Ventilation Defect Volume Research Articles

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

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

Assessment of Repeatability of Hyperpolarized Gas MR Ventilation Functional Imaging in Cystic Fibrosis

Hyperpolarized (HP) gas magnetic resonance imaging (MRI) is an advanced imaging technique that provides high-resolution regional information on lung function without using ionizing radiation. Before this modality can be considered for assessing clinical or investigational interventions, baseline repeatability needs to be established. We assessed repeatability of lung function measurement using HP helium-3 MRI (HP (3)He MRI) in a small cohort of patients with cystic fibrosis (CF). We examined repeatability of HP (3)He MR images of five patients with CF in four scanning sessions over a 4-week period. We acquired images on a Philips 3.0Tesla Achieva MRI scanner using a quadrature, flexible, wrap-around, (3)He radiofrequency coil with a fast gradient-echo pulse sequence. We determined ventilation volume and ventilation defect volume using an advanced semiautomatic segmentation algorithm and also quantified ventilation heterogeneity. There were no significant differences in total ventilation volume, ventilation defect volume, ventilation defect percentage, or mean ventilation heterogeneity (repeated-measures analysis of variance, P=.2116, P=.2825, P=.2871, and P=.7265, respectively) in the patients across the four scanning sessions. Our results indicate that total ventilation volume, ventilation defect volume, ventilation defect percentage, and mean ventilation heterogeneity as assessed by HP gas MRI in CF patients with stable health are reproducible over time. This repeatability and the technique's capability to provide noninvasive high-resolution data on regional lung function without ionizing radiation make (3)He MRI a potentially useful outcome measure for CF-related clinical trials.

Markers of Vascular Perturbation Correlate with Airway Structural Change in Asthma

Air trapping and ventilation defects on imaging are characteristics of asthma. Airway wall thickening occurs in asthma and is associated with increased bronchial vascularity and vascular permeability. Vascular endothelial cell products have not been explored as a surrogate to mark structural airway changes in asthma. Determine whether reporters of vascular endothelial cell perturbation correlate with airway imaging metrics in patients with asthma of varying severity. Plasma from Severe Asthma Research Program subjects was analyzed by ELISAs for soluble von Willebrand factor mature protein (VWF:Ag) and propeptide (VWFpp), P-selectin, and platelet factor 4. Additional subjects were analyzed over 48 hours after whole-lung antigen challenge. We calculated ventilation defect volume by hyperpolarized helium-3 magnetic resonance imaging and areas of low signal density by multidetector computed tomography (less than -856 Hounsfield units [HU] at functional residual capacity and -950 HU at total lung capacity [TLC]). VWFpp and VWFpp/Ag ratio correlated with and predicted greater percentage defect volume on hyperpolarized helium-3 magnetic resonance imaging. P-selectin correlated with and predicted greater area of low density on chest multidetector computed tomography less than -950 HU at TLC. Platelet factor 4 did not correlate. Following whole-lung antigen challenge, variation in VWFpp, VWFpp/Ag, and P-selectin among time-points was less than that among subjects, indicating stability and repeatability of the measurements. Plasma VWFpp and P-selectin may be useful as surrogates of functional and structural defects that are evident on imaging. The results raise important questions about why VWFpp and P-selectin are associated specifically with different imaging abnormalities.

Exercise-induced Bronchoconstriction: Reproducibility of Hyperpolarized3He MR Imaging

To quantitatively evaluate interday, interreader, and intersite agreement of readers of hyperpolarized helium 3 (HPHe) MR images in patients with exercise-induced bronchoconstriction. This HIPAA-compliant, institutional review board approved study included 13 patients with exercise-induced bronchoconstriction. On two separate days, HPHe MR imaging of the lungs was performed at baseline, immediately after a 10-minute exercise challenge (postchallenge), and 45 minutes after exercise (recovery). Patients were imaged at two sites, six at site A and seven at site B. Images were analyzed independently by multiple readers at each site. Lung volume, ventilation defect volume, ventilated volume, and the number of defects were measured quantitatively, and the location of defects was evaluated qualitatively at site A. Interday and interreader agreement were evaluated by using the intraclass correlation coefficient (ICC), and intersite agreement was evaluated by using a modified Bland-Altman analysis. The ICC between days for ventilation defect volume, ventilated volume, and number of defects was at least 0.74 at both sites. The ICC for lung volume was greater at site B (0.83-0.86) than at site A (0.60-0.65). Defects seen in the same location in the lung on both days included 19.7% of those seen on baseline images and 29.2% and 18.6% of defects on postchallenge and recovery images, respectively. Interreader ICC for each measurement was at least 0.82 for each site. Analysis of intersite agreement showed biases of 612 mL for lung volume, -60.7 mL for ventilation defect volume, 2.91% for ventilated volume, and -6.56 for number of defects. The reported measures of reproducibility of HPHe MR imaging may help in the design and interpretation of single- and multicenter studies of patients with exercise-induced bronchoconstriction.

Hyperpolarized 3He Magnetic Resonance Functional Imaging Semiautomated Segmentation

To improve intra- and interobserver variability and enable the use of functional magnetic resonance imaging (MRI) for multicenter, multiobserver studies, we generated a semiautomated segmentation method for hyperpolarized helium-3 ((3)He) MRI. Therefore the objective of this study was to compare the reproducibility and spatial agreement of manual and semiautomated segmentation of (3)He MRI ventilation defect volume (VDV) and ventilation volume (VV) in subjects with asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF). The multistep semiautomated segmentation method we developed employed hierarchical K-means clustering to classify (3)He MRI pixel intensity values into five user-determined clusters ranging from signal void to hyperintense. A seeded region-growing algorithm was also used to segment the (1)H MRI thoracic cavity for coregistration to the (3)He cluster-map, generating VDV and VV. We compared manual segmentation performed by an expert observer and semiautomated measurements of (3)He MRI VDV and observed strong significant correlations between the volumes generated using each method (asthma, n = 5, r = 0.89, P < .0001; COPD, n = 5, r = 0.84, P < .0001; CF, n = 5, r = 0.89, P < .0001). Semiautomated VDV had high interobserver reproducibility (coefficient of variation [CV] = 7%, intraclass correlation coefficient [ICC] = 0.96); intraobserver reproducibility was significantly higher for semiautomated (CV = 5%, ICC = 1.00) compared to manual VDV (CV = 12%, ICC = 0.98). Spatial agreement for VV determined using the Dice coefficient (D) was also high for all disease states (asthma, D = 0.95; COPD, D = 0.88; CF, D = 0.90). Semiautomated segmentation (3)He MRI provides excellent inter- and intraobserver precision with high spatial and quantitative agreement with manual measurements enabling its use in longitudinal studies.

Chronic Obstructive Pulmonary Disease: Quantification of Bronchodilator Effects by Using Hyperpolarized He MR Imaging

To evaluate short-acting bronchodilator effects in chronic obstructive pulmonary disease (COPD) by using hyperpolarized helium 3 (³He) magnetic resonance (MR) imaging, spirometry, and plethysmography. Fourteen ex-smokers with COPD provided written informed consent to a local ethics board-approved and Health Insurance and Portability Accountability Act-compliant protocol and underwent hyperpolarized ³He and hydrogen 1 MR imaging, spirometry, and plethysmography before and a mean of 25 minutes ± 2 (standard deviation) after administration of 400 μg salbutamol. Distribution of ³He gas was evaluated by using semiautomated segmentation of ³He voxel intensities, where cluster 1 represented regions of signal void or ventilation defect volume (VDV), and clusters 2-5 (C2-C5) represented gradations of signal intensity from hypointensity (C2) to hyperintensity (C5). ³He ventilation defect percentage (VDP) was calculated as VDV normalized to the thoracic cavity volume. Comparisons of pre- and post-salbutamol means were performed by using a two-way mixed-design repeated measures analysis of variance, and comparisons of the magnitude of the treatment effect between pulmonary function and ³He MR imaging measurements were performed by using effect size (ES) calculations. The relationships between pulmonary function and ³He MR imaging findings were determined by using Spearman correlation coefficients. After salbutamol administration, there were significant changes in forced expiratory volume in 1 second (FEV₁) (P = .001), total lung capacity (P = .04), and functional residual capacity (P = .03), as well as VDP (P < .0001) and ³He gas distribution (C2, P = .01; C3, P = .03; C4, P < .0001; and C5, P = .02). Treatment ES was greater for ³He VDP than for FEV(1) (0.50 vs 0.22). There was a significant correlation between baseline VDP and post-salbutamol FEV₁ change (r = -0.77, P = .001). Although five patients were classified as bronchodilator responders and nine patients were classified as bronchodilator nonresponders according to American Thoracic Society and European Respiratory Society criteria, there was no significant difference in the magnitude of the ³He MR imaging changes after salbutamol administration between responder groups. ³He MR imaging depicted significant improvements in the distribution of ³He gas after bronchodilator therapy in ex-smokers with COPD with and those without clinically important changes in FEV₁.

MO-F-211-08: Development and Application of Novel Hyperpolarized 3He Magnetic Resonance Imaging Segmentation to Measure Acute Treatment Effects in Pulmonary Disease

Purpose: To develop a semi‐automated segmentation method for generating novel helium‐3 (3He)magnetic resonance imaging(MRI) functional information from 3He and proton (1H) MRI, determine the relationship between measurements obtained by manual and semi‐automated segmentation, and apply this method in chronic obstructive pulmonary disease (COPD) patients to evaluate the lung functional effects of bronchodilator therapy. Methods: Fourteen COPD ex‐smokers provided written informed consent and underwent hyperpolarized 3He and 1H MRI, before and 25±2 minutes after administration of salbutamol. Semi‐ automated segmentation was accomplished in three steps: 1) hierarchical K‐ means clustering of 3HeMRimages into 5 clusters where cluster 1 (C1) represented regions of ventilation defect and background, and cluster 2 to cluster 5 (C2–C5) represented gradations of signal intensity/ventilation, 2) 1H MRI segmentation using seeded region‐growing algorithm, and 3) registration of 1H and 3HeMRI to differentiate the ventilation defects from the background. 3He VDP was generated using ventilation defect volume (VDV or C1) normalized to the thoracic cavity volume. 3He VV was generated by summing the remaining ventilation clusters (C2–C5). Results: Manual and semi‐automated segmentation were significantly correlated for 3He VDV (r=.95, p<.0001) and VV (r=.94, p<.0001). The time for manual segmentation was approximately 60 to 90 minutes per subject dataset, whereas the time for semi‐automated segmentation to complete a dataset was between 4 and 8 minutes. Following bronchodilator therapy, there was a significant decrease in VDP and 3He C2 (p=.01), and significant increases in C3 (p=.03), C4 (p<.0001) and C5 (p=.02). Conclusions: We developed a method for generating novel quantitative 3HeMRI functional information that enables sensitive detection of regional lung functional improvements that occur following inhaled therapy in COPD patients. This has implications for the broader translation of functional MRI in clinical therapy studies including those for smoking‐related lungcancer. Research funding support from CIHR Operating grants MOP 97748 and Team Grant CIF 97687.

Quantitative Evaluation of Hyperpolarized Helium-3 Magnetic Resonance Imaging of Lung Function Variability in Cystic Fibrosis

To better understand imaging measurement precision and reproducibility and to provide guidance for measurements in individual cystic fibrosis (CF) subjects, we evaluated CF adults on two occasions 7 ± 2 days apart using spirometry, plethysmography, and hyperpolarized helium-3 ((3)He) magnetic resonance imaging (MRI). Twelve CF subjects underwent spirometry, plethysmography, and (3)He MRI twice within 7 ± 2 days, reporting (3)He ventilation defect volume (VDV) and ventilation defect percent (VDP). Based on measurement variability, the smallest detectable difference (SDD) for (3)He VDV and VDP was determined to be 120 mL and 2%, respectively. Although no significant difference in spirometry or plethysmography was detected after 7 days, there was a significant difference in mean (3)He VDV (130 mL ± 250 mL, P < .0001) and VDP (3% ± 4%, P < .0001), although baseline and 7-day measurements were highly correlated (VDV: r = .85, P = .001; VDP: r = .94, P < .0001). We estimated the sample sizes required to detect a 5%/7%/10% change in (3)He VDP as 60/15/5 subjects per group. Hyperpolarized (3)He MRI VDP measurement precision resulted in an SDD for individual CF subjects of 2%, indicating that changes greater than this can be attributed to lung functional changes and not measurement error. After 7 days, significant changes in mean (3)He VDV and VDP were detected and these changes were not reflected by changes in pulmonary function measurements. These findings demonstrate the high sensitivity and reproducibility of (3)He MRI functional imaging that permits the use of relatively small samples sizes in CF interventional studies.

Chronic Obstructive Pulmonary Disease: Longitudinal Hyperpolarized3He MR Imaging

To quantitatively evaluate a small pilot group of ex-smokers with chronic obstructive pulmonary disease (COPD) and healthy volunteers during approximately 2 years by using hyperpolarized helium 3 ((3)He) magnetic resonance (MR) imaging. All subjects provided written informed consent to the study protocol, which was approved by the local research ethics board and Health Canada and was compliant with the Personal Information Protection and Electronic Documents Act and HIPAA. Hyperpolarized (3)He MR imaging, hydrogen 1 MR imaging, spirometry, and plethysmography were performed in 15 ex-smokers with COPD and five healthy volunteers (with the same mean age and age range) at baseline and 26 months +/- 2 (standard deviation) later. Apparent diffusion coefficients (ADCs) derived from (3)He MR imaging were calculated from diffusion-weighted (3)He MR images, and (3)He ventilation defect volume (VDV) and ventilation defect percentage (VDP) were generated after manual segmentation of (3)He MR spin-density images. For subjects with COPD, significant increases in (3)He MR imaging-derived VDV (P = .03), VDP (P = .006), and ADC (P = .02) were detected, whereas there was no significant change in forced expiratory volume in 1 second (FEV(1)) (P = .97). For healthy never-smokers, there was no significant change in imaging or pulmonary function measurements at follow-up. There was a significant correlation between changes in FEV(1) and changes in VDV (r = -0.70, P = .02) and VDP (r = -0.70, P = .03). For this small pilot group of ex-smokers with COPD, (3)He MR imaging-derived VDV, VDP, and ADC measurements worsened significantly, but there was no significant change in FEV(1), suggesting increased sensitivity of hyperpolarized (3)He MR imaging for depicting COPD changes during short time periods.

Sci-Thurs AM: YIS-06: Longitudinal Hyperpolarized 3He Magnetic Resonance Imaging of Chronic Obstructive Pulmonary Disease

RATIONALE: To date, no studies have quantitatively evaluated chronic obstructive pulmonary disease (COPD) longitudinally using hyperpolarized helium-3 () magnetic resonance imaging (MRI). OBJECTIVES: To evaluate COPD longitudinally using hyperpolarized MRI and to determine correlations between the changes in MRI ventilation defect volume (VDV), apparent diffusion coefficients (ADC) and changes in pulmonary function. METHODS: Hyperpolarized MRI, spirometry and plethysmography were performed in 15 COPD ex-smokers ( stage II and stage III/IV COPD) at baseline and 26±2 months later. MRI ADC values were calculated from MRI diffusion-weighted images and VDV were generated after manual segmentation of MRI spin-density images. MEASUREMENTS AND MAIN RESULTS: At follow-up, COPD subjects showed significant increases in MRI CS VDV (), WL VDV (), as well as ADC () and no significant change in (). There was a significant correlation between changes in and changes in CS VDV (, ), however no significant correlations between smoking history (years non-smoker at baseline) and changes in MRI measurements or was found. CONCLUSIONS: For COPD ex-smokers, MRI VDV and ADC measurements worsened significantly but there was no significant change in FEV1, suggesting higher sensitivity of hyperpolarized MRI to COPD changes over short periods of time.

Hyperpolarized 3He Magnetic Resonance Imaging of Chronic Obstructive Pulmonary Disease : Reproducibility at 3.0 Tesla

We assessed subjects with stage II and stage III chronic obstructive pulmonary disease (COPD) and age-matched healthy volunteers at a single center using (3)He magnetic resonance imaging (MRI) at 3.0 T. Measurements of the (3)He apparent diffusion coefficient (ADC) and center coronal slice (3)He ventilation defect volume (VDV) were examined for same-day and 7-day reproducibility as well as subgroup comparisons. Twenty-four subjects who provided written informed consent (15 males; mean age 67 +/-7 years) with stage II (n = 9), stage III COPD (n = 7), and age-matched healthy volunteers (n = 8) were enrolled based on their age and pulmonary function test results. All subjects underwent plethysmography, spirometry, and MRI at 3.0 T. The time frame between scans was 7 +/- 2 minutes (same-day rescan) and again 7 +/- 2 days later (7-day rescan). (3)He ADC and VDV reproducibility was evaluated using linear regression, intraclass correlation coefficients (ICC) and Lin's concordance correlation coefficients (CCC). ADC reproducibility was high for same-day rescan (r(2) = 0.934) and 7-day rescan (r(2) = 0.960, ICC and CCC of 0.96 and 0.98, respectively). Same-day rescan VDV reproducibility evaluated using the ICC and CCC (0.97 and 0.98, respectively) as well as linear regression (r(2) = 0.941) was also high, but VDV 7-day rescan reproducibility was lower and significantly different (r(2) = 0.576, P < .001, ICC 0.74, CCC 0.75, P < .01). Hyperpolarized (3)He MRI was well-tolerated in subjects with stage II and stage III COPD. Seven-day repeated scanning was highly reproducible for ADC and moderately reproducible for VDV.

Hyperpolarized 3He Magnetic Resonance Imaging of Ventilation Defects in Healthy Elderly Volunteers : Initial Findings at 3.0 Tesla

Hyperpolarized (3)He magnetic resonance imaging ventilation defects have been observed in subjects with respiratory disorders. We quantified (3)He ventilation defects in elderly and middle-aged subjects who had no history of smoking, respiratory, or cardiovascular disorders. Hyperpolarized (3)He magnetic resonance imaging ventilation defect volume (VDV) and ventilation defect score (VDS) were assessed in eight elderly healthy volunteers (mean 67+/-6 years) scanned twice within 7+/-2 minutes and again 7+/-2 days later. A younger cohort of 24 subjects (mean 44+/-10 years) was also scanned for direct comparison. Four observers blinded to scan timepoint and subject identity scored VDS and manually segmented VDV in all center coronal slices. Center coronal slice ventilation defects were observed in six of eight elderly subjects (ages 63-74 years, 5 males) in all scans acquired and in no middle-aged subjects. At the scan timepoint, mean VDS was 2.7 (mean VDV 52+/-34 cm(3)), whereas for same-day rescan, mean VDS was 2.5 (mean VDV 53+/-35 cm(3)) and at 7-day rescan, mean VDS was 3.6 (mean VDV 48+/-39 cm(3)). Interscan coefficients of variation (COV) for mean VDV was 1.8% (same-day rescan) and 5.3% (7-day rescan) and interobserver COV ranged from 10-12%. Elderly subjects have ventilation defects that are reproducible in same-day scanning and 7-day scanning visits. The observation of reproducible pulmonary ventilation defects in otherwise healthy elderly volunteers suggests caution must be used in interpreting results from (3)He studies of elderly subjects.

Hyperpolarized 3He Ventilation Defects and Apparent Diffusion Coefficients in Chronic Obstructive Pulmonary Disease

Hyperpolarized 3He magnetic resonance imaging (3He MRI) at 3.0 Tesla of healthy volunteers and chronic obstructive pulmonary disease (COPD) patients was performed for quantitative evaluation of ventilation defects and apparent diffusion coefficients (ADC) and for comparison to published results acquired at 1.5 Tesla. The reproducibility of 3He ADC and ventilation defects was also assessed in subjects scanned 3 times, twice within 10 minutes, and again within 7 +/- 2 days of the first MRI visit. Hyperpolarized 3He MRI was performed in 6 subjects. Two interleaved images with and without additional diffusion sensitization were acquired with the first image serving as a ventilation image from which defect score and volume were measured and the combination of the 2 images used to compute ADC maps and ADC histograms. He MRI at 3.0 Tesla showed increased mean ADC and ADC standard deviation for subjects with COPD compared with healthy volunteers (ADC healthy volunteer (0.24 +/- 0.12 cm2/s), mild-moderate COPD (0.34 +/- 0.14 cm2/s), and severe COPD (0.47 +/- 0.21 cm2/s), and these values were similar to previously reported results acquired at 1.5 Tesla. Reproducibility of mean ADC was high (coefficient of variation 2% in severe COPD, 3% in mild-moderate COPD, 4% in healthy volunteers) across all 3 scans. Higher same-day scan reproducibility was observed for ventilation defect volume compared with 1-week scan reproducibility in this small group of subjects. ADC values for emphysematous lungs were significantly increased compared with healthy lungs in age-matched subjects, and all values were comparable to those reported previously at 1.5 Tesla. Ventilation defect score and ventilation defect volume results were also comparable to results previously reported in COPD subjects Reproducibility of ADC for same-day scan-rescan and 7-day rescan was high and similar to previously reported results.