaging biomarker pipeline provides real-time and automated lung imaging measurements for point-of-care and high-throughput research.

Rationale and Objectives: In patients with severe emphysema and poor quality of life, bronchoscopic lung volume reduction (BLVR) may be considered and guided based on lobar emphysema severity. In particular, x-ray computed tomography (CT) emphysema measurements are used to identify the most diseased and the second-most diseased lobes as BLVR targets. Inhaled gas magnetic resonance imaging (MRI) also provides chronic obstructive pulmonary disease (COPD) biomarkers of lobar emphysema and ventilation abnormalities. Our objective was to retrospectively evaluate CT and MRI biomarkers of lobar emphysema and ventilation in patients with COPD eligible for BLVR. We hypothesized that MRI would provide complementary biomarkers of emphysema and ventilation that help determine the most appropriate lung lobar targets for BLVR in patients with COPD., Materials and Methods: We retrospectively evaluated 22 BLVR-eligible patients from the Thoracic Imaging Network of Canada cohort (diffusing capacity of the lung for carbon monoxide = 37 ± 12% predicted , forced expiratory volume in 1 second = 34 ± 7% predicted , total lung capacity = 131 ± 17% predicted , and residual volume = 216 ± 36% predicted ). Lobar CT emphysema, measured using a relative area of <-950 Hounsfield units (RA 950 ) and MRI ventilation defect percent, was independently used to rank lung lobe disease severity., Results: In 7 of 22 patients, there were different CT and MRI predictions of the most diseased lobe. In some patients, there were large ventilation defects in lobes not targeted by CT, indicative of a poorly ventilated lung. CT and MRI classification of the most diseased and the second-most diseased lobes showed a fair-to-moderate intermethod reliability (Cohen κ = 0.40-0.59)., Conclusions: In this proof-of-concept retrospective analysis, quantitative MRI ventilation and CT emphysema measurements provided different BLVR targets in over 30% of the patients. The presence of large MRI ventilation defects in lobes next to CT-targeted lobes might also change the decision to proceed or to guide BLVR to a different lobar target., (Copyright © 2018 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Rationale and Objectives: Thoracic x-ray computed tomography (CT) and hyperpolarized 3 He magnetic resonance imaging (MRI) provide quantitative measurements of airspace enlargement in patients with emphysema. For patients with panlobular emphysema due to alpha-1 antitrypsin deficiency (AATD), sensitive biomarkers of disease progression and response to therapy have been difficult to develop and exploit, especially those biomarkers that correlate with outcomes like quality of life. Here, our objective was to generate and compare CT and diffusion-weighted inhaled-gas MRI measurements of emphysema including apparent diffusion coefficient (ADC) and MRI-derived mean linear intercept (L m ) in patients with AATD, chronic obstructive pulmonary disease (COPD) ex-smokers, and elderly never-smokers., Materials and Methods: We enrolled patients with AATD (n = 8; 57 ± 7 years), ex-smokers with COPD (n = 8; 77 ± 6 years), and a control group of never-smokers (n = 5; 64 ± 2 years) who underwent thoracic CT, MRI, spirometry, plethysmography, the St. George's Respiratory Questionnaire, and the 6-minute walk test during a single 2-hour visit. MRI-derived ADC, L m , surface-to-volume ratio, and ventilation defect percent were generated for the apical, basal, and whole lung as was CT lung area ≤-950 Hounsfield units (RA 950 ), low attenuating clusters, and airway count., Results: In patients with AATD, there was a significantly different MRI-derived ADC (P = .03), L m (P < .0001), and surface-to-volume ratio (P < .0001), but not diffusing capacity of carbon monoxide, residual volume or total lung capacity, or CT RA 950 (P > .05) compared to COPD ex-smokers with a significantly different St. George's Respiratory Questionnaire., Conclusions: In this proof-of-concept demonstration, we evaluated CT and MRI lung emphysema measurements and observed significantly worse MRI biomarkers of emphysema in patients with AATD compared to patients with COPD, although CT RA 950 and diffusing capacity of carbon monoxide were not significantly different, underscoring the sensitivity of MRI measurements of AATD emphysema., (Copyright © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Rationale and Objectives: 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 1 H magnetic resonance imaging (FDMRI), and inhaled-gas MRI ventilation defect percent (VDP)., Materials and Methods: 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 (FEV 1 ) >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., Results: Hyperpolarized 3 He (P = .02) and FDMRI (P = .02) VDP significantly improved post-salbutamol and for four asthmatics who could perform MCh (n = 4). 3 He and FDMRI VDP significantly increased at the provocative concentration of MCh, resulting in a 20% decrease in FEV 1 (PC 20 ) and decreased post-bronchodilator (P = .02), with a significant difference between methods (P = .01). FDMRI VDP was moderately correlated with 3 He VDP (ρ = .61, P = .01), but underestimated VDP relative to 3 He VDP (-6 ± 9%). Whereas 3 He MRI VDP was significantly correlated with the lung clearance index, FDMRI was not (ρ = .49, P = .06)., Conclusions: FDMRI VDP generated in free-breathing asthmatic patients was correlated with static inspiratory breath-hold 3 He MRI VDP but underestimated VDP relative to 3 He MRI VDP. Although less sensitive to salbutamol and MCh, FDMRI VDP may be considered for asthma patient evaluations at centers without inhaled-gas MRI., (Copyright © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Rationale and Objectives: Evidence-based treatment and management for patients with bronchiectasis remain challenging. There is a need for regional disease measurements as focal distribution of disease is common. Our objective was to evaluate the ability of magnetic resonance imaging (MRI) to detect regional ventilation impairment and response to airway clearance therapy (ACT) in patients with noncystic fibrosis (CF) bronchiectasis, providing a new way to objectively and regionally evaluate response to therapy., Materials and Methods: Fifteen participants with non-CF bronchiectasis and 15 age-matched healthy volunteers provided written informed consent to an ethics board-approved Health Insurance Portability and Accountability Act-compliant protocol and underwent spirometry, plethysmography, computed tomography (CT), and hyperpolarized 3 He MRI. Bronchiectasis patients also completed a Six-Minute Walk Test, the St. George's Respiratory questionnaire, and Patient Evaluation Questionnaire (PEQ), and returned for a follow-up visit after 3 weeks of daily oscillatory positive expiratory pressure use. CT evidence of bronchiectasis was qualitatively reported by lobe, and MRI ventilation defect percent (VDP) was measured for the entire lung and individual lobes., Results: CT evidence of bronchiectasis and abnormal VDP (14 ± 7%) was observed for all bronchiectasis patients and no healthy volunteers. There was CT evidence of bronchiectasis in all lobes for 3 patients and in 3 ± 1 lobes (range = 1-4) for 12 patients. VDP in lobes with CT evidence of bronchiectasis (19 ± 12%) was significantly higher than in lobes without CT evidence of bronchiectasis (8 ± 5%, P = .001). For patients, VDP in lung lobes with (P < .0001) and without CT evidence of bronchiectasis (P = .006) was higher than in healthy volunteers (3 ± 1%). For all patients, mean PEQ-ease-bringing-up-sputum (P = .048) and PEQ-patient-global-assessment (P = .01) were significantly improved post-oscillatory positive expiratory pressure. An improvement in regional VDP greater than the minimum clinical important difference was observed for 8 of the 14 patients evaluated., Conclusions: There was CT and MRI evidence of structure-function abnormalities in patients with bronchiectasis; in approximately half, there was evidence of ventilation improvements after airway clearance therapy., (Copyright © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Pulmonary ventilation may be visualized and measured using hyperpolarized (3)He magnetic resonance imaging (MRI) while emphysema and its distribution can be quantified using thoracic computed tomography (CT). Our objective was to phenotype ex-smokers with COPD based on the apical-to-basal distribution of ventilation abnormalities and emphysema to better understand how these phenotypes change regionally as COPD progresses. We evaluated 100 COPD ex-smokers who provided written informed consent and underwent spirometry, CT and (3)He MRI. (3)He MRI ventilation imaging was used to quantify the ventilation defect percent (VDP) for whole-lung and individual lung lobes. Regional VDP was used to generate the apical-lung (AL)-to-basal-lung (BL) difference (ΔVDP); a positive ΔVDP indicated AL-predominant and negative ΔVDP indicated BL-predominant ventilation defects. Emphysema was quantified using the relative-area-of-the-lung ≤-950HU (RA950) of the CT density histogram for whole-lung and individual lung lobes. The AL-to-BL RA950 difference (ΔRA950) was generated with a positive ΔRA950 indicating AL-predominant emphysema and a negative ΔRA950 indicating BL-predominant emphysema. Seventy-two ex-smokers reported BL-predominant MRI ventilation defects and 71 reported AL-predominant CT emphysema. BL-predominant ventilation defects (AL/BL: GOLD I = 18%/82%, GOLD II = 24%/76%) and AL-predominant emphysema (AL/BL: GOLD I = 84%/16%, GOLD II = 72%/28%) were the major phenotypes in mild-moderate COPD. In severe COPD there was a more uniform distribution for ventilation defects (AL/BL: GOLD III = 40%/60%, GOLD IV = 43%/57%) and emphysema (AL/BL: GOLD III = 64%/36%, GOLD IV = 43%/57%). Basal-lung ventilation defects predominated in mild-moderate GOLD grades, and a more homogeneous distribution of ventilation defects was observed in more advanced grade COPD; these differences suggest that over time, regional ventilation abnormalities become more homogenously distributed during disease progression.

In asthma patients, magnetic resonance imaging (MRI) and the lung clearance index (LCI) have revealed persistent ventilation heterogeneity, although its relationship to asthma control is not well understood. Therefore, our goal was to explore the relationship of MRI ventilation defects and the LCI with asthma control and quality of life in patients with severe, poorly controlled asthma.18 patients with severe, poorly controlled asthma (mean±sd 46±12 years, six males/12 females) provided written informed consent to an ethics board approved protocol, and underwent spirometry, LCI and (3)He MRI during a single 2-h visit. Asthma control and quality of life were evaluated using the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ). Ventilation heterogeneity was quantified using the LCI and (3)He MRI ventilation defect percent (VDP).All participants reported poorly controlled disease (mean±sd ACQ score=2.3±0.9) and highly heterogeneous ventilation (mean±sd VDP=12±11% and LCI=10.5±3.0). While VDP and LCI were strongly correlated (r=0.86, p<0.0001), in a multivariate model that included forced expiratory volume in 1 s, VDP and LCI, VDP was the only independent predictor of asthma control (R(2)=0.38, p=0.01). There was also a significantly worse VDP, but not LCI in asthma patients with an ACQ score >2 (p=0.04) and AQLQ score <5 (p=0.04), and a trend towards worse VDP (p=0.053), but not LCI in asthma patients reporting ≥1 exacerbation in the past 6 months.In patients with poorly controlled, severe asthma MRI ventilation, but not LCI was significantly worse in those with worse ACQ and AQLQ., (Copyright ©ERS 2016.)

Purpose: To directly compare magnetic resonance (MR) imaging and computed tomography (CT) parametric response map (PRM) measurements of gas trapping and emphysema in ex-smokers both with and without chronic obstructive pulmonary disease (COPD)., Materials and Methods: Participants provided written informed consent to a protocol that was approved by a local research ethics board and Health Canada and was compliant with the HIPAA (Institutional Review Board Reg. #00000940). The prospectively planned study was performed from March 2014 to December 2014 and included 58 ex-smokers (mean age, 73 years ± 9) with (n = 32; mean age, 74 years ± 7) and without (n = 26; mean age, 70 years ± 11) COPD. MR imaging (at functional residual capacity plus 1 L), CT (at full inspiration and expiration), and spirometry or plethysmography were performed during a 2-hour visit to generate ventilation defect percent (VDP), apparent diffusion coefficient (ADC), and PRM gas trapping and emphysema measurements. The relationships between pulmonary function and imaging measurements were determined with analysis of variance (ANOVA), Holm-Bonferroni corrected Pearson correlations, multivariate regression modeling, and the spatial overlap coefficient (SOC)., Results: VDP, ADC, and PRM gas trapping and emphysema (ANOVA, P < .001) measurements were significantly different in healthy ex-smokers than they were in ex-smokers with COPD. In all ex-smokers, VDP was correlated with PRM gas trapping (r = 0.58, P < .001) and with PRM emphysema (r = 0.68, P < .001). VDP was also significantly correlated with PRM in ex-smokers with COPD (gas trapping: r = 0.47 and P = .03; emphysema: r = 0.62 and P < .001) but not in healthy ex-smokers. In a multivariate model that predicted PRM gas trapping, the forced expiratory volume in 1 second normalized to the forced vital capacity (standardized coefficients [βS] = -0.69, P = .001) and airway wall area percent (βS = -0.22, P = .02) were significant predictors. PRM emphysema was predicted by the diffusing capacity for carbon monoxide (βS = -0.29, P = .03) and VDP (βS = 0.41, P = .001). Helium 3 ADC values were significantly elevated in PRM gas-trapping regions (P < .001). The spatial relationship for ventilation defects was significantly greater with PRM gas trapping than with PRM emphysema in patients with mild (for gas trapping, SOC = 36% ± 28; for emphysema, SOC = 1% ± 2; P = .001) and moderate (for gas trapping, SOC = 34% ± 28; for emphysema, SOC = 7% ± 15; P = .006) COPD. For severe COPD, the spatial relationship for ventilation defects with PRM emphysema (SOC = 64% ± 30) was significantly greater than that for PRM gas trapping (SOC = 36% ± 18; P = .01)., Conclusion: In all ex-smokers, ADC values were significantly elevated in regions of PRM gas trapping, and VDP was quantitatively and spatially related to both PRM gas trapping and PRM emphysema. In patients with mild to moderate COPD, VDP was related to PRM gas trapping, whereas in patients with severe COPD, VDP correlated with both PRM gas trapping and PRM emphysema., ((©) RSNA, 2016 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on January 12, 2016.)

Rationale and Objectives: Pulmonary functional magnetic resonance imaging provides a way to quantify ventilation and its heterogeneity-a hallmark finding in chronic obstructive pulmonary disease (COPD). Unfortunately, the etiology and physiological meaning of ventilation defects and their relationship to pulmonary function and symptoms in COPD are not well understood. Another biomarker of ventilation heterogeneity is provided by the "poorly communicating fraction" (PCF), and is calculated as the ratio of total lung capacity to alveolar volume made using whole-body plethysmography. Our objective was to compare ventilation heterogeneity using hyperpolarized (3)He magnetic resonance imaging (MRI) and PCF measurements in elderly never-smokers and in ex-smokers with COPD., Materials and Methods: One hundred forty-six participants (71 ± 8 years, range = 48-87 years) provided written informed consent including 45 elderly never-smokers (71 ± 6 years, range = 61-84 years) and 101 ex-smokers with COPD (71 ± 8 years, range = 48-87 years). During a single 2-hour visit, spirometry, plethysmography, and hyperpolarized (3)He MRI were acquired. The MRI-derived ventilation defect percent (VDP) and plethysmography measurements were acquired and PCF values were calculated. Linear regression, Pearson correlations, and Bland-Altman analysis were used to evaluate the relationships for PCF and MRI VDP., Results: PCF (P < 0.001) and VDP (P < 0.001) were significantly increased with increasing COPD severity. There was a significant relationship for VDP and PCF (r = 0.68, P < 0.001) in all subjects and COPD subjects alone (r = 0.61, P < 0.001). Bland-Altman analysis showed that PCF and VDP were significantly different (mean bias = 9.7, upper limit = 32, lower limit = -13, P < 0.001), and in severe-grade COPD, PCF overestimates of VDP were significantly greater., Conclusions: In elderly never-smokers and in ex-smokers with COPD, PCF and VDP are moderately correlated estimates of COPD ventilation heterogeneity that may be reflecting similar pathophysiology., (Copyright © 2016 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Rationale and Objectives: (3)He magnetic resonance imaging (MRI) can be used to quantify functional responses to asthma therapy and provocation. Ventilation imaging offers quantitative information beyond ventilation defects that have not yet been exploited. Therefore, our objective was to evaluate hyperpolarized (3)He MRI ventilation defect percent (VDP) and compare this and pulmonary function measurements to ventilation image texture features and their changes post-bronchodilator administration in patients with asthma., Materials and Methods: Volunteers with a diagnosis of asthma provided written informed consent to an ethics board-approved protocol and underwent pulmonary function tests and MRI before and after salbutamol inhalation. MR images were analyzed using VDP, and their texture was evaluated via gray-level run-length matrices. These texture classifiers were compared to VDP in responders to bronchodilation based on VDP (VDP responders) and forced expiratory volume in 1 s (FEV1) (FEV1 responders)., Results: In total, 47 patients with asthma (18 males 39 ± 13 years, FEV1 = 79 ± 21%) reported significantly improved FEV1, FEV1/forced vital capacity (FVC), residual volume (RV)/total lung capacity (TLC) (all P = .0001) and VDP (P = .01) post-salbutamol. Post-salbutamol, VDP responders and nonresponders to salbutamol were significantly different for coarse-texture features including long-run emphasis (LRE) and long-run, low gray-level emphasis (LRLGE, both P < .05) and for FEV1 responders to salbutamol, there was significantly different long-run, high gray-level emphasis (LRHGE, P = .04). There were significant relationships for VDP with LRE (R = .50, P = .0003), LRLGE (R = .34, P = .02), and LRHGE (R = .56, P = .0001). Receiver operating characteristic curves showed VDP with the strongest performance (AUC = .92), followed by coarse-texture classifier LRHGE (AUC = .83), FEV1 (AUC = .80), LRE (AUC = .66), FVC (AUC = .58), and LRLGE (AUC = .42)., Conclusions: In patients with asthma, differences in ventilation patchiness post-salbutamol can be quantified using coarse-texture classifiers that are significantly different in bronchodilator responders., (Copyright © 2015 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Evidence-based guidance for the use of airway clearance techniques (ACT) in chronic obstructive pulmonary disease (COPD) is lacking in-part because well-established measurements of pulmonary function such as the forced expiratory volume in 1s (FEV1) are relatively insensitive to ACT. The objective of this crossover study was to evaluate daily use of an oscillatory positive expiratory pressure (oPEP) device for 21-28 days in COPD patients who were self-identified as sputum-producers or non-sputum-producers. COPD volunteers provided written informed consent to daily oPEP use in a randomized crossover fashion. Participants completed baseline, crossover and study-end pulmonary function tests, St. George's Respiratory Questionnaire (SGRQ), Patient Evaluation Questionnaire (PEQ), Six-Minute Walk Test and (3)He magnetic resonance imaging (MRI) for the measurement of ventilation abnormalities using the ventilation defect percent (VDP). Fourteen COPD patients, self-identified as sputum-producers and 13 COPD-non-sputum-producers completed the study. Post-oPEP, the PEQ-ease-bringing-up-sputum was improved for sputum-producers (p = 0.005) and non-sputum-producers (p = 0.04), the magnitude of which was greater for sputum-producers (p = 0.03). There were significant post-oPEP improvements for sputum-producers only for FVC (p = 0.01), 6MWD (p = 0.04), SGRQ total score (p = 0.01) as well as PEQ-patient-global-assessment (p = 0.02). Clinically relevant post-oPEP improvements for PEQ-ease-bringing-up-sputum/PEQ-patient-global-assessment/SGRQ/VDP were observed in 8/7/9/6 of 14 sputum-producers and 2/0/3/3 of 13 non-sputum-producers. The post-oPEP change in (3)He MRI VDP was related to the change in PEQ-ease-bringing-up-sputum (r = 0.65, p = 0.0004) and FEV1 (r = -0.50, p = 0.009). In COPD patients with chronic sputum production, PEQ and SGRQ scores, FVC and 6MWD improved post-oPEP. FEV1 and PEQ-ease-bringing-up-sputum improvements were related to improved ventilation providing mechanistic evidence to support oPEP use in COPD. Clinical Trials # NCT02282189 and NCT02282202.

Purpose: To determine the role of imaging measurements of emphysema and airway disease in determining chronic obstructive pulmonary disease (COPD) symptoms and exercise limitation in patients with COPD, particularly in patients with mild-to-moderate disease., Materials and Methods: Participants (n = 116) with Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade U (unclassified) or grade I-IV COPD provided informed consent to an ethics board-approved HIPAA-compliant protocol and underwent spirometry and plethysmography, completed the St George's Respiratory Questionnaire (SGRQ), completed a 6-minute walk test for the 6-minute walk distance (6MWD), and underwent hyperpolarized helium 3 ((3)He) magnetic resonance (MR) imaging and computed tomography (CT). Emphysema was estimated by using the MR imaging apparent diffusion coefficient (ADC) and the relative area of the CT attenuation histogram with attenuation of -950 HU or less (RA950). Airway disease was measured by using the CT airway wall thickness of airways with an internal perimeter of 10 mm and total airway count. Ventilation defect percentage at (3)He MR imaging was used to measure ventilation. Multivariable regression models for the 6MWD and SGRQ symptom subscore were used to evaluate the relationships between physiologic and imaging measurements., Results: Multivariate modeling for the 6MWD in 80 patients with GOLD grade U-II COPD showed that ADC (β = 0.34, P = .04), diffusing capacity of the lung for carbon monoxide (β = 0.60, P = .0008), and residual volume/total lung capacity (β = -0.26, P = .02) were significant variables, while forced expiratory volume in 1 second (FEV1) and airway disease measurements were not. In 36 patients with GOLD grade III or IV disease, FEV1 (β = 0.48, P = .01) was the only significant contributor in a multivariate model for 6MWD. MR imaging emphysema measurements also made the greatest relative contribution to symptoms in patients with milder (GOLD grade U-II) COPD (ADC: β = 0.60, P = .005; RA950: β = -0.52, P = .02; FEV1: β = -0.45, P = .0002) and in grade III or IV disease (ADC: β = 0.95, P = .01; RA950: β = -0.62, P = .07; airway count: β = -0.49, P = .01)., Conclusion: In patients with mild-to-moderate COPD, MR imaging emphysema measurements played a dominant role in the expression of exercise limitation, while both CT and MR imaging measurements of emphysema explained symptoms.

Diffusion-weighted magnetic resonance imaging (MRI) provides a way to generate in vivo lung images with contrast sensitive to the molecular displacement of inhaled gas at subcellular length scales. Here, we aimed to evaluate hyperpolarized (3)He MRI estimates of the alveolar dimensions in 38 healthy elderly never-smokers (73 ± 6 years, 15 males) and 21 elderly ex-smokers (70 ± 10 years, 14 males) with (n = 8, 77 ± 6 years) and without emphysema (n = 13, 65 ± 10 years). The ex-smoker and never-smoker subgroups were significantly different for FEV1/FVC (P = 0.0001) and DLCO (P = 0.009); while ex-smokers with emphysema reported significantly diminished FEV1/FVC (P = 0.02) and a trend toward lower DLCO (P = 0.05) than ex-smokers without emphysema. MRI apparent diffusion coefficients (ADC) and CT measurements of emphysema (relative area-CT density histogram, RA950) were significantly different (P = 0.001 and P = 0.007) for never-smoker and ex-smoker subgroups. In never-smokers, the MRI estimate of mean linear intercept (260 ± 27 μm) was significantly elevated as compared to the results previously reported in younger never-smokers (210 ± 30 μm), and trended smaller than in the age-matched ex-smokers (320 ± 72 μm, P = 0.06) evaluated here. Never-smokers also reported significantly smaller internal (220 ± 24 μm, P = 0.01) acinar radius but greater alveolar sheath thickness (120 ± 4 μm, P < 0.0001) than ex-smokers. Never-smokers were also significantly different than ex-smokers without emphysema for alveolar sheath thickness but not ADC, while ex-smokers with emphysema reported significantly different ADC but not alveolar sheath thickness compared to ex-smokers without CT evidence of emphysema. Differences in alveolar measurements in never- and ex-smokers demonstrate the sensitivity of MRI measurements to the different effects of smoking and aging on acinar morphometry., (© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Rationale and Objectives: Hyperpolarized (3)He magnetic resonance imaging (MRI) ventilation abnormalities are visible in ex-smokers without airflow limitation, but the clinical relevance of this is not well-understood. Our objective was to phenotype healthy ex-smokers with normal and abnormally elevated ventilation defect percent (VDP)., Materials and Methods: Sixty ex-smokers without airflow limitation provided written informed consent to (3)He MRI, computed tomography (CT), and pulmonary function tests in a single visit. (3)He MRI VDP and apparent diffusion coefficients (ADCs) were measured for whole-lung and each lung lobe as were CT measurements of emphysema (relative area [RA] with attenuation ≤-950 HU, RA950) and airway morphology (wall area percent [WA%], lumen area [LA] and LA normalized to body surface area [LA/BSA])., Results: In 42 ex-smokers, there was abnormally elevated VDP and no significant differences for pulmonary function, RA950, or airway measurements compared to 18 ex-smokers with normal VDP. Ex-smokers with abnormally elevated VDP reported significantly greater (3)He ADC in the apical lung (right upper lobe [RUL], P = .02; right middle lobe [RML], P = .04; and left upper lobe [LUL], P = .009). Whole lung (r = 0.40, P = .001) and lobar VDP (RUL, r = 0.32, P = .01; RML, r = 0.46, P = .002; right lower lobe [RLL], r = 0.38, P = .003; LUL, r = 0.35, P = .006; and left lower lobe, r = 0.37, P = .004) correlated with regional (3)He ADC. Although whole-lung VDP and CT airway morphology measurements were not correlated, regional VDP was correlated with RUL LA (r = -0.37, P = .004), LA/BSA (r = -0.42, P = .0008), RLL WA% (r = 0.28, P = .03), LA (r = -0.28, P = .03), and LA/BSA (r = -0.37, P = .004)., Conclusions: Abnormally elevated VDP in ex-smokers without airflow limitation was coincident with very mild emphysema detected using MRI and regional airway remodeling detected using CT representing a subclinical obstructive lung disease phenotype., (Copyright © 2015 AUR. Published by Elsevier Inc. All rights reserved.)

Background: To evaluate ultra-short-echo-time (UTE) MRI pulmonary signal-intensity measurements and reproducibility in chronic obstructive pulmonary disease (COPD)., Methods: A two-dimensional sequence (echo-time = 0.05 ms; acquisition-time = 13 s) with interleaved half-pulse excitation and radial ramp-sampling was used with compressed-sensing to reconstruct UTE images from under-sampled data. Five healthy volunteers and 15 subjects with COPD provided written informed consent to imaging and pulmonary-function-tests. Healthy volunteers underwent MRI at four lung volumes: full-expiration, functional-residual-capacity (FRC), FRC+1L, and full-inhalation; COPD patients underwent computed-tomography (CT) and MRI at FRC+1L. Three-week reproducibility was evaluated and the relative area of the density histogram ≤ -950 HU (RA950 ) was compared with mean MRI signal-intensity. The 15th percentile of signal-intensity-histogram (SI15 ) was compared with the 15th percentile of the CT-density-histogram (HU15 )., Results: In healthy subjects, signal-intensity correlated with the inverse of lung volume (r = 0.99; P = 0.007). Contrast-to-noise and signal-to-noise ratios were significantly improved for 32-channel UTE (P < 0.01). The coefficient of variation for 3-week repeated measurements was 4%. There were significant correlations for signal-intensity with RA950 (r = -0.71; P = 0.005), FEV1 /FVC (r = 0.59; P = 0.02), and for SI15 with HU15 (r = 0.62; P = 0.01)., Conclusion: Pulmonary signal-intensity is reproducible and related to tissue density. In COPD subjects with and without bronchiectasis, signal-intensity was also related to pulmonary function and CT measurements., (© 2014 Wiley Periodicals, Inc.)

Rationale and Objectives: 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., Materials and Methods: 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., Results: Twenty-six subjects were evaluated including 12 COPD subjects (67 ± 9 years) and 14 bronchiectasis subjects (70 ± 11 years). 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)., Conclusions: 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., (Copyright © 2015 AUR. Published by Elsevier Inc. All rights reserved.)

It is well-established that COPD patients have a burden of vascular disease that cannot be fully-explained by smoking history but the mechanistic links between atherosclerosis and pulmonary disease in COPD patients are not well-understood. Moreover, in ex-smokers without symptoms or other evidence of COPD, subclinical pulmonary and vascular disease, although potentially present, has not been described or evaluated. Hence our aim was to use sensitive three-dimensional (3D) pulmonary and carotid imaging to quantify pulmonary airway/parenchyma abnormalities and atherosclerosis in ex-smokers without airflow limitation or symptoms consistent with COPD. We evaluated 61 subjects without airflow limitation including 34 never- (72 ± 6 years) and 27 ex-smokers (73 ± 9 years), who provided written informed consent to spirometry, plethysmography, (3)He magnetic resonance imaging (MRI) and carotid ultrasound (US) and, for ex-smokers alone, thoracic X-ray computed tomography (CT). Ex-smokers had significantly greater (3)He ventilation defect percent (VDP = 7%, p = 0.001) and carotid total plaque volume (TPV = 250 mm(3), p = 0.002) than never-smokers, although there were no significant differences for spirometry or plethysmography, and CT airway and emphysema measurements were normal. There were univariate relationships for (3)He VDP with carotid intima media thickness (IMT, r = 0.42, p = 0.004), TPV (r = 0.41, p = 0.006) and vessel wall volume (VWV, r = 0.40, p = 0.007). Multivariate models that included age, BMI, FEV1, DLCO and VDP showed that only VDP significantly predicted IMT (β = 0.41, p = 0.001), VWV (β = 0.45, p = 0.003) and TPV (β = 0.38, p = 0.005). In summary, there was imaging evidence of mild airways disease and carotid plaque burden that were related and significantly greater in ex-smokers without airflow limitation than in never-smokers.

Purpose: To evaluate the predictive value of imaging and clinical and physiological measurements of chronic obstructive pulmonary disease ( COPD chronic obstructive pulmonary disease ) in patients monitored for more than 5 years for pulmonary exacerbations that required hospitalization., Materials and Methods: Exacerbations requiring hospitalization were monitored over 5 years in 91 subjects who provided written informed consent. Study was local research ethics board and Health Canada approved and HIPAA compliant. Subjects with COPD chronic obstructive pulmonary disease underwent spirometry, plethysmography, diffusing capacity of carbon monoxide, St George's Respiratory Questionnaire, 6-minute walk test, and imaging. Computed tomographic (CT) wall area and relative area with attenuation values less than -950 HU ( RA950 relative area with attenuation values less than -950 HU ), helium 3 ((3)He) magnetic resonance (MR) imaging ventilation defect percentage ( VDP ventilation defect percentage ), and apparent diffusion coefficient were generated. Zero-inflated Poisson model was used to compare number of hospitalizations with lung function and imaging measurements., Results: Twenty-four subjects were hospitalized 58 times and had significantly worse forced expiratory volume in 1 second ( FEV1 forced expiratory volume in 1 second ) (P < .0001), CT RA950 relative area with attenuation values less than -950 HU (P = .02), and (3)He VDP ventilation defect percentage (P < .0001) than values in 67 subjects who were not hospitalized. In mild to moderate COPD chronic obstructive pulmonary disease , nine hospitalized subjects had significantly worse FEV1 forced expiratory volume in 1 second (P = .02) and (3)He VDP ventilation defect percentage (P = .02) than values in 52 subjects who were not hospitalized. (3)He VDP ventilation defect percentage was quantitatively related to CT airway morphology (r = 0.26, P = .01) and quantitatively (r = 0.61, P < .0001) and spatially related to emphysema; this spatial relationship was significantly greater for hospitalized patients with COPD chronic obstructive pulmonary disease than unhospitalized patients (P = .0006). For all subjects, number of prior hospitalizations (P < .0001), 6-minute walk test distance (P < .0001), CT RA950 relative area with attenuation values less than -950 HU (P = .03), and (3)He VDP ventilation defect percentage (P = .002) were significantly related to number of hospitalizations. For 61 subjects with mild to moderate COPD chronic obstructive pulmonary disease , only (3)He VDP ventilation defect percentage was significantly associated with COPD chronic obstructive pulmonary disease exacerbations (P = .01)., Conclusion: (3)He MR imaging VDP ventilation defect percentage represents a mixed airways-emphysema phenotype and helps identify subjects with mild to moderate COPD chronic obstructive pulmonary disease who are at risk for exacerbation that requires hospitalization., (© RSNA, 2014.)

Rationale and Objectives: Hyperpolarized (3)He magnetic resonance imaging (MRI) previously revealed the temporal and spatial heterogeneity of ventilation defects in asthmatics, but these findings have not been used in treatment studies or to guide personalized therapy. Our objective was to exploit the temporal and spatial information inherent to (3)He MRI and develop image processing methods to generate pulmonary ventilation temporal-spatial maps that could be used to measure, optimize, and guide asthma therapy., Materials and Methods: In this proof-of-concept study, seven asthmatics provided written informed consent to an approved protocol and underwent spirometry and (3)He MRI on three occasions, each 5 ± 2 days apart. A registration and segmentation pipeline was developed to generate three-dimensional, temporal-spatial, pulmonary function maps. Briefly, (3)He ventilation images were segmented to generate ventilation masks that were coregistered and voxels classified according to their temporal behavior. This enabled the regional mapping of temporally persistent and intermittent ventilation defects that were normalized to the (1)H MRI thoracic cavity volume to generate persistent ventilation defect percent (VDPP) and intermittent ventilation defect percent (VDPI)., Results: (3)He temporal-spatial pulmonary function maps identified temporally persistent and intermittent ventilation defects. VDP(I) was significantly greater in the posterior (P = .04) and inferior (P = .04) lung as compared to the anterior and superior lung. Persistent and intermittent ventilation defect percent were strongly correlated with forced expiratory volume in one second/forced vital capacity (VDP(P): r = -0.87, P = .01; VDP(I): r = -0.96, P = .0008)., Conclusions: Temporal-spatial pulmonary maps generated from (3)He MRI can be used to quantify temporally persistent and intermittent ventilation defects as asthma intermediate end points and targets for therapy., (Copyright © 2014 AUR. Published by Elsevier Inc. All rights reserved.)

Although the human and societal burden and cost of COPD is staggering, there are few clinical tools that provide earlier diagnoses or a means to regionally monitor disease in a way that might lead to improved therapies and outcomes. In acknowledgement of the current gaps in COPD therapy, the objective of the Thoracic Imaging Network of Canada (TINCan) is to improve COPD patient phenotyping through imaging, to provide methods and imaging-based intermediate endpoints for the development of new treatments, and to evaluate disease progression and patient-based outcomes in COPD patients and those at risk of COPD. Here we summarize and outline the TINCan study protocol and describe our objectives. TINCan is a prospective study that aims to identify and quantify novel COPD phenotypes from thoracic computed tomography (CT) and thoracic hyperpolarized noble gas magnetic resonance imaging (MRI) in 200 ex-smokers, 50 years of age or greater, including asymptomatic ex-smokers with normal pulmonary function and Global initiative for chronic Obstructive Lung Disease (GOLD) Unclassified (U) , and GOLD stages I-IV patients. Baseline and 2-year follow-up measurements will be acquired using spirometry, plethysmography, diffusing capacity of the lung for carbon monoxide (DL CO ), St. George's Respiratory Questionnaire (SGRQ), 6-minute walk test (6MWT), thoracic CT and hyperpolarized helium-3 ( 3 He) and xenon 129 ( 129 Xe) MRI. TINCan provides a unique opportunity to quantify and compare novel lung structure-function measurements and investigate their relationship with well-established clinical measurements and outcomes. Such intermediate endpoints of COPD may be used to stratify patients for personalized treatments and to develop new treatments to improve outcomes, a long-standing clinical goal., Competing Interests: M. Kirby gratefully acknowledges support from the Canadian Institute of Health Research (CIHR) Bisby Post-doctoral Scholarship, the CIHR Integrated and Mentored Pulmonary and Cardiovascular Training program (IMPACT) and the Michael Smith Foundation for Health Research. D. D Sin holds a Tier 1 Canada Research Chair in COPD. H.O. Coxson is supported by a Roberta R. Miller Fellowship in Thoracic Imaging from the British Columbia Lung Association and a service contract with GlaxoSmithKline Inc. for the quantitative analysis of CT data not related to this study. G. Parraga gratefully acknowledges support from a CIHR New Investigator Award. Ongoing research funding from CIHR Team Grant CIF# 97687 (Thoracic Imaging Network of Canada, TINCan) and support from the Canadian Respiratory Research Network (CRRN), also funded by CIHR, is gratefully acknowledged. The authors are solely responsible for the writing of this article and none have conflicts in relation to the study described here.

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., (Copyright © 2014 the American Physiological Society.)

Noble gas pulmonary magnetic resonance imaging (MRI) is transitioning away from (3)He to (129)Xe gas, but the physiological/clinical relevance of (129)Xe apparent diffusion coefficient (ADC) parenchyma measurements is not well understood. Therefore, our objective was to generate (129)Xe MRI ADC for comparison with (3)He ADC and with well-established measurements of alveolar structure and function in older never-smokers and ex-smokers with chronic obstructive pulmonary disease (COPD). In four never-smokers and 10 COPD ex-smokers, (3)He (b = 1.6 sec/cm(2)) and (129)Xe (b = 12, 20, and 30 sec/cm(2)) ADC, computed tomography (CT) density-threshold measurements, and the diffusing capacity for carbon monoxide (DLCO) were measured. To understand regional differences, the anterior-posterior (APG) and superior-inferior (∆SI) ADC differences were evaluated. Compared to never-smokers, COPD ex-smokers showed greater (3)He ADC (P = 0.006), (129)Xe ADCb12 (P = 0.006), and ADCb20 (P = 0.006), but not for ADCb30 (P > 0.05). Never-smokers and COPD ex-smokers had significantly different APG for (3)He ADC (P = 0.02), (129)Xe ADCb12 (P = 0.006), and ADCb20 (P = 0.01), but not for ADCb30 (P > 0.05). ∆SI for never- and ex-smokers was significantly different for (3)He ADC (P = 0.046), but not for (129)Xe ADC (P > 0.05). There were strong correlations for DLCO with (3)He ADC and (129)Xe ADCb12 (both r = -0.95, P < 0.05); in a multivariate model (129)Xe ADCb12 was the only significant predictor of DLCO (P = 0.049). For COPD ex-smokers, CT relative area <-950 HU (RA950) correlated with (3)He ADC (r = 0.90, P = 0.008) and (129)Xe ADCb12 (r = 0.85, P = 0.03). In conclusion, while (129)Xe ADCb30 may be appropriate for evaluating subclinical or mild emphysema, in this small group of never-smokers and ex-smokers with moderate-to-severe emphysema, (129)Xe ADCb12 provided a physiologically appropriate estimate of gas exchange abnormalities and alveolar microstructure., (© 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Objective: The aim of this study was to quantitatively evaluate the relationship between short echo time pulmonary (1)H magnetic resonance imaging (MRI) signal intensity (SI) and (3)He MRI apparent diffusion coefficients (ADC), high-resolution computed tomography (CT) measurements of emphysema, and pulmonary function measurements., Materials and Methods: Nine healthy never-smokers and 11 COPD subjects underwent same-day plethysmography, spirometry, short echo time ((TE)=1.2ms) (1)H and diffusion-weighted hyperpolarized (3)He MRI (b=1.6s/cm(2)) at 3.0T. In addition, for COPD subjects only, CT densitometry was also performed., Results: Mean (1)H SI was significantly greater for never-smokers (12.1 ± 1.1 arbitrary units (AU)) compared to COPD subjects (10.9 ± 1.3 AU, p=0.04). The (1)H SI AP-gradient was also significantly greater for never-smokers (0.40 AU/cm, R(2)=0.94) compared to COPD subjects (0.29 AU/cm, R(2)=0.968, p=0.05). There was a significant correlation between (1)H SI and (3)He ADC (r=-0.58, p=0.008) and significant correlations between (1)H MR SI and CT measurements of emphysema (RA950, r=-0.69, p=0.02 and HU15, r=0.66, p=0.03)., Conclusions: The significant and moderately strong relationship between (1)H SI and (3)He ADC, as well as between (1)H SI and CT measurements of emphysema suggests that these imaging methods and measurements may be quantifying similar tissue changes in COPD and that pulmonary (1)H SI may be used to monitor emphysema as a complement to CT and noble gas MRI., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Hyperpolarised (3)He MRI provides a way to visualise regional pulmonary functional abnormalities that in asthma are thought to be related to airway morphological abnormalities. However, the exact aetiology of ventilation defects in asthma is not well understood., Objective: To better understand the determinants of ventilation defects in asthma, we evaluated well-established clinical as well as (3)He MRI and X-ray CT airway measurements in healthy subjects and subjects with asthma., Methods: Thirty-four subjects (n=26 subjects with asthma, n=8 healthy volunteers) underwent MRI, spirometry, plethysmography, fraction of exhaled nitric oxide analysis, methacholine challenge and CT for a region-of-interest proximal to ventilation defects. For subjects who consented to CT (n=18 subjects with asthma, n=5 healthy volunteers), we evaluated 3(rd) to 5th generation airway wall area and wall thickness per cent and lumen area., Results: Seventeen subjects with asthma (17/26=65%) had visually obvious evidence of (3)He ventilation defects prior to bronchoprovocation and nine subjects with asthma had no ventilation defects prior to bronchoprovocation (9/26=35%). Subjects with asthma with defects were older (p=0.01) with worse forced expiratory volume in 1 s (FEV1)/forced vital capacity (p=0.0003), airways resistance (p=0.004), fraction of exhaled nitric oxide (p=0.03), greater bronchoprovocation concentration of methacholine that reduced FEV1 by 20% (p=0.008) and wall thickness per cent (p=0.02) compared with subjects with asthma without defects. There was a moderate correlation for wall area per cent with ventilation defect per cent (r=0.43, p=0.04)., Conclusions: Subjects with asthma with (3)He ventilation defects were older with significantly worse airway hyper-responsiveness, inflammation and airway remodelling but similar FEV1 as subjects with asthma without defects; hyperpolarised (3)He ventilation abnormalities were spatially and quantitatively related to abnormally remodelled airways.

Purpose: To compare hyperpolarized helium-3 ((3) He) and xenon-129 ((129) Xe) MRI in asthmatics before and after salbutamol inhalation., Materials and Methods: 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., Results: 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) )., Conclusion: In asthma, hyperpolarized (129) Xe MRI may help reveal ventilation abnormalities before bronchodilation that are not observed using hyperpolarized (3) He MRI., (Copyright © 2013 Wiley Periodicals, Inc.)

Purpose: The goal of this work was to investigate lung morphological changes associated with chronic obstructive pulmonary disease (COPD) using hyperpolarized (129) Xe diffusion-weighted MRI., Methods: Hyperpolarized (129) Xe MRI was performed at three different nonzero diffusion sensitizations (b-value = 12, 20, and 30 s/cm(2) ) in the lungs of four subjects with COPD and four healthy volunteers. The image signal intensities were fit as a function of b-value to obtain anisotropic diffusion coefficient maps for all subjects. The image signal intensities were also fit to a morphological model allowing extraction of length scales associated with the terminal airways: external radius (R), internal radius (r), mean airspace chord length (Lm ), and depth of alveolar sleeve (h)., Results: Longitudinal (DL ) and transverse (DT ) anisotropic diffusion coefficients were both significantly increased (both P= 0.004) in the COPD subjects (0.102 ± 0.02 cm(2) /s and 0.072 ± 0.02 cm(2) /s, respectively) compared with the healthy subjects (0.083 ± 0.011 cm(2) /s and 0.046 ± 0.017 cm(2) /s, respectively). Significant morphological differences were observed between the COPD subjects and healthy volunteers, specifically decreases in h (68 ± 36 µm vs. 95 ± 710 µm, respectively, P = 0.019) and increases in Lm (352 ± 57 µm vs. 253 ± 37 µm, respectively, P = 0.002) consistent with values obtained previously using hyperpolarized (3) He MRI in similar subjects., Conclusions: Diffusion-weighted hyperpolarized (129) Xe MRI is a promising technique for mapping changes in human lung morphology and may be useful for early detection of emphysema associated with COPD., (Copyright © 2013 Wiley Periodicals, Inc.)