LAUSR

Alpha-1 antitrypsin deficiency (AATD) leads to disabling chronic obstructive pulmonary disease (COPD). Current therapy aimed at slowing lung disease progression includes exogenous alpha-1 antitrypsin augmentation therapy, but there are few potential new treatments under development. Currently used measurements of AATD-related emphysema include the forced expiratory volume in 1 second (FEV1) and the diffusing capacity of carbon monoxide (DLCO); both are relatively insensitive to therapy, 1 although computed tomography (CT) lung density measurements have been shown to worsen more slowly in treated patients. Hyperpolarized magnetic resonance imaging (MRI) has emerged as a possible alternative or complementary method for evaluating lung microstructure and function. Longitudinal worsening of MRI ventilation-defect-percent (VDP) was shown to be related to symptoms and exercise capacity in COPD patients in whom FEV1 was not predictive. The apparent diffusion coefficient (ADC) measured using He and Xe MRI has also been demonstrated in patients with AATD. Although He MRI ADC is highly reproducible, these values only report from well-ventilated lung, which is important because as AATD emphysema worsens over time, no inhaled gas MRI information can be gleaned from unventilated lung regions. Our goal was to develop a new biomarker of AATD emphysema that incorporates functional and microstructural abnormalities that would be sensitive to disease changes over time. We evaluated a single patient with a clinical diagnosis of AATD, who provided written informed consent to study protocols (registered at clinicaltrials.gov as NCT02279329 and NCT02723474), approved by a local Research Ethics Board and federal regulatory agency. He was evaluated using spirometry, plethysmography according to guidelines and MRI at each visit; he also completed the St. George Respiratory Questionnaire (SGRQ), 6-minute walk test (6MWT) and thoracic CT on a 64-slice Lightspeed VCT scanner (General Electric Healthcare, Milwaukee, WI) (64 3 0.625 mm, 120 kVp, 100 effective mA, tube rotation time5 500 msec, and pitch 5 1.0) in breath-hold after inhalation of a 1-L N2 bag from FRC on visits 2, 4, and 6. The total effective dose was 1.8 mSv (Health Protection Agency of the United Kingdom, NRPBSR250). MRI was performed on a 3T system (MR750 Discovery, GE HealthCare) as previously described with diffusion-weighted data acquired using a multislice interleaved 2D gradient echo diffusionweighted sequence for seven 30-mm coronal slices (900 ls selective radio frequency pulse, flip angle h 5 48, echo time 5 3.9 msec, repetition time 5 5.6 msec, bandwidth 5 62.5 kHz, in-plane resolution 5 3.125 3 3.125 mm, b 5 0, 1.6 s/cm); the diffusionsensitization gradient pulse ramp up-down time 5 500 ls and diffusion time 5 1460 ls. The relative area of the CT density-histogram with values< –950 Hounsfield Units (HU) (RA950) and MRI ventilation-defect-percent (VDP) were measured using custom-built (MatLab R2014b; MathWorks, Natick, MA) software. ADC maps were generated using He diffusion-weighted images as previously described. To determine regional information, the apical region was segmented from the basal region based on the location of the carina. It was previously shown in patients with severe COPD that ventilation defects spatially and quantitatively correlated with emphysematous bullae, which reinforces the notion that lung regions with severe emphysema have long time-constants for filling and cannot be ventilated during a short breath-hold scan. To account for this, we considered the diffusing capacity of the lung for carbon monoxide (DLCO) normalized to the ventilated alveolar volume, which generates KCO, as shown in Eq. 1: