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Key points Multibreath imaging to estimate regional gas mixing efficiency is superior to intensity-based single-breath ventilation markers, as it is capable of revealing minute but essential measures of ventilation heterogeneity which may be sensitive to subclinical alterations in the early stages of both obstructive and restrictive respiratory disorders. Large-scale convective stratification of ventilation in central-to-peripheral directions is the dominant feature of observed ventilation heterogeneity when imaging a heavy/less diffusive xenon gas mixture; smaller-scale patchiness, probably originating from asymmetric lung function at bronchial airway branching due to the interaction of convective and diffusive flows, is the dominant feature when imaging a lighter/more diffusive helium gas mixture. Since detecting low regional ventilation is crucial for characterizing diseased lungs, our results suggest that dilution with natural abundance helium and imaging at higher lung volumes seem advisable when imaging with hyperpolarized 129 Xe; this will allow the imaging gas to reach slow-filling and/or non-dependent lung regions, which might otherwise be impossible to distinguish from total ventilation shunt regions. The ability to differentiate these regions from those of total shunt is worse with typical single-breath imaging techniques. Abstract The mixing of freshly inhaled gas with gas already present in the lung can be directly assessed with heretofore unachievable precision via magnetic resonance imaging of signal build-up resulting from multiple wash-ins of a hyperpolarized (HP) gas. Here, we used normoxic HP 3 He and 129 Xe mixtures to study regional ventilation at different spatial scales in five healthy mechanically ventilated supine rabbits at two different inspired volumes. To decouple the respective effects of density and diffusion rates on ventilation heterogeneity, two additional studies were performed: one in which 3 He was diluted with an equal fraction of natural abundance xenon, and one in which 129 Xe was diluted with an equal fraction of 4 He. We observed systematic differences in the spatial scale of specific ventilation heterogeneity between HP 3 He and 129 Xe. We found that large-scale, central-to-peripheral convective ventilation inhomogeneity is the dominant cause of observed heterogeneity when breathing a normoxic xenon gas mixture. In contrast, small-scale ventilation heterogeneity in the form of patchiness, probably originating from asymmetric lung function at bronchial airway branching due to interactions between convective and diffusive flows, is the dominant feature when breathing a normoxic helium gas mixture, for which the critical zone occurs more proximally and at an imageable spatial scale. We also showed that the existence of particular underventilated non-dependent lung regions when breathing a heavy gas mixture is the result of the density of that mixture - rather than, for example, its diffusion rate or viscosity. Finally, we showed that gravity-dependent ventilation heterogeneity becomes substantially more uniform at higher inspired volumes for xenon gas mixtures compared to helium mixtures.

To demonstrate the utility of continuous-wave (CW) saturation pulses in xenon-polarization transfer contrast (XTC) MRI and MRS, to investigate the selectivity of CW pulses applied to dissolved-phase resonances, and to develop a correction method for measurement biases from saturation of the nontargeted dissolved-phase compartment.Studies were performed in six healthy Sprague-Dawley rats over a series of end-exhale breath holds. Discrete saturation schemes included a series of 30 Gaussian pulses (8 ms FWHM), spaced 25 ms apart; CW saturation schemes included single block pulses, with variable flip angle and duration. In XTC imaging, saturation pulses were applied on both dissolved-phase resonance frequencies and off-resonance, to correct for other sources of signal loss and compromised selectivity. In spectroscopy experiments, saturation pulses were applied at a set of 19 frequencies spread out between 185 and 200 ppm to map out modified z-spectra.Both modified z-spectra and imaging results showed that CW RF pulses offer sufficient depolarization and improved selectivity for generating contrast between presaturation and postsaturation acquisitions. A comparison of results obtained using a variety of saturation parameters confirms that saturation pulses applied at higher powers exhibit increased cross-contamination between dissolved-phase resonances.Using CW RF saturation pulses in XTC contrast preparation, with the proposed correction method, offers a potentially more selective alternative to traditional discrete saturation. The suppression of the red blood cell contribution to the gas-phase depolarization opens the door to a novel way of quantifying exchange time between alveolar volume and hemoglobin.

Purpose To demonstrate the feasibility of generating red blood cell (RBC) and tissue/plasma (TP)-specific gas-phase (GP) depolarization maps using xenon-polarization transfer contrast (XTC) MR imaging. Methods Imaging was performed in three healthy subjects, an asymptomatic smoker, and a chronic obstructive pulmonary disease (COPD) patient. Single-breath XTC data were acquired through a series of three GP images using a 2D multi-slice GRE during a 12 s breath-hold. A series of 8 ms Gaussian inversion pulses spaced 30 ms apart were applied in-between the images to quantify the exchange between the GP and dissolved-phase (DP) compartments. Inversion pulses were either centered on-resonance to generate contrast, or off-resonance to correct for other sources of signal loss. For an alternative scheme, inversions of both RBC and TP resonances were inserted in lieu of off-resonance pulses. Finally, this technique was extended to a multi-breath protocol consistent with tidal breathing, involving 30 consecutive acquisitions. Results Inversion pulses shifted off-resonance by 20 ppm to mimic the distance between the RBC and TP resonances demonstrated selectivity, and initial GP depolarization maps illustrated stark magnitude and distribution differences between healthy and diseased subjects that were consistent with traditional approaches. Conclusion The proposed DP-compartment selective XTC MRI technique provides information on gas exchange between all three detectable states of xenon in the lungs and is sufficiently sensitive to indicate differences in lung function between the study subjects. Investigated extensions of this approach to imaging schemes that either minimize breath-hold duration or the overall number of breath-holds open avenues for future research to improve measurement accuracy and patient comfort.

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

Hyperpolarized 129Xe magnetic resonance imaging is a powerful modality capable of assessing lung structure and function. While it has shown promise as a clinical tool for the longitudinal assessment of lung function, its utility as an investigative tool for animal models of pulmonary diseases is limited by the necessity of invasive intubation and mechanical ventilation procedures. In this paper, we overcame this limitation by developing a gas delivery system and implementing a set of imaging schemes to acquire high-resolution gas- and dissolved-phase images in free-breathing mice. Gradient echo pulse sequences were used to acquire both high- and low-resolution gas-phase images, and regional fractional ventilation was quantified by comparing signal buildup among low-resolution gas-phase images acquired at two flip-angles. Dissolved-phase images were acquired using both ultra-short echo time and chemical shift imaging sequences with discrete sets of flip-angle/repetition time combinations to visualize gas uptake and distribution throughout the body. Spectral features distinct to various anatomical regions were identified in images acquired using the latter sequence and were used for the quantification of gas arrival times for respective compartments.

Rationale and Objectives In this study, we compared a newly developed multibreath simultaneous alveolar oxygen tension and apparent diffusion coefficient (PAO2-ADC) imaging sequence to a single-breath acquisition, with the aim of mitigating the compromising effects of intervoxel flow and slow-filling regions on single-breath measurements, especially in chronic obstructive pulmonary disease (COPD) subjects. Materials and Methods Both single-breath and multibreath simultaneous PAO2-ADC imaging schemes were performed on a total of 10 human subjects (five asymptomatic smokers and five COPD subjects). Estimated PAO2 and ADC values derived from the different sequences were compared both globally and regionally. The distribution of voxels with nonphysiological values was also compared between the two schemes. Results The multibreath protocol decreased the ventilation defect volumes by an average of 12.9 ± 6.6%. The multibreath sequence generated nonphysiological PAO2 values in 11.0 ± 8.5% fewer voxels than the single-breath sequence. Single-breath PAO2 maps also showed more regions with gas-flow artifacts and general signal heterogeneity. On average, the standard deviation of the PAO2 distribution was 16.5 ± 7.0% lower using multibreath PAO2-ADC imaging, suggesting a more homogeneous gas distribution. Both mean and standard deviation of the ADC increased significantly from single- to multibreath imaging (p = 0.048 and p = 0.070, respectively), suggesting more emphysematous regions in the slow-filling lung. Conclusion Multibreath PAO2-ADC imaging provides superior accuracy and efficiency compared to previous imaging protocols. PAO2 and ADC maps generated by multibreath imaging allowed for the qualification of various regions as emphysematous or obstructed, which single-breath PAO2 maps can only identify as defects. The simultaneous PAO2 and ADC measurements generated by the presented multibreath method were also more physiologically realistic, and allowed for more detailed analysis of the slow-filling regions characteristic of COPD subjects.

The mixing of freshly inhaled gas with gas already present in the lung can be directly assessed with heretofore unachievable precision via magnetic resonance imaging of signal build-up resulting from multiple wash-ins of a hyperpolarized (HP) gas. Here, we used normoxic HP (3)He and (129)Xe mixtures to study regional ventilation at different spatial scales in five healthy mechanically ventilated supine rabbits at two different inspired volumes. To decouple the effects of density and diffusion rates on ventilation heterogeneity, two additional studies were performed: one in which (3)He was diluted with an equal fraction of natural abundance xenon, and one in which (129)Xe was diluted with an equal fraction of (4)He. We observed systematic differences in the spatial scale of specific ventilation heterogeneity between HP (3)He and (129)Xe; we found that large-scale, central-to-peripheral convective ventilation inhomogeneity is the dominant cause of observed heterogeneity when breathing a normoxic xenon gas mixture. Alternately, smaller-scale ventilation heterogeneity in the form of patchiness, likely originating from asymmetric lung function at bronchial airway branching due to interactions between convective and diffusive flows, is the dominant feature when breathing a normoxic helium gas mixture, for which the critical zone occurs more proximally at an imageable spatial scale. We also showed that particular underventilated nondependent lung regions when breathing a heavy gas mixture result from the density of that mixture—rather than, e.g., its diffusion rate or viscosity. Finally, we showed that gravity-dependent ventilation heterogeneity becomes substantially more uniform at higher inspired volumes for xenon gas mixtures compared to helium mixtures.

Increased pulmonary lactate production is correlated with severity of lung injury and outcome in acute respiratory distress syndrome (ARDS) patients. This study was conducted to investigate the relative contributions of inflammation and hypoxia to the lung's metabolic shift to glycolysis in an experimental animal model of ARDS using hyperpolarized (HP) 13 C MRI. Fifty-three intubated and mechanically ventilated male rats were imaged using HP 13 C MRI before, and 1, 2.5 and 4 hours after saline (sham) or hydrochloric acid (HCl; 0.5 ml/kg) instillation in the trachea, followed by protective and nonprotective mechanical ventilation (HCl-PEEP and HCl-ZEEP) or the start of moderate or severe hypoxia (Hyp90 and Hyp75 groups). Pulmonary and cardiac HP lactate-to-pyruvate ratios were compared among groups for different time points. Postmortem histology and immunofluorescence were used to assess lung injury severity and quantify the expression of innate inflammatory markers and local tissue hypoxia. HP pulmonary lactate-to-pyruvate ratio progressively increased in rats with lung injury and moderate hypoxia (HCl-ZEEP), with no significant change in pulmonary lactate-to-pyruvate ratio in noninjured but moderately hypoxic rats (Hyp90). Pulmonary lactate-to-pyruvate ratio was elevated in otherwise healthy lung tissue only in severe systemic hypoxia (Hyp75 group). ex vivo histological and immunopathological assessment further confirmed the link between elevated glycolysis and the recruitment into and presence of activated neutrophils in injured lungs. HP lactate-to-pyruvate ratio is elevated in injured lungs predominantly as a result of increased glycolysis in activated inflammatory cells, but can also increase due to severe inflammation-induced hypoxia.

Purpose To investigate biases in the measurement of apparent alveolar septal wall thickness (SWT) with hyperpolarized xenon-129 (HXe) as a function of acquisition parameters. Methods The HXe MRI scans with simultaneous gas-phase and dissolved-phase excitation were performed using 1-dimensional projection scans in mechanically ventilated rabbits. The dissolved-phase magnetization was periodically saturated, and the dissolved-phase xenon uptake dynamics were measured at end inspiration and end expiration with temporal resolutions up to 10 ms using a Look-Locker-type acquisition. The apparent alveolar septal wall thickness was extracted by fitting the signal to a theoretical model, and the findings were compared with those from the more commonly use chemical shift saturation recovery MRI spectroscopy technique with several different delay time arrangements. Results It was found that repeated application of RF saturation pulses in chemical shift saturation recovery acquisitions caused exchange-dependent gas-phase saturation that heavily biased the derived SWT value. When this bias was reduced by our proposed method, the SWT dependence on lung inflation disappeared due to an inherent insensitivity of HXe dissolved-phase MRI to thin alveolar structures with very short T 2 ∗ . Furthermore, perfusion-based macroscopic gas transport processes were demonstrated to cause increasing apparent SWTs with TE (2.5 μm/ms at end expiration) and a lung periphery-to-center SWT gradient. Conclusion The apparent SWT measured with HXe MRI was found to be heavily dependent on the acquisition parameters. A method is proposed that can minimize this measurement bias, add limited spatial resolution, and reduce measurement time to a degree that free-breathing studies are feasible.

Purpose To evaluate the reproducibility and regional variation of parameters obtained from localized 129 Xe chemical shift saturation recovery (CSSR) MR spectroscopy in healthy volunteers and patients with chronic obstructive pulmonary disease (COPD) and to compare the results to 129 Xe dissolved-phase MR imaging. Methods Thirteen healthy volunteers and 10 COPD patients were scanned twice using 129 Xe dissolved-phase imaging, CSSR, and ventilation imaging sequences. A 16-channel phased-array coil in combination with the regularized spectral localization achieved by sensitivity heterogeneity (SPLASH) method was used to perform a regional analysis of CSSR data. Lung function and microstructural parameters were obtained using Patz model functions and their reproducibility was assessed. Results The Patz model alveolar wall thickness parameter shows good reproducibility on a regional basis with a median coefficient of variation of 6.5% in healthy volunteers and 12.4% in COPD patients. Significant regional differences of lung function parameters derived from localized CSSR were found in healthy volunteers and correlations with spirometric indices were found. Conclusion Localized 129 Xe CSSR provides reproducible estimates of alveolar wall thickness and is able to detect regional differences of lung microstructure.

Purpose To develop and evaluate a protocol for hyperpolarized helium-3 (HHe) ventilation magnetic resonance imaging (MRI) of the lungs of non-sedated infants and children. Materials and methods HHe ventilation MRI was performed on seven children ≤ 4 years old. Contiguous 2D–spiral helium-3 images were acquired sequentially with a scan time of ≤ 0.2 s/slice. Results Motion-artifact–free, high signal-to-noise ratio (SNR) images of lung ventilation were obtained. Gas was homogeneously distributed in healthy individuals; focal ventilation defects were found in patients with respiratory diseases. Conclusion HHe ventilation MRI can aid assessment of pediatric lung disease even at a young age.

Purpose To investigate pulmonary metabolic alterations during progression of acute lung injury. Methods Using hyperpolarized [1-13C] pyruvate imaging, we measured pulmonary lactate and pyruvate in 15 ventilated rats 1, 2, and 4 h after initiation of mechanical ventilation. Lung compliance was used as a marker for injury progression. 5 untreated rats were used as controls; 5 rats (injured-1) received 1 ml/kg and another 5 rats (injured-2) received 2 ml/kg hydrochloric acid (pH 1.25) in the trachea at 70 min. Results The mean lactate-to-pyruvate ratio of the injured-1 cohort was 0.15 ± 0.02 and 0.15 ± 0.03 at baseline and 1 h after the injury, and significantly increased from the baseline value 3 h after the injury to 0.23 ± 0.02 (P = 0.002). The mean lactate-to-pyruvate ratio of the injured-2 cohort decreased from 0.14 ± 0.03 at baseline to 0.08 ± 0.02 1 h after the injury and further decreased to 0.07 ± 0.02 (P = 0.08) 3 h after injury. No significant change was observed in the control group. Compliance in both injured groups decreased significantly after the injury (P

Respiration is a dynamic process accompanied by morphological changes in the airways. Although deformation of large airways is expected to exacerbate pulmonary disease symptoms by obstructing airflow during increased minute ventilation, its quantitative effects on airflow characteristics remain unclear. Here, we used in vivo dynamic imaging and examined the effects of tracheal deformation on airflow characteristics under different conditions based on imaging data from a single healthy volunteer. First, we measured tracheal deformation profiles of a healthy lung using magnetic resonance imaging (MRI) during forced exhalation, which we simulated to characterize the subject-specific airflow patterns. Subsequently, for both inhalation and exhalation, we compared the airflows when the modeled deformation in tracheal cross-sectional area was 0% (rigid), 33% (mild), 50% (moderate), or 75% (severe). We quantified differences in airflow patterns between deformable and rigid airways by computing the correlation coefficients (R) and the root-mean-square of differences (Drms) between their velocity contours. For both inhalation and exhalation, airflow patterns were similar in all branches between the rigid and mild conditions (R > 0.9; Drms 0.1, Drms 0.2, Drms

While hyperpolarized xenon-129 (HXe) MRI offers a wide array of tools for assessing functional aspects of the lung, existing techniques provide only limited quantitative information about the impact of an observed pathology on overall lung function. By selectively destroying the alveolar HXe gas phase magnetization in a volume of interest and monitoring the subsequent decrease in the signal from xenon dissolved in the blood inside the left ventricle of the heart, it is possible to directly measure the contribution of that saturated lung volume to the gas transport capacity of the entire lung. In mechanically ventilated rabbits, we found that both xenon gas transport and transport efficiency exhibited a gravitation-induced anterior-to-posterior gradient that disappeared or reversed direction, respectively, when the animal was turned from supine to prone position. Further, posterior ventilation defects secondary to acute lung injury could be re-inflated by applying positive end expiratory pressure, although at the expense of decreased gas transport efficiency in the anterior volumes. These findings suggest that our technique might prove highly valuable for evaluating lung transplants and lung resections, and could improve our understanding of optimal mechanical ventilator settings in acute lung injury.

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 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

A characteristic feature of obstructive lung diseases is the narrowing of small airways, which affects regional airflow patterns within the lung. However, the extent to which these patterns differ between healthy and diseased states is unknown. To investigate airflow patterns in detail, we first used particle image velocimetry measurements to validate a large eddy simulation model of flow in a patient-specific geometry. We then predicted flow patterns in the central airway under exhalation for three flow conditions—normal, intermediate, and severe—where boundary conditions represented the effect of lower airway obstructions. We computed Pearson correlation coefficients ( R ) to assess the similarity of flow patterns, and found that flow patterns demonstrated the greatest differentiation between flow conditions in the right main bronchi ( R ≤ 0.60), whereas those in the secondary branches and regions of the trachea showed high correlation ( R ≥ 0.90). These results indicate that although flow patterns are distinct between flow conditions, the choice of measurement location is critical for differentiation.

PURPOSE: To investigate the feasibility of describing the impact of any flip angle - repetition time (TR) combination on the resulting distribution of the hyperpolarized xenon-129 (HXe) dissolved-phase magnetization in the chest using a single virtual parameter, TR(90°,equiv). METHODS: HXe MRI scans with simultaneous gas- (GP) and dissolved-phase (DP) excitation were performed using 2D projection scans in mechanically ventilated rabbits. Measurements with DP flip angles ranging from 6–90° and TRs ranging from 8.3–500 ms were conducted. DP maps based on acquisitions of similar radio frequency pulse-induced relaxation rates were compared. RESULTS: The observed distribution of the DP magnetization was strongly affected by acquisition flip angle and TR. However, for flip angles up to 60°, measurements with the same radio frequency pulse-induced relaxation rates resulted in very similar DP images despite the presence of significant macroscopic gas transport processes. For flip angles approaching 90°, the downstream signal component decreased noticeably relative to acquisitions with lower flip angles. Nevertheless, the total DP signal continued to follow an empirically verified conversion equation over the entire investigated parameter range, which yields the equivalent TR of a hypothetical 90° measurement for any experimental flip angle - TR combination. CONCLUSION: We have introduced a method for converting the flip angle and TR of a given HXe DP measurement to a standardized metric based on the virtual quantity, TR(90°,equiv), using their equivalent RF relaxation rates. This conversion permits the comparison of measurements obtained with different pulse sequence types, or by different research groups using various acquisition parameters.

RATIONALE AND OBJECTIVES: Hyperpolarized xenon-129 magnetic resonance (MR) provides sensitive tools that may detect early stages of lung disease in smokers before it has progressed to chronic obstructive pulmonary disease (COPD) apparent to conventional spirometric measures. We hypothesized that the functional alveolar wall thickness as assessed by hyperpolarized xenon-129 MR spectroscopy would be elevated in clinically healthy smokers before xenon MR diffusion measurements would indicate emphysematous tissue destruction. MATERIALS AND METHODS: Using hyperpolarized xenon-129 MR we measured the functional septal wall thickness and apparent diffusion coefficient of the gas phase in 16 subjects with smoking-related COPD, 9 clinically healthy current or former smokers, and 10 healthy never smokers. All subjects were age-matched and characterized by conventional pulmonary function tests. 11 data sets from younger healthy never smokers were added to determine the age dependence of the septal wall thickness measurements. RESULTS: In healthy never smokers the septal wall thickness increased by 0.04 µm per year of age. The healthy smoker cohort exhibited normal pulmonary function test measures that did not significantly differ from the never-smoker cohort. The age-corrected septal wall thickness correlated well with diffusion capacity for carbon monoxide (R(2) = 0.56) and showed a highly significant difference between healthy subjects and COPD patients (8.8 µm versus 12.3 µm; p < 0.001), but was the only measure that actually discriminated healthy subjects from healthy smokers (8.8 µm versus 10.6 µm; p < 0.006). CONCLUSION: Functional alveolar wall thickness assessed by hyperpolarized xenon-129 MR allows discrimination between healthy subjects and healthy smokers and could become a powerful new measure of early-stage lung disease.

Many forms of lung disease manifest themselves as pathological changes in the transport of gas to the circulatory system, yet the difficulty of imaging this process remains a central obstacle to the comprehensive diagnosis of lung disorders. Using hyperpolarized xenon-129 as a surrogate marker for oxygen, we derived the temporal dynamics of gas transport from the ratio of two lung images obtained with different timing parameters. Additionally, by monitoring changes in the total hyperpolarized xenon signal intensity in the left side of the heart induced by depletion of xenon signal in the alveolar airspaces of interest, we quantified the contributions of selected lung volumes to the total pulmonary gas transport. In a rabbit model, we found that it takes at least 200 ms for xenon gas to enter the lung tissue and travel the distance from the airspaces to the heart. Additionally, our method shows that both lungs contribute fairly equally to the gas transport in healthy rabbits, but that this ratio changes in a rabbit model of acid aspiration. These results suggest that hyperpolarized xenon-129 MRI may improve our ability to measure pulmonary gas transport and detect associated pathological changes.