Quantitative MRI-PET Imaging of Pulmonary Fibrosis

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Abstract The administrative supplement will help the PI to maintain productivity while fulfilling her caregiving responsibilities and achieve the goal of the parent K25 project to develop and implement an MR-PET lung imaging tool to accurately quantify molecular abnormalities associated with pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease with a median survival of less than 4 years from the time of diagnosis. The treatment options remain limited due to highly variable clinical courses and poorly understood pathogenic mechanisms. Current strategies to diagnose and monitor IPF include lung biopsy, pulmonary function tests that measure global lung function, and anatomic imaging tools such as high-resolution computed tomography. Yet these methods are limited in their ability to detect disease early, determine disease activity, provide accurate prognosis or monitor the therapeutic response. Molecular imaging may be an alternative approach that is more sensitive to detect early fibrosis and potentially capable of distinguishing new, active fibrosis from stable disease – urgent and unmet clinical needs. Advancing the capacity of quantitative imaging tools to determine IPF disease activity would improve patient care and facilitate much-needed drug development. Magnetic resonance (MR) imaging can provide multiple readouts of morphology, physiology, metabolism, and molecular processes, while positron emission tomography (PET) offers exquisite sensitivity to interrogate pathobiology. Advanced MR and PET techniques have had major impacts on oncology, cardiovascular diseases, and neurological disorders. However, their application to lung imaging has been historically limited because of low proton density and the fast signal decay due to susceptibility artifacts at air- tissue interfaces for MRI, while PET quantification remains challenging due to respiratory motion, photon attenuation, and regional variations in tissue, air, and blood fractions. Recently, we developed a gallium(Ga)-68 labeled collagen-binding PET probe for fibrosis imaging. Ex vivo measurement showed a 5-fold higher uptake in bleomycin-injured fibrotic lungs than controls. However, both in vivo animal and first-in-human studies showed a PET signal difference of 35-40%. This discrepancy highlights the importance of motion, attenuation, and partial volume correction in PET quantification. Our preliminary simulation results show that attenuation and motion correction substantially increase the imaging contrast. Recent technical advances such as parallel imaging, ultra- short time to echo (UTE), and rotating phase encoding have enabled advanced proton MR imaging of the lung. Thus, simultaneous MR-PET promises to improve PET quantification by using the spatially and temporally correlated MR information to correct for motion, partial volume, and photon attenuation effects. Capitalizing on the technical advances in imaging and the sensitive collagen-targeted probe, this proposal aims to establish an MR-PET lung imaging tool to accurately quantify collagen deposition in the lung of IPF patients for precise assessment of disease activity.