Measurement of T1 relaxation time in lungs - Preclinical and clinical MRI applications to COPD

Abstract: Monitoring of regional lung function in clinical trials of chronic obstructive pulmonary disease (COPD) requires alternative endpoints beyond global pulmonary function tests (PFTs), which is the most common approach for diagnosing lung function abnormalities in humans. A promising magnetic resonance imaging (MRI) biomarker of lung disease in humans and animals is the T1 relaxation parameter. Only a limited amount of data on native T1 behaviour in COPD patients and animal models of COPD are available, especially in relation to other relevant markers such as computed tomography (CT) and PFTs in humans; and bronchoalveolar lavage (BAL) fluid analysis and histology in animals. The smoking history in humans and tobacco smoke (TS) exposure in animals are important factors that need to be investigated in relation to lung T1 since tobacco smoking is the major cause for development of COPD. Therefore, we have investigated whether lung T1 can be used as a biomarker of COPD in man, if there is a direct effect of TS on lung T1 in healthy current smokers, and the repeatability of T1 measurements acquired at two visits. T1 was also related to smoking history, CT and PFTs. Subsequently, lung T1 was investigated in a mouse model of COPD and correlated to BAL, lung mechanics and histology to increase the understanding of how T1 relates to the pathophysiological aspects of COPD. A preclinical three dimensional (3D) ultra-short echo time (UTE) T1 mapping protocol was developed to enable the COPD study in mouse. We found from the human studies that: lung T1 shortens in COPD patients, ageing shortens T1 and that TS exposure does not affect T1 in healthy smokers. Additionally, lung T1 was repeatable and correlated with CT lung density and PFT parameters. Lung T1 was also shortened in the TS exposed mice, most likely due to early signs of disease. In naive mice, high lung T1 repeatability over one month was found. In conclusion, lung T1 mapping is an attractive imaging biomarker of COPD in mouse and man for future longitudinal studies. The potential of MRI-based T1 mapping to evaluate early COPD has been enhanced by the advances in this thesis.