Miranda Kirby

Hyperpolarized 3He magnetic resonance functional imaging semiautomated segmentation.

RATIONALE AND OBJECTIVES 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). MATERIALS AND METHODS 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. RESULTS 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). CONCLUSIONS 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.

Hyperpolarized 3He and 129Xe MR Imaging in Healthy Volunteers and Patients with Chronic Obstructive Pulmonary Disease

PURPOSE To quantitatively compare hyperpolarized helium 3 (3He) and xenon 129 (129Xe) magnetic resonance (MR) images obtained within 5 minutes in healthy volunteers and patients with chronic obstructive pulmonary disease (COPD) and to evaluate the correlations between 3He and 129Xe MR imaging measurements and those from spirometry and plethysmography. MATERIALS AND METHODS This study was approved by an ethics board and compliant with HIPAA. Written informed consent was obtained from all subjects. Eight healthy volunteers and 10 patients with COPD underwent MR imaging, spirometry, and plethysmography. Ventilation defect percentages (VDPs) at 3He and 129Xe imaging were obtained by using semiautomated segmentation. Apparent diffusion coefficients (ADCs) were calculated from 3He (b=1.6 sec/cm2) and 129Xe (b=12 sec/cm2) diffusion-weighted images. VDPs at hyperpolarized 3He and 129Xe imaging were compared with a two-tailed Wilcoxon signed rank test and analysis of variance; Pearson correlation coefficients were used to evaluate the relationships among measurements. RESULTS 129Xe VDP was significantly greater than 3He VDP for patients with COPD (P<.0001) but not for healthy volunteers (P=.35), although 3He and 129Xe VDPs showed a significant correlation for all subjects (r=0.91, P<.0001). The forced expiratory volume in 1 second (FEV1) showed a similar and significant correlation with 3He VDP (r=-0.84, P<.0001) and 129Xe VDP (r=-0.89, P<.0001), although the correlation between the FEV1/forced vital capacity (FVC) ratio and 129Xe VDP (r=-0.95, P<.0001) was significantly greater (P=.01) than that for FEV1/FVC and 3He VDP (r=-0.84, P<.0001). A significant correlation was also observed for 3He and 129Xe ADC (r=0.97, P<.0001); 129Xe ADC was significantly correlated with diffusing capacity of lung for carbon monoxide (r=-0.79, P=.03) and computed tomographic emphysema measurements (areas with attenuation values in the 15th percentile: r=-0.91, P=.0003; relative areas with attenuation values of less than -950 HU: r=0.87, P=.001). CONCLUSION In patients with COPD, the VDP obtained with hyperpolarized 29Xe MR imaging was significantly greater than that with 3He MR imaging, suggesting incomplete or delayed filling of lung regions that may be related to the different properties of 129Xe gas and physiologic and/or anatomic abnormalities in COPD.

Chronic Obstructive Pulmonary Disease: Longitudinal Hyperpolarized 3He MR Imaging

PURPOSE 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. MATERIALS AND METHODS 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. RESULTS 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). CONCLUSION 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.

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

To compare hyperpolarized helium‐3 (3He) and xenon‐129 (129Xe) MRI in asthmatics before and after salbutamol inhalation.

Chronic obstructive pulmonary disease: quantification of bronchodilator effects by using hyperpolarized ³He MR imaging.

PURPOSE 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. MATERIALS AND METHODS 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. RESULTS 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. CONCLUSION 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.

Characteristics of COPD in never-smokers and ever-smokers in the general population: results from the CanCOLD study

Background There is limited data on the risk factors and phenotypical characteristics associated with spirometrically confirmed COPD in never-smokers in the general population. Aims To compare the characteristics associated with COPD by gender and by severity of airway obstruction in never-smokers and in ever-smokers. Method We analysed the data from 5176 adults aged 40 years and older who participated in the initial cross-sectional phase of the population-based, prospective, multisite Canadian Cohort of Obstructive Lung Disease study. Never-smokers were defined as those with a lifetime exposure of <1/20 pack year. Logistic regressions were constructed to evaluate associations for ‘mild’ and ‘moderate-severe’ COPD defined by FEV1/FVC <5th centile (lower limits of normal). Analyses were performed using SAS V.9.1 (SAS Institute, Cary, North Carolina, USA). Results The prevalence of COPD (FEV1/FVC<lower limits of normal) in never-smokers was 6.4%, constituting 27% of all COPD subjects. The common independent predictors of COPD in never-smokers and ever-smokers were older age, self reported asthma and lower education. In never-smokers a history of hospitalisation in childhood for respiratory illness was discriminative, while exposure to passive smoke and biomass fuel for heating were discriminative for women. COPD in never-smokers and ever-smokers was characterised by increased respiratory symptoms, ‘respiratory exacerbation’ events and increased residual volume/total lung capacity, but only smokers had reduced DLCO/Va and emphysema on chest CT scans. Conclusions The study confirmed the substantial burden of COPD among never-smokers, defined the common and gender-specific risk factors for COPD in never-smokers and provided early insight into potential phenotypical differences in COPD between lifelong never-smokers and ever-smokers. Trial registration number NCT00920348 (ClinicalTrials.gov); study ID number: IRO-93326.

Hyperpolarized 3He magnetic resonance imaging: Preliminary evaluation of phenotyping potential in chronic obstructive pulmonary disease

RATIONALE AND OBJECTIVES Emphysema and small airway obstruction are the pathological hallmarks of chronic obstructive pulmonary disease (COPD). The aim of this pilot study in a small group of chronic obstructive pulmonary disease (COPD) patients was to quantify hyperpolarized helium-3 ((3)He) magnetic resonance imaging (MRI) functional and structural measurements and to explore the potential role for (3)He MRI in detecting the lung structural and functional COPD phenotypes. MATERIALS AND METHODS We evaluated 20 ex-smokers with stage I (n=1), stage II (n=9) and stage III COPD (n=10). All subjects underwent same-day plethysmography, spirometry, (1)H MRI and hyperpolarized (3)He MRI at 3.0T. (3)He ventilation defect percent (VDP) was generated from (3)He static ventilation images and (1)H thoracic images and the (3)He apparent diffusion coefficient (ADC) was derived from diffusion-weighted MRI. RESULTS Based on the relative contribution of normalized ADC and VDP, there was evidence of a predominant (3)He MRI measurement in seven patients (n=3 mainly ventilation defects or VDP dominant (VD), n=4 mainly increased ADC or ADC dominant (AD)). Analysis of variance (ANOVA) showed significantly lower ADC for subjects with predominantly elevated VDP (p=0.02 compared to subjects with predominantly elevated ADC; p=0.008 compared to mixed group) and significantly decreased VDP for subjects with predominantly elevated ADC (p=0.003, compared to mixed group). CONCLUSION In this small pilot study, a preliminary analysis shows the potential for (3)He MRI to categorize or phenotype COPD ex-smokers, providing good evidence of feasibility for larger prospective studies.

Hyperpolarized (3)he ventilation defects used to predict pulmonary exacerbations in mild to moderate chronic obstructive pulmonary disease.

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 Georges 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.

What are ventilation defects in asthma

Background Hyperpolarised 3He 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 3He 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 3rd 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 3He 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 3He ventilation defects were older with significantly worse airway hyper-responsiveness, inflammation and airway remodelling but similar FEV1 as subjects with asthma without defects; hyperpolarised 3He ventilation abnormalities were spatially and quantitatively related to abnormally remodelled airways.

Pulmonary ventilation visualized using hyperpolarized helium-3 and xenon-129 magnetic resonance imaging: differences in COPD and relationship to emphysema

In subjects with chronic obstructive pulmonary disease (COPD), hyperpolarized xenon-129 ((129)Xe) magnetic resonance imaging (MRI) reveals significantly greater ventilation defects than hyperpolarized helium-3 ((3)He) MRI. The physiological and/or morphological determinants of ventilation defects and the differences observed between hyperpolarized (3)He and (129)Xe MRI are not yet understood. Here we aimed to determine the structural basis for the differences in ventilation observed between (3)He and (129)Xe MRI in subjects with COPD using apparent diffusion coefficients (ADC) and computed tomography (CT). Ten COPD ex-smokers provided written, informed consent and underwent MRI, CT, spirometry, and plethysmography. (3)He and (129)Xe MRI ventilation volume was generated using semiautomated segmentation, and ADC maps were registered to generate ADC values for lung regions of interest ventilated by both gases (ADCHX) and by (3)He gas only (ADCHO). CT wall area percentage and the lowest 15th percentile point of the CT lung density histogram (HU15%) were also evaluated. For lung regions accessed by (3)He gas only, mean (3)He ADCHO was significantly greater than for regions accessed by both gases (ADCHO = 0.503 ± 0.119 cm(2)/s, ADCHX = 0.470 ± 0.125 cm(2)/s, P < 0.0001). The difference between (3)He and (129)Xe ventilation volume was significantly correlated with CT HU15% (r = -65, P = 0.04) and (3)He ADCHO (r = 0.70, P = 0.02), but not CT wall area percentage (r = -0.34, P = 0.33). In conclusion, in this small study in COPD subjects, we observed significantly decreased (129)Xe MRI ventilation compared with (3)He MRI, and these regions of decreased (129)Xe ventilation were spatially and significantly correlated with regions of increased pulmonary emphysema, but not airway wall thickness.