Evaluating Small Airways Disease in Asthma and COPD using the Forced Oscillation Technique and Magnetic Resonance Imaging

Obstructive lung disease, including asthma and chronic obstructive pulmonary disease (COPD), is characterized by heterogeneous ventilation. Unfortunately, the underlying structure-function relationships and the relationships between measurements of heterogeneity and patient quality-of-life in obstructive lung disease are not well understood. Hyperpolarized noble gas MRI is used to visualize and quantify ventilation distribution and the forced oscillation technique (FOT) applies a multi-frequency pressure oscillation at the mouth to measure respiratory impedance to airflow (including resistance and reactance). My objective was to use FOT, ventilation MRI and computational airway tree modeling to better understand ventilation heterogeneity in asthma and COPD. FOT-measured respiratory system impedance was correlated with MRI ventilation heterogeneity and both were related to quality-of-life in asthma and COPD. FOT-measurements and model-predictions of reactance and small-airways resistance were correlated in asthma and COPD respectively. This study is the first to demonstrate the relationships between FOT-measured impedance, MRI ventilation heterogeneity, and patient quality-of-life

Functional lung imaging with synchrotron radiation : Methods and preclinical applications

Many lung disease processes are characterized by structural and functional heterogeneity that is not directly appreciable with traditional physiological measurements. Experimental methods and lung function modeling to study regional lung function are crucial for better understanding of disease mechanisms and for targeting treatment. Synchrotron radiation offers useful properties to this end: coherence, utilized in phase-contrast imaging, and high flux and a wide energy spectrum which allow the selection of very narrow energy bands of radiation, thus allowing imaging at very specific energies. K-edge subtraction imaging (KES) has thus been developed at synchrotrons for both human and small animal imaging. The unique properties of synchrotron radiation extend X-ray computed tomography (CT) capabilities to quantitatively assess lung morphology, and also to map regional lung ventilation, perfusion, inflammation and biomechanical properties, with microscopic spatial resolution. Four-dimensional imaging, allows the investigation of the dynamics of regional lung functional parameters simultaneously with structural deformation of the lung as a function of time. This review summarizes synchrotron radiation imaging methods and overviews examples of its application in the study of disease mechanisms in preclinical animal models, as well as the potential for clinical translation both through the knowledge gained using these techniques and transfer of imaging technology to laboratory X-ray sources.Peer reviewe

Airspace Diameter Map-A Quantitative Measurement of All Pulmonary Airspaces to Characterize Structural Lung Diseases.

(1) Background: Stereological estimations significantly contributed to our understanding of lung anatomy and physiology. Taking stereology fully 3-dimensional facilitates the estimation of novel parameters. (2) Methods: We developed a protocol for the analysis of all airspaces of an entire lung. It includes (i) high-resolution synchrotron radiation-based X-ray tomographic microscopy, (ii) image segmentation using the free machine-learning tool Ilastik and ImageJ, and (iii) calculation of the airspace diameter distribution using a diameter map function. To evaluate the new pipeline, lungs from adult mice with cystic fibrosis (CF)-like lung disease (βENaC-transgenic mice) or mice with elastase-induced emphysema were compared to healthy controls. (3) Results: We were able to show the distribution of airspace diameters throughout the entire lung, as well as separately for the conducting airways and the gas exchange area. In the pathobiological context, we observed an irregular widening of parenchymal airspaces in mice with CF-like lung disease and elastase-induced emphysema. Comparable results were obtained when analyzing lungs imaged with μCT, sugges-ting that our pipeline is applicable to different kinds of imaging modalities. (4) Conclusions: We conclude that the airspace diameter map is well suited for a detailed analysis of unevenly distri-buted structural alterations in chronic muco-obstructive lung diseases such as cystic fibrosis and COPD

Morphometrische Analyse des Azinus der humanen Lunge mittels synchrotron-basierter Mikro-Computertomographie

In der vorliegenden Arbeit wurde erstmals ein vollständiger dreidimensionaler Datensatz des Azinus der humanen Lunge mittels der Synchrotron-basierten Mikro-CT-Technik erstellt und anschließend eine quantitative Untersuchung der Strukturen des Azinus durchgeführt. Eine humane Lunge wurde durch die Beatmung mit Formalindampf in Inspirationsstellung fixiert und in einem 64-Zeilen Computertomographen gescannt. Die anschließend ausgestanzten Proben (N = 12, Durchmesser = 8 mm, Höhe = 10 mm) wurden mit Osmiumtetroxid kontrastverstärkt und mit einer Auflösung von 3,9 µm3 Voxelgröße in einem Mikro-CT mit Synchrotronstrahlenquelle gescannt. Mit einem automatisierten „Tree-Analysis“ Softwareprogramm konnten 8 Azini aus dem Volumendatensatz segmentiert werden. Die Morphometrischen Daten wurden mit dem Softwareprogramm ANALYZE 9.0 erhoben. Die Atemwege innerhalb der Azini verzweigten sich über 11 Generationen. Das mittlere Azinusvolumen wurde mit 131,3 ± 29,2 mm3 berechnet und die mittlere Oberfläche des Azinus betrug 1012 ± 26 cm2. Der Innere Durchmesser verringerte sich ausgehend von dem Bronchiolus terminalis von 0,66 ± 0,04 mm auf 0,34 ± 0,06 mm (P < 0,001) und blieb nach der siebten Generation konstant (P < 0,5). Die Länge der einzelnen Generationen variierte zwischen 0,52 und 0,93 mm und zeigte keine signifikanten Unterschiede zwischen der zweiten und elften Generation. Der Verzweigungswinkel der „Tochteräste“ schwankte zwischen 113º und 134º ohne signifikante Unterschiede zwischen den Generationen (P < 0,3). Die in vorangegangenen Arbeiten gezeigten Ergebnisse bezüglich der Morphometrie des humanen Azinus basieren auf den Methoden der Histomorphometrie. Diese arbeitet gewebedestruktiv und stellt lediglich Rückschlüsse von zweidimensionalen Serienschnitten auf dreidimensionale Strukturen her. Unsere Arbeit zeigt die Möglichkeit der quantitativen Erfassung der Strukturen des Azinus anhand eines vollständigen Volumendatensatzes unter Verwendung der Synchrotron- basierten Mikro-CT- Technik.Structural data about the human lung fin structure are mainly based on stereological methods applied to serial sections. As these methods utilize 2D images, which are often not contiguous, they suffer from inaccuracies which are overcome by analysis of 3D micro-CT images of the never-sectioned specimen. The purpose of our study was to generate a complete data set of the intact three-dimensional architecture of the human acinus using high resolution synchrotron-based micro-CT (synMCT). A human lung was inflation-fixed by formaldehyde ventilation and then scanned in a 64-slice CT over its apex to base extent. Lung samples (8-mm diameter, 10 mm height, N = 12) were punched out, stained with osmium tetroxide, and scanned using synMCT at (4 µm)3 voxel size. The lung functional unit (acinus, N = 8) was segmented from the 3D tomographic image using an automated tree-analysis software program. Morphometric data of the lung were analyzed by ANOVA. Intra-acinar airways branching occurred over 11 generations. The mean acinar volume was 131, 3 ± 29, 2 mm3 (range 92, 5- 171, 3 mm3) and the mean acinar surface was calculated with 1012 ± 26 cm2. The airway internal diameter (starting from the bronchiolus terminalis) decreases distally from 0,66 ± 0,04 mm to 0,34 ± 0,06 mm (P < 0,001) and remains constant after the seventh generation (P < 0,5). The length of each generation ranges between 0, 52 and 0, 93 mm and did not show significant differences between the second and eleventh generation. The branching angle between daughter branches varies between 113-degree and 134-degree without significant differences between the generations (P < 0, 3). This study demonstrates the feasibility of quantitating the 3D structure of the human acinus at the spatial resolution readily achievable using synMCT

Non-invasive Quantification of Alveolar Morphometry Measurements in Older Never-smokers

Diffusion-weighted noble gas pulmonary magnetic resonance imaging (MRI) provides in vivo images with a contrast uniquely sensitive to molecular displacement at cellular and sub-cellular length scales. We estimated the external airway radius (R) and internal airway radius (r) of the alveolar dimensions to evaluate potential differences in acinar duct morphometries in healthy older never-smokers and compared those with a group of ex-smokers. The acinar duct and alveolar MRI morphometry results were within the physiologically-valid range of parameters. Estimated values of internal (r) and external (R) airway radius as well as alveolar sheath (h) and mean linear intercept (Lm) for individual subjects were similar with low variance. Results showed that MRI measurements of lung air space size in healthy older never-smokers were elevated compared to previous results reported in younger never-smokers, and lower than in age-matched ex-smokers (p\u3c.05). Specifically, older never-smokers had significantly lower external and internal airway radius and mean linear intercept, but higher alveolar sheath thickness, alveolar density and surface area-to-volume ratio than ex-smokers (p\u3c.05). Such results are compatible with the senile emphysematous changes to healthy parenchyma that accompany aging. These results demonstrate the potential MRI has with regards to replacing histology and lung stereology as the gold standard for measuring pulmonary acinus microstructure

Measuring and modelling lung microstructure with hyperpolarised gas MRI

This thesis is concerned with the development of new techniques for measuring and modelling lung microstructure with hyperpolarised gas magnetic resonance imaging (MRI). This aim was pursued in the following five chapters: Development of a framework for lobar comparison of lung microstructure measurements derived from computed tomography (CT) and 3He diffusion-weighted MRI evaluated in an asthmatic cohort. Statistically significant linear correlations were obtained between 3He diffusion-weighted MRI and CT lung microstructure metrics in all lobar regions. Implementation of compressed sensing (CS) to facilitate the acquisition of 3D multiple b-value 3He diffusion-weighted MRI in a single breath-hold for whole lung morphometry mapping. Good agreement between CS-derived and fully-sampled whole lung morphometry maps demonstrates that CS undersampled 3He diffusion-weighted MRI is suitable for clinical lung imaging studies. Acquisition of whole lung morphometry maps with 129Xe diffusion-weighted MRI and CS. An empirically-optimised 129Xe diffusion time (8.5 ms) was derived and 129Xe lung morphometry values demonstrated strong agreement with 3He equivalent measurements. This indicates that 129Xe diffusion-weighted MRI is a viable alternative to 3He for whole lung morphometry mapping. Implementation of an in vivo comparison of the stretched exponential and cylinder theoretical gas diffusion models with both 3He and 129Xe diffusion-weighted MRI. Stretched exponential model diffusive length scale was related to cylinder model mean chord length in a non-linear power relationship; while the cylinder model mean alveolar diameter demonstrated excellent agreement with diffusive length scale. Investigation of clinical and physiological changes in lung microstructure with 3He and 129Xe diffusion-weighted MRI. Longitudinal studies with 3He and 129Xe diffusion-weighted MRI were used investigate changes in lung microstructure in cystic fibrosis and idiopathic pulmonary fibrosis. Lung inflation mechanisms at the acinar level were also investigated with 3He and 129Xe diffusion-weighted MRI acquired at two different lung volumes

In Vivo Magnetic Resonance Imaging Morphometry Measurements of Pulmonary Airspace Enlargement

Diffusion-weighted magnetic resonance imaging (MRI) provides unparalleled information and measurements of lung structure and function without the burden of ionizing radiation. In particular, diffusion-weighted MRI provides estimates of airspace enlargement, which is a hallmark characteristic of emphysema. MRI provides a way to measure in vivo mean-linear-intercept (Lm) and this is a promising measurement for clinical evaluation of disease progression in patients with Alpha-1 Antitrypsin Deficiency (AATD) in which airspace enlargement begins early in life. As such, our objective was to evaluate MRI measurements of airspace enlargement in AATD patients and compare these measurements to ex-smokers with chronic obstructive pulmonary disease (COPD) and healthy never-smokers. We compared these measurements with standard clinical measurements provided by spirometry, plethysmography and computed tomography; we also demonstrated that MRI detected differences in disease severity in patients with clinically similar measurements

Texture Analysis and Machine Learning to Predict Pulmonary Ventilation from Thoracic Computed Tomography

Chronic obstructive pulmonary disease (COPD) leads to persistent airflow limitation, causing a large burden to patients and the health care system. Thoracic CT provides an opportunity to observe the structural pathophysiology of COPD, whereas hyperpolarized gas MRI provides images of the consequential ventilation heterogeneity. However, hyperpolarized gas MRI is currently limited to research centres, due to the high cost of gas and polarization equipment. Therefore, I developed a pipeline using texture analysis and machine learning methods to create predicted ventilation maps based on non-contrast enhanced, single-volume thoracic CT. In a COPD cohort, predicted ventilation maps were qualitatively and quantitatively related to ground-truth MRI ventilation, and both maps were related to important patient lung function and quality-of-life measures. This study is the first to demonstrate the feasibility of predicting hyperpolarized MRI-based ventilation from single-volume, breath-hold thoracic CT, which has potential to translate pulmonary ventilation information to widely available thoracic CT imaging