The goal of this proposal is to develop and evaluate hyperpolarized helium-3 diffusion magnetic resonance imaging (He-3 dMRI) and low dose quantitative computed tomography (LD-QCT) indexes of emphysema as noninvasive biomarkers for the presence, severity, and progression of emphysema. Emphysema is a pathologic abnormality of the lungs defined by enlargement of terminal airspaces and destruction of airspace walls 1, and is commonly present in the millions of patients with chronic obstructive pulmonary disease. The pathologic changes begin before spirometric abnormalities develop, and do not correlate strongly with spirometry. Spirometry is thus a relatively insensitive and inaccurate means of assessing for emphysema. A sensitive and accurate biomarker of emphysema would allow for early diagnosis, intervention, and evaluation of new therapies. Previous studies have established conventional CT as a highly accurate test for the presence and severity of emphysema 2-6,which can be quantified by the decrease in x-ray attenuation of the lungs that results from airspace enlargement and alveolar destruction. However, CT is performed using relatively high doses of ionizing radiation, which greatly limits its acceptability as a screening and follow-up test, particularly in early or mild disease. In recent years, other noninvasive imaging tests for emphysema have been designed that require no or greatly reduced ionizing radiation. One new test, He-3 dMRI, uses a specially constructed MRI pulse sequence to measure the degree to which diffusivity of inhaled hyperpolarized He-3 gas is restricted by alveolar walls. We 7and others 8 have shown that this measurement, the apparent diffusion coefficient (ADC), is increased (gas diffusion is less restricted) when alveolar spaces are enlarged in emphysema. Although these studies have confirmed that the ADC is altered in emphysema, they have not focused on how early the disease can be detected, or how well He-3 dMRI can discriminate different degrees of emphysema severity. Another test, low dose CT scanning, allows depiction of substantial lung detail at less than 20 percent of the radiation dose of conventional CT 9. However, the radiation dose reduction comes at the cost of an increase in image noise, which alters tissue density measurements. In addition, the technological innovation of multidetector CT scanning allows several options for slice thickness and reconstruction algorithm (smooth vs. sharp) from the same scan data, each producing a different lung density profile. Though promising, the optimal technique and validity of both He-3 dMRI and LD-QCT have yet to be established. We hypothesize that 1) Optimizing He-3 dMRI and LD-QCT techniques will allow sensitive and accurate assessment of emphysema, compared to lung morphometry, 2) The optimized He-3 dMRI and LD-QCT techniques will provide valid biomarkers of emphysema that can be applied to other populations, and 3) He-3 dMRI and LD-QCT will allow identification of emphysema progression over time. To further the development of He-3 dMRI and LD-QCT measurements as noninvasive biomarkers of emphysema, we propose to: I. Optimize the He-3 dMRI and LD-QCT scanning and analysis parameters for quantifying emphysema, compared to the gold standard of lung morphometry. II. Validate optimized He-3 dMRI and LD-QCT as quantitative tests of emphysema, compared to the gold standard of lung morphometry. III. Determine the detectability of emphysema progression from serial He-3 dMRI and LD-QCT imaging, relative to functional progression of the disease. We will study three separate groups of subjects. In the first group, we will determine which scanning and analysis parameters provide ADC and LD-QCT lung tissue density measurements that most accurately quantify the amount of emphysema present pathologically in lobectomy specimens (Aim I). We will then use the optimized scanning and analysis techniques to validate these measurements in a different group, compared to the amount of emphysema present in lobectomy specimens (Aim II.). In a third group of subjects, we will determine ADC and LD-QCT lung attenuation measurements at serial time points to assess for emphysema progression (Aim III). Aim III. Determine the detectability of emphysema progression from serial He-3 dMRI and LD-QCT imaging, relative to functional progression of the disease