Imaging Biomarkers of Pulmonary Structure and Function

Asthma and chronic obstructive pulmonary disease (COPD) are characterized by airflow limitations resulting from airway obstruction and/or tissue destruction. The diagnosis and monitoring of these pulmonary diseases is primarily performed using spirometry, specifically the forced expiratory volume in one second (FEV1), which measures global airflow obstruction and provides no regional information of the different underlying disease pathologies. The limitations of spirometry and current therapies for lung disease patients have motivated the development of pulmonary imaging approaches, such as computed tomography (CT) and magnetic resonance imaging (MRI). Inhaled hyperpolarized noble gas MRI, specifically using helium-3 (3He) and xenon-129 (129Xe) gases, provides a way to quantify pulmonary ventilation by visualizing lung regions accessed by gas during a breath-hold, and alternatively, regions that are not accessed - coined “ventilation defects.” Despite the strong foundation and many advantages hyperpolarized 3He MRI has to offer research and patient care, clinical translation has been inhibited in part due to the cost and need for specialized equipment, including multinuclear-MR hardware and polarizers, and personnel. Accordingly, our objective was to develop and evaluate imaging biomarkers of pulmonary structure and function using MRI and CT without the use of exogenous contrast agents or specialized equipment. First, we developed and compared CT parametric response maps (PRM) with 3He MR ventilation images in measuring gas-trapping and emphysema in ex-smokers with and without COPD. We observed that in mild-moderate COPD, 3He MR ventilation abnormalities were related to PRM gas-trapping whereas in severe COPD, ventilation abnormalities correlated with both PRM gas-trapping and PRM emphysema. We then developed and compared pulmonary ventilation abnormalities derived from Fourier decomposition of free-breathing proton (1H) MRI (FDMRI) with 3He MRI in subjects with COPD and bronchiectasis. This work demonstrated that FDMRI and 3He MRI ventilation defects were strongly related in COPD, but not in bronchiectasis subjects. In COPD only, FDMRI ventilation defects were spatially related with 3He MRI ventilation defects and emphysema. Based on the FDMRI biomarkers developed in patients with COPD and bronchiectasis, we then evaluated ventilation heterogeneity in patients with severe asthma, both pre- and post-salbutamol as well as post-methacholine challenge, using FDMRI and 3He MRI. FDMRI free-breathing ventilation abnormalities were correlated with but under-estimated 3He MRI static ventilation defects. Finally, based on the previously developed free-breathing MRI approach, we developed a whole-lung free-breathing pulmonary 1H MRI technique to measure regional specific-ventilation and evaluated both asthmatics and healthy volunteers. These measurements not only provided similar information as specific-ventilation measured using plethysmography, but also information about regional ventilation defects that were correlated with 3He MRI ventilation abnormalities. These results demonstrated that whole-lung free-breathing 1H MRI biomarker of specific-ventilation may reflect ventilation heterogeneity and/or gas-trapping in asthma. These important findings indicate that imaging biomarkers of pulmonary structure and function using MRI and CT have the potential to regionally reveal the different pathologies in COPD and asthma without the use of exogenous contrast agents. The development and validation of these clinically meaningful imaging biomarkers are critically required to accelerate pulmonary imaging translation from the research workbench to being a part of the clinical workflow, with the overall goal to improve patient outcomes

Pulmonary Imaging to Better Understand Asthma

Asthma is characterized using the spirometry measurement of the forced expiratory volume in one second (FEV1). Simple and inexpensive, FEV1 provides a global estimate of lung function but this metric cannot regionally identify airways responsible for airflow limitation, asthma symptoms or control. Work that brought about an understanding that airway abnormalities are heterogeneously distributed within the lung in asthma patients has motivated the development of pulmonary imaging approaches, such as hyperpolarized helium-3 (3He) and xenon-129 (129Xe) magnetic resonance imaging (MRI). These methods provide a way to visualize and quantify lung regions accessed by gas during a breath-hold, as well as those not accessed, referred to as “ventilation defects.” Despite the strong foundation for the use of MRI in asthma clinical care, clinical translation has been inhibited in part due to the current limited clinical and physiological understanding of ventilation defects. Accordingly, our objective was to better understand the structural determinants and clinical consequences of MRI ventilation defects observed in asthma and to provide a foundation for imaging to guide clinical decisions and asthma therapy. We evaluated the effect of gas properties on ventilation defects. In asthmatics, we compared hyperpolarized 3He and 129Xe MRI before and after bronchodilator administration and showed greater gas distribution abnormalities using 129Xe compared to 3He before bronchodilation. The temporal behavior of asthma ventilation defects was then investigated by generating personalized temporal-spatial pulmonary function maps from 3He MR images acquired on three occasions. Persistent and intermittent defects were visualized and quantified using this tool and were recognized as potential intermediate endpoints or targets for treatment. We then evaluated clinical and emerging computed tomography-derived airway morphology measurements in asthmatics with and without defects. Ventilation defects were observed in two-thirds of well-controlled asthmatics who had worse lung function, increased airway inflammation, airway hyperresponsiveness and greater airway wall thickness than asthmatics without ventilation defects. Acknowledging that asthma control is the primary goal of asthma treatment, we investigated the relationship, and established a link between worse ventilation and poor control. These findings provide a better understanding of asthma ventilation defects and strongly support their potential as a novel treatment target