Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

Grace Parraga

Abstract

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.


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