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PURPOSE In this study, we compared hyperpolarized 3He and 129Xe images from patients with cystic fibrosis using two commonly applied magnetic resonance sequences, standard gradient echo (GRE) and balanced steady-state free precession (TrueFISP) to quantify regional similarities and differences in signal distribution and defect analysis. MATERIALS AND METHODS Ten patients (7M/3F) with cystic fibrosis underwent hyperpolarized gas MR imaging with both 3He and 129Xe. Six had MRI with both GRE, and TrueFISP sequences and four patients had only GRE sequence but not TrueFISP. Ventilation defect percentages (VDPs) were calculated as lung voxels with

Hyperpolarized (HP) 129 Xe MRI uniquely images pulmonary ventilation, gas exchange, and terminal airway morphology rapidly and safely, providing novel information not possible using conventional imaging modalities or pulmonary function tests. As such, there is mounting interest in expanding the use of biomarkers derived from HP 129 Xe MRI as outcome measures in multi-site clinical trials across a range of pulmonary disorders. Until recently, HP 129 Xe MRI techniques have been developed largely independently at a limited number of academic centers, without harmonizing acquisition strategies. To promote uniformity and adoption of HP 129 Xe MRI more widely in translational research, multi-site trials, and ultimately clinical practice, this position paper from the 129 Xe MRI Clinical Trials Consortium (https://cpir.cchmc.org/XeMRICTC) recommends standard protocols to harmonize methods for image acquisition in HP 129 Xe MRI. Recommendations are described for the most common HP gas MRI techniques-calibration, ventilation, alveolar-airspace size, and gas exchange-across MRI scanner manufacturers most used for this application. Moreover, recommendations are described for 129 Xe dose volumes and breath-hold standardization to further foster consistency of imaging studies. The intention is that sites with HP 129 Xe MRI capabilities can readily implement these methods to obtain consistent high-quality images that provide regional insight into lung structure and function. While this document represents consensus at a snapshot in time, a roadmap for technical developments is provided that will further increase image quality and efficiency. These standardized dosing and imaging protocols will facilitate the wider adoption of HP 129 Xe MRI for multi-site pulmonary research.

Cardiac magnetic resonance imaging (CMR) provides many cardiac functional insights. The reliance of standard cine CMR upon breath holds is not feasible for some patients. Its process of combining multiple heartbeats is unsuited to arrhythmias. Real-time cine methods sidestep these problems but can introduce respiratory displacement of the heart. To aid CMR acquisitions during breathing, we developed post-processing software to diminish the effects of respiratory displacement of the heart. It uses principal component analysis to resolve respiratory motions from cardiac cycles in the dynamic image. The software groups heartbeats from expiration and inspiration to decrease the appearance of respiratory motion. The effects of respiratory motion and such motion correction were evaluated on short-axis views (acquired with compressed sensing) of 11 healthy subjects and 8 cardiac patients. The smallest correlation coefficients between end-systolic frames of the original dynamic scans averaged 0.79. After segregation of cardiac cycles by respiratory phase, the mean correlation coefficients between cardiac cycles were 0.94 ± 0.03 at end-expiration and 0.90 ± 0.08 at end-inspiration. The improvements in correlation coefficients were significant in paired t-tests, i.e., P ≤ 0.01 for healthy subjects and P ≤ 0.001 for heart patients at end-expiration. Two expert cardiothoracic radiologists, blinded to the processing, assessed the dynamic images in terms of blood-myocardial contrast, endocardial interface definition, and motion artifacts. Clinical assessment preferred cardiac cycles during end-expiration, which maintained or enhanced scores in 90% of healthy subjects and 83% of the heart patients. Performance remained high in a case of arrhythmia and irregular breathing. Heartbeats collected from end-expiration reliably mitigated respiratory motion when the new software was applied to DICOM files from real-time acquisitions.

Background: Alveolar development and lung parenchymal simplification are not well characterized in vivo in neonatal patients with respiratory morbidities, such as bronchopulmonary dysplasia (BPD). Hyperpolarized (HP) gas diffusion magnetic resonance imaging (MRI) is a sensitive, safe, nonionizing, and noninvasive biomarker for measuring airspace size in vivo but has not yet been implemented in young infants. Objective: This work quantified alveolar airspace size via HP gas diffusion MRI in healthy and diseased explanted infant lung specimens, with comparison to histological morphometry. Methods: Lung specimens from 8 infants were obtained: 7 healthy left upper lobes (0–16 months, post-autopsy) and 1 left lung with filamin-A mutation, closely representing BPD lung disease (11 months, post-transplantation). Specimens were imaged using HP 3He diffusion MRI to generate apparent diffusion coefficients (ADCs) as biomarkers of alveolar airspace size, with comparison to mean linear intercept (Lm) via quantitative histology. Results: Mean ADC and Lm were significantly increased throughout the diseased specimen (ADC = 0.26 ± 0.06 cm2/s, Lm = 587 ± 212 µm) compared with healthy specimens (ADC = 0.14 ± 0.03 cm2/s, Lm = 133 ± 37 µm; p < 1 × 10−7); increased values reflect enlarged airspaces. Mean ADCs in healthy specimens were significantly correlated to Lm (r = 0.69, p = 0.041). Conclusions: HP gas diffusion MRI is sensitive to healthy and diseased regional alveolar airspace size in infant lungs, with good comparison to quantitative histology in ex vivo specimens. This work demonstrates the translational potential of gas MRI techniques for in vivo assessment of normal and abnormal alveolar development in neonates with pulmonary disease.

RATIONALE Hyperpolarized (HP) 129 Xe-MRI provides non-invasive methods to quantify lung function and structure, with the 129 Xe apparent diffusion coefficient (ADC) being a well validated measure of alveolar airspace size. However, the experimental factors that impact the precision and accuracy of HP 129 Xe ADC measurements have not been rigorously investigated. Here, we introduce an analytical model to predict the experimental uncertainty of 129 Xe ADC estimates. Additionally, we report ADC dependence on age in healthy pediatric volunteers. METHODS An analytical expression for ADC uncertainty was derived from the Stejskal-Tanner equation and simplified Bloch equations appropriate for HP media. Parameters in the model were maximum b-value (bmax ), number of b-values (Nb ), number of phase encoding lines (Nph ), flip angle and the ADC itself. This model was validated by simulations and phantom experiments, and five fitting methods for calculating ADC were investigated. To examine the lower range for 129 Xe ADC, 32 healthy subjects (age 6-40 years) underwent diffusion-weighted 129 Xe MRI. RESULTS The analytical model provides a lower bound on ADC uncertainty and predicts that decreased signal-to-noise ratio yields increases in relative uncertainty (ϵADC) . As such, experimental parameters that impact non-equilibrium 129 Xe magnetization necessarily impact the resulting ϵADC . The values of diffusion encoding parameters (Nb and bmax ) that minimize ϵADC strongly depend on the underlying ADC value, resulting in a global minimum for ϵADC . Bayesian fitting outperformed other methods (error

RATIONALE: Hyperpolarized (HP) (129)Xe-MRI provides non-invasive methods to quantify lung function and structure, with the (129)Xe apparent diffusion coefficient (ADC) being a well-validated measure of alveolar airspace size. However, the experimental factors that impact the precision and accuracy of HP (129)Xe ADC measurements have not been rigorously investigated. Here, we introduce an analytical model to predict the experimental uncertainty of (129)Xe ADC estimates. Additionally, we report ADC dependency on age in healthy pediatric volunteers. METHODS: An analytical expression for ADC uncertainty was derived from the Stejskal–Tanner equation and a simplified Bloch equations appropriate for hyperpolarized media. Parameters in the model were maximum b-value (b(max)), number of b-values (N(b)), number of phase encoding lines (N(ph)), flip angle and the ADC itself. This model was validated by simulations and phantom experiments, and five fitting methods for calculating ADC were investigated. To examine the lower range for (129)Xe ADC, 32 healthy subjects (age 6–40 years) underwent diffusion-weighted (129)Xe MRI. RESULTS: The analytical model provides a lower bound on ADC uncertainty and predicts decreased signal-to-noise ratio yields increases in relative uncertainty (ϵ(ADC)). As such, experimental parameters that impact non-equilibrium (129)Xe magnetization necessarily impact the resulting ϵ(ADC). The values of diffusion encoding parameters (N(b) and b(max)) that minimize ϵ(ADC) strongly depend on the underlying ADC value, resulting in a global minimum for ϵ(ADC). Bayesian fitting outperformed other methods (error

Bronchiectasis is the permanent abnormal dilation of the airways and can be associated with various pathogeneses and outcomes. Proper diagnosis and evaluation of bronchiectasis employs x-ray CT, though emerging research has also shown MRI to be sensitive to the disease. The goal of this article is to review recent research in CT and MRI of bronchiectasis and associated diseases. Techniques in quantitative CT continue to improve and may improve consistency in bronchiectasis evaluation and reduce reader scoring load. While CT is the “gold standard” for evaluation of bronchiectasis, new techniques in magnetic resonance imaging have dramatically increased in sensitivity to bronchiectasis though without patient exposure to ionizing radiation. MRI may therefore be an attractive alternative to CT in some cases, yet further clinical trials are necessary. Although bronchiectasis is an irreversible disease, new understanding of airway structure-function relationships may improve clinical management.

Background The ventilation defect percent (VDP), measured from hyperpolarized (HP) 129Xe magnetic resonance imaging (MRI), is sensitive to functional changes in cystic fibrosis (CF) lung disease. The purpose of this study was to measure and compare VDP from HP 129Xe MRI acquired at two institutions in stable pediatric CF subjects with preserved lung function. Methods This retrospective analysis included 26 participants from two institutions (18 CF, 8 healthy, age range 10–17). Pulmonary function tests, N2 multiple breath washout (to measure lung clearance index, LCI), and HP 129Xe MRI were performed. VDP measurements were compared between two trained analysts using mean-anchored linear binning. Correlations were investigated for VDP compared to the forced expiratory volume in one second (FEV1) and LCI. Results VDP measurements agreed for the two analysts with an intraclass correlation coefficient of 0.99. In the combined dataset, VDP measured by Analyst 1 was 5.96 ± 1.82% and 15.96 ± 6.76% for the healthy and CF groups, respectively (p = .0004). Analyst 2 showed similar differences between healthy and CF (p = .0003). VDP measured by either analyst was shown to correlate with FEV1 (R2 = 0.33, p = .003; and R2 = 0.26, p = .009 for Analysts 1 and 2, respectively) and LCI (R2 = 0.76, p Conclusion HP 129Xe MRI provides a robust measurement of ventilation heterogeneity in stable pediatric CF subjects at two sites. Since measurements performed at two sites yielded similar VDP values with near-identical values between different analysts, implementation of the technique in multi-center trials in CF appears feasible.

Computational fluid dynamics (CFD) simulations of respiratory airflow have the potential to change the clinical assessment of regional airway function in health and disease, in pulmonary medicine and otolaryngology. For example, in diseases where multiple sites of airway obstruction occur, such as obstructive sleep apnea (OSA), CFD simulations can identify which sites of obstruction contribute most to airway resistance and may therefore be candidate sites for airway surgery. The main barrier to clinical uptake of respiratory CFD to date has been the difficulty in validating CFD results against a clinical gold standard. Invasive instrumentation of the upper airway to measure respiratory airflow velocity or pressure can disrupt the airflow and alter the subject’s natural breathing patterns. Therefore, in this study, we instead propose phase contrast (PC) velocimetry magnetic resonance imaging (MRI) of inhaled hyperpolarized 129Xe gas as a non-invasive reference to which airflow velocities calculated via CFD can be compared. To that end, we performed subject-specific CFD simulations in airway models derived from 1H MRI, and using respiratory flowrate measurements acquired synchronously with MRI. Airflow velocity vectors calculated by CFD simulations were then qualitatively and quantitatively compared to velocity maps derived from PC velocimetry MRI of inhaled hyperpolarized 129Xe gas. The results show both techniques produce similar spatial distributions of high velocity regions in the anterior-posterior and foot-head directions, indicating good qualitative agreement. Statistically significant correlations and low Bland-Altman bias between the local velocity values produced by the two techniques indicates quantitative agreement. This preliminary in vivo comparison of respiratory airway CFD and PC MRI of hyperpolarized 129Xe gas demonstrates the feasibility of PC MRI as a technique to validate respiratory CFD and forms the basis for further comprehensive validation studies. This study is therefore a first step in the pathway towards clinical adoption of respiratory CFD.

Rationale: Adverse events have limited the use of bronchial thermoplasty (BT) in severe asthma. Objectives: We sought to evaluate the effectiveness and safety of using (129)Xe magnetic resonance imaging ((129)Xe MRI) to prioritize the most involved airways for guided BT. Methods: Thirty subjects with severe asthma were imaged with volumetric computed tomography and (129)Xe MRI to quantitate segmental ventilation defects. Subjects were randomized to treatment of the six most involved airways in the first session (guided group) or a standard three-session BT (unguided). The primary outcome was the change in Asthma Quality of Life Questionnaire score from baseline to 12 weeks after the first BT for the guided group compared with after three treatments for the unguided group. Measurements and Main Results: There was no significant difference in quality of life after one guided compared with three unguided BTs (change in Asthma Quality of Life Questionnaire guided = 0.91 [95% confidence interval, 0.28–1.53]; unguided = 1.49 [95% confidence interval, 0.84–2.14]; P = 0.201). After one BT, the guided group had a greater reduction in the percentage of poorly and nonventilated lung from baseline when compared with unguided (−17.2%; P = 0.009). Thirty-three percent experienced asthma exacerbations after one guided BT compared with 73% after three unguided BTs (P = 0.028). Conclusions: Results of this pilot study suggest that similar short-term improvements can be achieved with one BT treatment guided by (129)Xe MRI when compared with standard three-treatment-session BT with fewer periprocedure adverse events.

Background: Although adolescent idiopathic scoliosis (AIS) is associated with decreased respiratory quality of life, it is unknown how AIS impacts distal lung microstructure. Recent reports indicate that alveoloalarization continues throughout adolescence, and human and animal studies have demonstrated the importance of mechanical forces on normal lung development. We therefore performed this pilot study hypothesizing that patients with AIS would have alterations in alveolar-airspace size, number, or structure compared to adolescents without AIS. Objective and Study Design: We conducted a prospective observational trial using hyperpolarized helium (HHe) MRI in control and adolescent idiopathic scoliosis (AIS) subjects to determine if AIS is associated with lung microstructural changes and whether posterior spinal fusion (PSF) impacts these changes. Methods We used hyperpolarized helium (HHe) and proton MRI to assess lung microstructure in 13 AIS and 16 control subjects aged 8-21 years. Clinical trial registration number NCT03539770. Results: At baseline, there were no significant differences in alveolar size, number, or alveolar duct morphometry between AIS and control subjects or between the concave and convex lungs of AIS subjects. At one year after PSF AIS subjects had an increase in alveolar density in the formerly convex lung (p=0.05), likely reflecting a change in thoracic anatomy, but there were no other significant changes in lung microstructure. Modeling of alveolar size over time demonstrated similar rates of alveolar growth in control and AIS subjects in both right and left lungs pre- and post-PSF. Conclusions: In this study, we found no evidence that AIS or PSF impacts lung microstructure.

Fast apparent transverse relaxation (short T(2)*) is a common obstacle when attempting to perform quantitative (1)H MRI of the lungs. While T(2)* times are longer for pulmonary hyperpolarized (HP) gas functional imaging—in particular for gaseous (129)Xe—T(2)* can still lead to quantitative inaccuracies for sequences requiring longer echo times (such as diffusion weighted images) or longer readout duration (such as spiral). This is especially true in preclinical studies, where high magnetic fields lead to shorter relaxation times than are typically seen in human studies. However, T(2)* of HP (129)Xe in the most common animal model of human disease (mice) has not been reported. Herein, we present a multi-echo radial Flyback imaging sequence and use it to measure HP (129)Xe T(2)* at 7T under a variety of respiratory conditions. This sequence mitigates the impact of T(1) relaxation outside the animal by using multiple gradient-refocused echoes to acquire images at a number of effective echo times for each radio frequency (RF) excitation. After validating the sequence using a phantom containing water doped with superparamagnetic iron oxide nanoparticles, we measured the (129)Xe T(2)* in vivo for ten healthy C57Bl/6J mice and found T(2)* ~ 5 ms in the lung airspaces. Interestingly, T(2)* was relatively constant over all experimental conditions and did not vary significantly with age, sex, mass, or the O(2) content of the inhaled gas mixture. These results are discussed in the context of T(2)* relaxation within porous media.

Adolescent idiopathic scoliosis (AIS) is associated with decreased respiratory quality of life and impaired diaphragm function. Recent hyperpolarized helium (HHe) MRI studies show alveolarization continues throughout adolescence, and mechanical forces are known to impact alveolarization. We therefore hypothesized that patients with AIS would have alterations in alveolar size, alveolar number, or alveolar septal dimensions compared to adolescents without AIS, and that posterior spinal fusion (PSF) might reverse these differences. We conducted a prospective observational trial using HHe MRI to test for changes in alveolar microstructure in control and AIS subjects at baseline and one year. After obtaining written informed consent from subjects' legal guardians and assent from the subjects, we performed HHe and proton MRI in 14 AIS and 16 control subjects aged 8-21 years. The mean age of control subjects (12.9 years) was significantly less than AIS (14.9 years, p = 0.003). At baseline, there were no significant differences in alveolar size, number, or alveolar duct morphometry between AIS and control subjects or between the concave (compressed) and convex (expanded) lungs of AIS subjects. At one year after PSF AIS subjects had an increase in alveolar density in the formerly convex lung (p = 0.05), likely reflecting a change in thoracic anatomy, but there were no other significant changes in lung microstructure. Modeling of alveolar size over time demonstrated similar rates of alveolar growth in control and AIS subjects in both right and left lungs pre- and post-PSF. Although this study suffered from poor age-matching, we found no evidence that AIS or PSF impacts lung microstructure. Trial registration: Clinical trial registration number NCT03539770.

Purpose To demonstrate that ultrashort echo time (UTE) magnetic resonance imaging (MRI) can achieve computed tomography (CT)-like quantification of lung parenchyma in free-breathing, non-sedated neonates. Because infant CTs are used sparingly, parenchymal disease evaluation via UTE MRI has potential for translational impact. Materials and Methods Two neonatal control cohorts without suspected pulmonary morbidities underwent either a research UTE MRI (n = 5; 1.5T) or a clinically-ordered CT (n = 9). Whole-lung means and anterior–posterior gradients of UTE-measured image intensity (arbitrary units, au, normalized to muscle) and CT-measured density (g/cm3) were compared (Mann–Whitney U-test). Separately, a diseased neonatal cohort (n = 5) with various pulmonary morbidities underwent both UTE MRI and CT. UTE intensity and CT density were compared with Spearman correlations within ∼33 anatomically matched regions of interest (ROIs) in each diseased subject, spanning low- to high-density tissues. Radiological classifications were evaluated in all ROIs, with mean UTE intensities and CT densities compared in each classification. Results In control subjects, whole-lung UTE intensities (0.51 ± 0.04 au) were similar to CT densities (0.44 ± 0.09 g/cm3) (P = 0.062), as were UTE (0.021 ± 0.020 au/cm) and CT (0.034 ± 0.024 [g/cm3]/cm) anterior–posterior gradients (P = 0.351). In diseased subjects' ROIs, significant correlations were observed between UTE and CT (P ≤0.007 in each case). Relative differences between UTE and CT were small in all classifications (4–25%). Conclusion These results demonstrate a strong association between UTE image intensity and CT density, both between whole-lung tissue in control patients and regional radiological pathologies in diseased patients. This indicates the potential for UTE MRI to longitudinally evaluate neonatal pulmonary disease and to provide visualization of pathologies similar to CT, without sedation/anesthesia or ionizing radiation. Level of Evidence: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:992–1000.

Rationale: Lymphangioleiomyomatosis (LAM) is a rare disease associated with cystic destruction of the pulmonary parenchyma and chronic respiratory failure, and there are trials underway to determine if early intervention can prevent disease progression. An imaging technique that is sensitive to early regional disease would therefore be valuable for patient care and clinical trials. Objectives: We postulated that hyperpolarized (129)Xe MRI would be sensitive to ventilation abnormalities and alveolar airspace dilation in patients with mild LAM disease and normal pulmonary function and that (129)Xe MRI would reveal important features of cyst ventilation. Methods: (129)Xe ventilation and diffusion-weighted MR images were acquired in 22 patients with LAM during two breath-holds of hyperpolarized (129)Xe. (129)Xe ventilation defect percentage (VDP; percentage of voxels

Hyperpolarized 129Xe is a promising contrast agent for MRI of pediatric lung function, but its safety and tolerability in children have not been rigorously assessed. To assess the feasibility, safety and tolerability of hyperpolarized 129Xe gas as an inhaled contrast agent for pediatric pulmonary MRI in healthy control subjects and in children with cystic fibrosis. Seventeen healthy control subjects (ages 6–15 years, 11 boys) and 11 children with cystic fibrosis (ages 8–16 years, 4 boys) underwent 129Xe MRI, receiving up to three doses of 129Xe gas prepared by either a commercially available or a homebuilt 129Xe polarizer. Subject heart rate and SpO2 were monitored for 2 min post inhalation and compared to resting baseline values. Adverse events were reported via follow-up phone call at days 1 and 30 (range ±7 days) post-MRI. All children tolerated multiple doses of 129Xe, and no children withdrew from the study. Relative to baseline, most children who received a full dose of gas for imaging (10 of 12 controls and 8 of 11 children with cystic fibrosis) experienced a nadir in SpO2 (mean –6.0 ± standard deviation 7.2%, P≤0.001); however within 2 min post inhalation SpO2 values showed no significant difference from baseline (P=0.11). There was a slight elevation in heart rate (mean +6.6 ± 13.9 beats per minute [bpm], P=0.021), which returned from baseline within 2 min post inhalation (P=0.35). Brief side effects related to the anesthetic properties of xenon were mild and quickly resolved without intervention. No serious or severe adverse events were observed; in total, four minor adverse events (14.3%) were reported following 129Xe MRI, but all were deemed unrelated to the study. The feasibility, safety and tolerability of 129Xe MRI has been assessed in a small group of children as young as 6 years. SpO2 changes were consistent with the expected physiological effects of a short anoxic breath-hold, and other mild side effects were consistent with the known anesthetic properties of xenon and with previous safety assessments of 129Xe MRI in adults. Hyperpolarized 129Xe is a safe and well-tolerated inhaled contrast agent for pulmonary MR imaging in healthy children and in children with cystic fibrosis who have mild to moderate lung disease.

PURPOSE To determine the feasibility of pulmonary magnetic resonance imaging (MRI) of neonatal lung structures enabled by combining two novel technologies: first, a 3D radial ultrashort echo time (UTE) pulse sequence capable of high spatial resolution full-chest imaging in nonsedated quiet-breathing neonates; and second, a unique, small-footprint 1.5T MRI scanner design adapted for neonatal imaging and installed within the neonatal intensive care unit (NICU). MATERIALS AND METHODS Ten patients underwent MRI within the NICU, in accordance with an approved Institutional Review Board protocol. Five had clinical diagnoses of bronchopulmonary dysplasia (BPD), and five had putatively normal lung function. Pulmonary imaging was performed at 1.5T using 3D radial UTE and standard 3D fast gradient recalled echo (FGRE). Diagnostic quality, presence of motion artifacts, and apparent severity of lung pathology were evaluated by two radiologists. Quantitative metrics were additionally used to evaluate lung parenchymal signal. RESULTS UTE images showed significantly higher signal in lung parenchyma (P < 0.0001) and fewer apparent motion artifacts compared to FGRE (P = 0.046). Pulmonary pathology was more severe in patients diagnosed with BPD relative to controls (P = 0.001). Infants diagnosed with BPD also had significantly higher signal in lung parenchyma, measured using UTE, relative to controls (P = 0.002). CONCLUSION These results demonstrate the technical feasibility of pulmonary MRI in free-breathing, nonsedated infants in the NICU at high, isotropic resolutions approaching that achievable with computed tomography (CT). There is potential for pulmonary MRI to play a role in improving how clinicians understand and manage care of neonatal and pediatric pulmonary diseases. J. Magn. Reson. Imaging 2016. LEVEL OF EVIDENCE 2 J. Magn. Reson. Imaging 2017;45:463-471.

Purpose To further validate the ability of ultrashort echo-time (UTE) magnetic resonance imaging (MRI) in quantifying lung density in patients diagnosed with chronic obstructive pulmonary disease (COPD) and to develop an MRI-based emphysema index (EI). Materials and Methods Ten subjects clinically diagnosed with COPD (5M/5F, age 62.6 ± 8.5 years) and ten healthy subjects (2M/8F, age 48.9 ± 19.2 years) were imaged via UTE MRI at 3T (4 mm slices, 1.39 × 1.39 mm2 pixels). Chest computed tomography (CT) images (generally 5 mm slices, ≈0.55 × 0.55 mm2 pixels), acquired retrospectively, were compared to UTE MRI. CT lung densities, MR lung-signal density, and EI were quantified from both CT and UTE MR images via a quantitative automated analysis and compared to the percent predicted forced expiratory volume in 1 second (FEV1% predicted). Results EI quantified in controls via CT and UTE MRI was 0.23 ± 0.78% and 2.40 ± 1.50%, respectively; in COPD subjects it was 13.3 ± 14.9% (P = 0.021) and 12.0 ± 9.8% (P = 0.013), respectively. Bland–Altman determined the mean differences and 95% limits of agreement for COPD subjects and healthy controls were 0.06 (12.50 to –12.38). Strong correlation (R2 = 0.79, P < 0.0001) existed between EIs quantified from both CT and UTE MRI. There was a slightly higher correlation between FEV1% predicted and the UTE MRI EI (R2 = 0.65, P < 0.0001) compared to CT EI (R2 = 0.49, P < 0.0001). Conclusion Our results demonstrate a significant positive correlation between lung density and EI assessed with CT and MRI. Furthermore, UTE MRI exhibits its potential as a diagnostic alternative to CT for assessing the extent and the severity of emphysema, particularly for longitudinal studies. J. Magn. Reson. Imaging 2016;44:1656–1663.

Purpose To implement pulmonary three-dimensional (3D) radial ultrashort echo-time (UTE) MRI in non-sedated, free-breathing neonates and adults with retrospective motion tracking of respiratory and intermittent bulk motion, to obtain diagnostic-quality, respiratory-gated images. Methods Pulmonary 3D radial UTE MRI was performed at 1.5 tesla (T) during free breathing in neonates and adult volunteers for validation. Motion-tracking waveforms were obtained from the time course of each free induction decay's initial point (i.e., k-space center), allowing for respiratory-gated image reconstructions that excluded data acquired during bulk motion. Tidal volumes were calculated from end-expiration and end-inspiration images. Respiratory rates were calculated from the Fourier transform of the motion-tracking waveform during quiet breathing, with comparison to physiologic prediction in neonates and validation with spirometry in adults. Results High-quality respiratory-gated anatomic images were obtained at inspiration and expiration, with less respiratory blurring at the expense of signal-to-noise for narrower gating windows. Inspiration-expiration volume differences agreed with physiologic predictions (neonates; Bland-Altman bias = 6.2 mL) and spirometric values (adults; bias = 0.11 L). MRI-measured respiratory rates compared well with the observed rates (biases = -0.5 and 0.2 breaths/min for neonates and adults, respectively). Conclusions Three-dimensional radial pulmonary UTE MRI allows for retrospective respiratory self-gating and removal of intermittent bulk motion in free-breathing, non-sedated neonates and adults. Magn Reson Med 77:1284-1295, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Purpose Chronic obstructive pulmonary disease (COPD) is an irreversible lung disease characterized by small-airway obstruction and alveolar-airspace destruction. Hyperpolarized 129Xe diffusion MRI of lung is a promising biomarker for assessing airspace enlargement, but has yet to be validated by direct comparison to lung histology. Here we have compared diffusion measurements of hyperpolarized (HP) 129Xe in explanted lungs to regionally matched morphological measures of airspace size. Methods Explanted lungs from five COPD patients and two idiopathic pulmonary fibrosis (IPF) patients were imaged using MRI with hyperpolarized 129Xe using a two-b-value gradient-echo diffusion sequence, and 34 histological samples were taken from these lungs for quantitative histology. Mean-linear-intercept (Lm) was compared with spatially matched measures of apparent diffusion coefficient (ADC) from 129Xe MRI. Results The mean ADC from COPD lung samples was 0.071 ± 0.011 cm2/s, and for IPF lungs was 0.033 ± 0.001 cm2/s (P

Bronchopulmonary dysplasia (BPD) is a prevalent yet poorly characterized pulmonary complication of premature birth; the current definition is based solely on oxygen dependence at 36 weeks postmenstrual age without objective measurements of structural abnormalities across disease severity.We hypothesize that magnetic resonance imaging (MRI) can spatially resolve and quantify the structural abnormalities of the neonatal lung parenchyma associated with premature birth.Using a unique, small-footprint, 1.5-T MRI scanner within our neonatal intensive care unit (NICU), diagnostic-quality MRIs using commercially available sequences (gradient echo and spin echo) were acquired during quiet breathing in six patients with BPD, six premature patients without diagnosed BPD, and six full-term NICU patients (gestational ages, 23-39 wk) at near term-equivalent age, without administration of sedation or intravenous contrast. Images were scored by a radiologist using a modified Ochiai score, and volumes of high- and low-signal intensity lung parenchyma were quantified by segmentation and threshold analysis.Signal increases, putatively combinations of fibrosis, edema, and atelectasis, were present in all premature infants. Infants with diagnosed BPD had significantly greater volume of high-signal lung (mean ± SD, 26.1 ± 13.8%) compared with full-term infants (7.3 ± 8.2%; P = 0.020) and premature infants without BPD (8.2 ± 6.4%; P = 0.026). Signal decreases, presumably alveolar simplification, only appeared in the most severe BPD cases, although cystic appearance did increase with severity.Pulmonary MRI reveals quantifiable, significant differences between patients with BPD, premature patients without BPD, and full-term control subjects. These methods could be implemented to individually phenotype disease, which may impact clinical care and predict future outcomes.

The ability to produce hyperpolarized noble gases 3He and 129Xe has opened up exciting possibilities for pulmonary magnetic resonance imaging (MRI). We have recently built a hyperpolarizer with the goal of using hyperpolarized 3He gas for MRI in neonatal lungs in a dedicated small foot-print 1.5 T MR scanner developed at our institution and sited in our Neonatal Intensive Care Unit. Although hyperpolarized gas imaging can provide unique insights into lung ventilation, acinar microstructure, and gas-exchange dynamics, there is an undiminished need for 1H MRI of the lung to provide anatomic references, B1 and B0 maps, and 1H images of lung parenchyma. To address this need, we designed, built and tested a novel radiofrequency body coil that provides a high-pass birdcage coil that can be used for both 3He and 1H frequencies (48.65 and 63.86 MHz, respectively, at 1.5 T). To switch between frequencies, the birdcage coil has a large mechanical actuator that simultaneously changes the capacitance between every rung of the birdcage. Advantages of this coil design include: 1) quadrature excitation and reception at the 3He and 1H frequencies, 2) identical B1 field maps for 3He and 1H imaging, 3) excellent signal-to-noise ratio and B1 homogeneity at both frequencies, and 4) rapid (10–20 s) switching times between 3He and 1H operation. This report provides details of the coil's design and fabrication. Images of hyperpolarized 3He and 1H in phantoms and ex vivo rabbit lungs demonstrate the image quality obtained with the coil. © 2015 Wiley Periodicals, Inc. Concepts Magn Reson Part B (Magn Reson Engineering) 45B: 174–182, 2015

Purpose To demonstrate that longitudinal, noninvasive monitoring via MRI can characterize acute cellular rejection in mouse orthotopic lung allografts. Methods Nineteen Balb/c donor to C57BL/6 recipient orthotopic left lung transplants were performed, further divided into control-Ig versus anti-CD4/anti-CD8 treated groups. A two-dimensional multislice gradient-echo pulse sequence synchronized with ventilation was used on a small-animal MR scanner to acquire proton images of lung at postoperative days 3, 7, and 14, just before sacrifice. Lung volume and parenchymal signal were measured, and lung compliance was calculated as volume change per pressure difference between high and low pressures. Results Normalized parenchymal signal in the control-Ig allograft increased over time, with statistical significance between day 14 and day 3 posttransplantation (0.0460.789; P

Background Cystic fibrosis (CF) is a genetic disease which carries high morbidity and mortality from lung-function decline. Monitoring disease progression and treatment response in young patients is desirable, but serial imaging via CT is often considered prohibitive, and detailed functional information cannot be obtained using conventional imaging techniques. Hyperpolarized 129 Xe magnetic resonance imaging (MRI) can depict and quantify regional ventilation, but has not been investigated in pediatrics. We hypothesized that 129 Xe MRI is feasible and would demonstrate ventilation defects in mild CF lung disease with greater sensitivity than FEV 1 . Methods 11 healthy controls (age 6–16years) and 11 patients with mild CF (age 8–16years, Forced Expiratory Volume (FEV 1 ) percent predicted >70%) were recruited for this study. Nine CF patients had an FEV 1 >85%. Each subject was imaged via hyperpolarized 129 Xe MRI, and the ventilation defect percentage (VDP) was measured. FEV 1 and VDP were compared between the groups. Results FEV 1 for controls was 100.3%±8.5% (mean±sd) and for CF patients was 97.9%±16.0% (p=0.67). VDP was 6.4%±2.8% for controls and 18.3%±8.6% for CF (p 1 (>85%), the mean FEV 1 was 103.1%±12.3% (p=0.57 compared to controls) and VDP was 15.4%±6.3% (p=0.002). Conclusions Hyperpolarized 129 Xe MRI demonstrated ventilation defects in CF patients with normal FEV 1 and more effectively discriminated CF from controls than FEV 1 . Thus 129 Xe may be a useful outcome measure to detect mild CF lung disease, to investigate regional lung function in pediatric lung diseases, and to follow disease progression.

To implement pulmonary three-dimensional (3D) radial ultrashort echo-time (UTE) MRI in non-sedated, free-breathing neonates and adults with retrospective motion tracking of respiratory and intermittent bulk motion, to obtain diagnostic-quality, respiratory-gated images.Pulmonary 3D radial UTE MRI was performed at 1.5 tesla (T) during free breathing in neonates and adult volunteers for validation. Motion-tracking waveforms were obtained from the time course of each free induction decay's initial point (i.e., k-space center), allowing for respiratory-gated image reconstructions that excluded data acquired during bulk motion. Tidal volumes were calculated from end-expiration and end-inspiration images. Respiratory rates were calculated from the Fourier transform of the motion-tracking waveform during quiet breathing, with comparison to physiologic prediction in neonates and validation with spirometry in adults.High-quality respiratory-gated anatomic images were obtained at inspiration and expiration, with less respiratory blurring at the expense of signal-to-noise for narrower gating windows. Inspiration-expiration volume differences agreed with physiologic predictions (neonates; Bland-Altman bias = 6.2 mL) and spirometric values (adults; bias = 0.11 L). MRI-measured respiratory rates compared well with the observed rates (biases = -0.5 and 0.2 breaths/min for neonates and adults, respectively).Three-dimensional radial pulmonary UTE MRI allows for retrospective respiratory self-gating and removal of intermittent bulk motion in free-breathing, non-sedated neonates and adults. Magn Reson Med 77:1284-1295, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Chronic obstructive pulmonary disease (COPD) is an irreversible lung disease characterized by small-airway obstruction and alveolar-airspace destruction. HyperpolarizedExplanted lungs from five COPD patients and two idiopathic pulmonary fibrosis (IPF) patients were imaged using MRI with hyperpolarizedThe mean ADC from COPD lung samples was 0.071 ± 0.011 cmDiffusion MRI of HP

Accurate measurements of the optical properties of living cells are essential for both therapeutic and diagnostic applications of biomedical optics. Changes in the index of refraction of red blood cells, for example, have been used to chart the progress of the malaria parasite (1). The cellular index of refraction is also of critical importance in cellular biomechanics measurements. In the optical stretcher, a dual-beam optical trap, small variations in the index of refraction can lead to substantial errors in the assessment of single-cell elasticity. To determine the cell-to-cell variation of the index of refraction, we have integrated a Mach-Zehnder interferometer with a conventional transmitted light microscope to obtain high-resolution interferograms of individual cells. Quantitative phase images are obtained by performing a Hilbert transform and using Goldstein's algorithm to unwrap the wrapped phase image. The decoupling technique of Rappaz et al. was used to obtain cell height and index of refraction maps (2). By employing several laser sources, the cellular index of refraction can be measured as function of wavelength. Measurements of multiple cell lines at several wavelengths indicate that the refractive index can, in fact, vary significantly from cell-to-cell. Along with these results we will discuss the implications for accurate single-cell biomechanical measurements made with the optical stretcher.1. Park et al. Proc. Natl. Acad. Sci. USA 105, 1730 (2008)2. Rappaz et al. Opt. Express 13, 9361 (2005)Supported by NIH P20 RR16469 from the National Center for Research Resources (NCRR) and NIH R15 GM085776

While it has been known for some time that bone mass is remodeled in response to mechanical stress, the identity of the primary mechanosensor has yet to be clearly established. To determine if cellular elasticity may play a role in the cell's ability to detect a pressure variation, we have used the optical stretcher to measure the elasticity of individual osteogenic cells. To determine cell elasticity from measurements of cellular deformation, the optical pressure on the cell surface is computed using a ray optics model which assumes a value for the index of refraction of the cell. Previously we have estimated this value from measurements of other eukaryotic cells, but the optical pressure varies significantly with small changes in refractive index. Therefore, digital holographic microscopy is used to improve estimates of this critical parameter. We consider the overall impact that a spatial variation in the index of refraction can have on the determination of the optical stress, and compare single-cell elasticity measurements of red blood cells, 2T3 osteoblast and MLO-Y4 osteocyte cells.∗ This work was supported by P20 RR016475 from the INBRE Program of the National Center for Research Resources.