Background Breathlessness is a common symptom in Long COVID (LC). Using hyperpolarised xenon MRI ( 129 Xe-MRI), we assessed whether this symptom could be attributed to abnormalities in the alveolar-capillary membrane not detected by standard investigations. We focused on never-hospitalised individuals without an identified cause for breathlessness. Methods In this prospective, multicentre study, we compared 129 Xe-MRI, lung function, exercise capacity, and symptom questionnaires in LC patients with breathlessness (BLC) to those without breathlessness (NBLC) and healthy controls. Primary outcome was whether BLC demonstrated measurable impairments in gas exchange focusing on dissolved-phase 129 Xe-MRI metrics: red-blood cell to membrane ratio (RBC:M) and red-blood cell to gas ratio (RBC:Gas). We also explored associations between symptoms and physiological measures. Results Of 269 participants recruited, 196 were included in the analysis (109 BLC, 43 NBLC, 44 controls), with age and sex well matched across groups. BLC had a significantly longer interval from infection to imaging (median 632 days; p<0·001). No significant differences in global or regional RBC:M or RBC:Gas were observed across groups. BLC showed lower FEV 1 , FVC, TLCO, and KCO z-scores compared to controls, though >90% of values remained within normal range. A subset of BLC participants with low TLCO (14/109) showed reduced 129 Xe-MRI metrics and higher breathlessness scores. Interpretation Most non-hospitalised LC participants exhibited no detectable pulmonary abnormalities, including those with breathlessness. However, approximately 13% of breathless individuals demonstrated minor reductions in TLCO and 129 Xe-MRI gas exchange suggesting a potential pulmonary contribution for symptoms in this subgroup.

Background:Breathlessness is a common symptom in long COVID (LC). Using hyperpolarised xenon magnetic resonance imaging (129Xe-MRI), we assessed whether this symptom could be attributed to abnormalities in the alveolar-capillary membrane not detected by standard investigations. We focused on never-hospitalised individuals without an identified cause for breathlessness. Methods:In this prospective, multicentre study, we compared 129Xe-MRI, lung function, exercise capacity and symptom questionnaires in LC patients with breathlessness (BLC) to those without breathlessness (NBLC) and healthy controls. Primary outcome was whether BLC demonstrated measurable impairments in gas exchange focusing on dissolved-phase 129Xe-MRI metrics: red blood cell to membrane ratio (RBC:M) and red blood cell to gas ratio (RBC:Gas). We also explored associations between symptoms and physiological measures. Results:Of 269 participants recruited, 196 were included in the analysis (109 BLC, 43 NBLC, 44 controls), with age and sex well matched across groups. BLC had a significantly longer interval from infection to MRI (median 632 days; p<0.001). No significant differences in global or regional RBC:M or RBC:Gas were observed across groups. BLC showed lower forced expiratory volume in 1 s, forced vital capacity, transfer factor of the lung for carbon monoxide (T L CO), and carbon monoxide transfer coefficient (K CO) z-scores compared to controls, though >90% of values remained within normal range. A subset of BLC participants with low T L CO (14 out of 109) showed reduced 129Xe-MRI metrics and higher breathlessness scores. Interpretation:Most nonhospitalised LC participants exhibited no detectable pulmonary abnormalities, including those with breathlessness. However, ∼13% of breathless individuals demonstrated minor reductions in T L CO and 129Xe-MRI gas exchange suggesting a potential pulmonary contribution for symptoms in this subgroup.

Background:In primary ciliary dyskinesia (PCD), impaired mucociliary clearance leads to respiratory infections. Whilst forced expiratory volume in 1 s (FEV1) is commonly used to evaluate lung function in PCD its sensitivity to detect abnormalities in mild disease is limited. This study explores the utility of 129Xe ventilation and 1H anatomical magnetic resonance imaging (MRI) to assess lung health in children with PCD. Methods:This prospective cohort study assessed clinically stable children with PCD (aged 5-18 years) using 129Xe MRI, 1H MRI and spirometry during one session. Ventilation defect percentage (VDP) was the primary metric calculated from 129Xe MRI. Results:35 children were assessed (mean±sd age 12.3±3.3 years, FEV1 z-score -1.5±1.7). Most children had visible ventilation abnormalities and 82.8% had an abnormal 129Xe VDP (median (interquartile range) 129Xe VDP 6.3% (1.3-16.1%)). 16 participants had a normal FEV1 (z-score > -1.6); however, 12 of these individuals had abnormal 129Xe VDP. 1H MRI found 55.9% participants had a region of collapse, 61.3% had bronchiectasis and 50.0% had evidence of air trapping. Conclusions:129Xe MRI can identify early lung function abnormalities in children with PCD and demonstrates that the extent of ventilation distribution abnormalities in PCD varies between individuals. 1H MRI provides complementary diagnostic information on structural abnormalities.

Background Pulmonary gas exchange is assessed by the transfer factor of the lungs (TL) for carbon monoxide (TLCO), and can also be measured with inhaled xenon-129 (129Xe) magnetic resonance imaging (MRI). A model has been proposed to estimate TL from 129Xe MRI metrics, but this approach has not been fully validated and does not utilise the spatial information provided by three-dimensional 129Xe MRI. Methods Three models for predicting TL from 129Xe MRI metrics were compared: 1) a previously-published physiology-based model, 2) multivariable linear regression and 3) random forest regression. Models were trained on data from 150 patients with asthma and/or COPD. The random forest model was applied voxel-wise to 129Xe images to yield regional TL maps. Results Coefficients of the physiological model were found to differ from previously reported values. All models had good prediction accuracy with small mean absolute error (MAE): 1) 1.24±0.15 mmol·min−1·kPa−1, 2) 1.01±0.06 mmol·min−1·kPa−1, 3) 0.995±0.129 mmol·min−1·kPa−1. The random forest model performed well when applied to a validation group of post-COVID-19 patients and healthy volunteers (MAE=0.840 mmol·min−1·kPa−1), suggesting good generalisability. The feasibility of producing regional maps of predicted TL was demonstrated and the whole-lung sum of the TL maps agreed with measured TLCO (MAE=1.18 mmol·min−1·kPa−1). Conclusion The best prediction of TLCO from 129Xe MRI metrics was with a random forest regression framework. Applying this model on a voxel-wise level to create parametric TL maps provides a useful tool for regional visualisation and clinical interpretation of 129Xe gas exchange MRI.

MR imaging holds the potential to enhance drug development efficiency by de-risking early phase studies and increasing confidence in results. It can improve patient selection, increase repeatability, and provide greater sensitivity to change, thereby enabling smaller, faster clinical trials. For trials in the pulmonary space, hyperpolarized 129Xe MRI is appealing because it provides 3-dimensional imaging of pulmonary ventilation and gas exchange in a brief, non-invasive exam. Metrics derived from 129Xe MRI may be more sensitive to disease progression than conventional lung function assessments and may thus provide a valuable means to evaluate numerous novel pharmacologic and biologic therapies now in development. However, despite the acute need for better patient selection and for prognostic and monitoring biomarkers, 129Xe MR imaging is not yet widely utilized in pulmonary drug development, partly because such trials must be conducted at multiple centers to enroll enough participants. Thus, incorporating 129Xe MRI requires broader dissemination, harmonized image acquisition protocols, standardized dose delivery, visualization, and quantification. Multi-site trials must also be able to operate across all major MRI vendor platforms and diverse software/hardware revisions. To this end, the 129Xe MRI Clinical trials consortium has published a harmonized protocol describing four recommended acquisitions. Here we report on the first industry-sponsored study to deploy this 129Xe MRI/MRS protocol in a multi-center, multi-platform, multi-national study to evaluate longitudinal progression of chronic obstructive pulmonary disease (COPD). We demonstrate the steps necessary to implement standardized 129Xe-MRI acquisition techniques across multiple sites and discuss the practices implemented, quality control approaches, and lessons learned for facilitating and accelerating the implementation of future trials that incorporate this technology. Level of Evidence: 5.

Hyperpolarized (HP) gas pulmonary MR ventilation images are typically quantified using ventilation defect percent (VDP); however, the test-retest variability of VDP has not been systematically established in multi-center trials. Herein, we perform a systematic review of the test-retest literature on the variability of VDP, and similar metrics, generated from HP MRI. This review utilizes the Medline, EMBASE, and EBM Reviews databases and includes studies that assessed the variability of HP MRI VDP. The protocol was registered to PROSPERO: CRD42022328535. Imaging techniques and statistical analysis characteristics were extracted and used to group studies to evaluate the overall ability to pool data across grouped studies. The ability to pool data to provide systematic evidence was assessed using a modified COSMIN tool. A total of 22 studies with 37 distinct aims for repeated HP MRI acquisition or quantification were included. Studies were grouped into six categories based on HP gas and analysis type: repeated imaging (129Xe n = 13, 3He n = 12), interobserver repeated analysis (129Xe n = 4, 3He n = 4) or intraobserver repeated analysis (129Xe n = 1, 3He n = 2). Studies assessed variability using a variety of statistical tests including absolute difference, percent coefficient of variation, Bland-Altman limits of agreement, coefficient of reproducibility, or the intra-class correlation. Individual studies generally reported low variability of VDP (ICC range: 0.5-1.0; Bland-Altman bias range: -6.9-20%), but there was an overall inability to pool data and provide a meta-analysis due to methodological inconsistencies and small sample size. Overall, we found that VDP has low variability in most studies. However, inconsistent image acquisition and quantification methodologies between studies limits direct comparability and precludes grouping of study data for meta-analyses. Despite early efforts to standardize HP MRI acquisition, further work is necessary to standardize VDP quantification to allow broader validation and clinical implementation. Evidence Level: 2 Technical Efficacy: Stage 3.

Longitudinal changes of 129Xe MRI metrics in patients with asthma and/or COPD have not yet been reported. 140 patients with asthma and/or COPD were scanned at 2 visits, 1 year apart, using 129Xe gas transfer and diffusion MRI. From visit 1 to visit 2 red blood cell (RBC) / membrane (M) and RBC/gas decreased and the amplitude of red blood cell oscillations (ARBCO) increased when all patients were considered. RBC/M and RBC/gas decreased in asthma+COPD, and RBC/M decreased and ARBCO increased in asthma from visit 1 to visit 2. M/gas and acinar microstructure metrics did not change significantly between visits.

Pulmonary MRI of hyperpolarized xenon-129 (hp129Xe) dissolved in the lung parenchyma and vascular phase is gaining increasing attention for clinical assessment of gas exchange in multiple diseases. These conditions can involve thickening of barrier tissues due to fibrotic scarring or reduced capillary blood flow leading to diminished gas-blood exchange hence, the ratios between hp129Xe signals arising from the lung membrane (M), the red blood cells (RBC), and the gas phase hold significant diagnostic value. However, comparing hp129Xe signal ratios quantitatively across different studies may pose challenges due to varied experimental conditions and opted pulse sequence protocols. A solution to this problem arises from materials science applications of hp129Xe where xenon dissolved in porous materials or polymers can display chemical shifts similar to the M and RBC shift in lungs. This work explored the generation of MR spectral profiles with respect to chemical shift and signal intensity ratios that closely resemble spectral profiles observed in human lungs in health and disease. At ambient temperatures, reticulated open cell polyurethane foam treated with olive oil as a fatty phase produced dissolved phase 129Xe chemical shifts of 215 ppm and 196 ppm, respectively, that emulate typical RBC and M signals. The uptake kinetics into the non-toxic materials was sufficiently similar to pulmonary signal uptake to enable hp129Xe MRI with dissolved phase ratios that closely resembled clinical data. A phantom assembly was devised to allow for gas handling protocols that matched clinical protocols. The current iteration of the developed phantom enables rapid testing of basic experimental protocols and can be used for training purposes without regulatory approval and governance. Furthermore, the introduced concept shows a pathway for the development of a quantitative universal phantom standard for dissolved phase pulmonary hp129Xe MRI. A robust phantom standard will require materials with longer shelf lifetime than the oil-foam system used in this study and would benefit from a hierarchical porous network with more defined microstructure similar to that found in lungs.

PURPOSE:Three-dimensional hyperpolarized 129Xe gas exchange imaging suffers from low SNR and long breath-holds, which could be improved using compressed sensing (CS). The purpose of this work was to assess whether gas exchange ratio maps are quantitatively preserved in CS-accelerated dissolved-phase 129Xe imaging and to investigate the feasibility of CS-dissolved 129Xe imaging with reduced-cost natural abundance (NA) xenon. METHODS:129Xe gas exchange imaging was performed at 1.5 T with a multi-echo spectroscopic imaging sequence. A CS reconstruction with an acceleration factor of 2 was compared retrospectively with conventional gridding reconstruction in a cohort of 16 healthy volunteers, 5 chronic obstructive pulmonary disease patients, and 23 patients who were hospitalized following COVID-19 infection. Metrics of comparison included normalized mean absolute error, mean gas exchange ratio, and red blood cell (RBC) image SNR. Dissolved 129Xe CS imaging with NA xenon was assessed in 4 healthy volunteers. RESULTS:CS reconstruction enabled acquisition time to be halved, and it reduced background noise. Median RBC SNR increased from 6 (2-18) to 11 (2-100) with CS, and there was strong agreement between CS and gridding mean ratio map values (R2 = 0.99). Image fidelity was maintained for gridding RBC SNR > 5, but below this, normalized mean absolute error increased nonlinearly with decreasing SNR. CS increased the mean SNR of NA 129Xe images 3-fold. CONCLUSION:CS reconstruction of dissolved 129Xe imaging improved image quality with decreased scan time, while preserving key gas exchange metrics. This will benefit patients with breathlessness and/or low gas transfer and shows promise for NA-dissolved 129Xe imaging.

PURPOSE:To evaluate the feasibility and utility of a deep learning (DL)-based reconstruction for improving the SNR of hyperpolarized 129Xe lung ventilation MRI. METHODS:129Xe lung ventilation MRI data acquired from patients with asthma and/or chronic obstructive pulmonary disease (COPD) were retrospectively reconstructed with a commercial DL reconstruction pipeline at five different denoising levels. Quantitative imaging metrics of lung ventilation including ventilation defect percentage (VDP) and ventilation heterogeneity index (VHI) were compared between each set of DL-reconstructed images and alternative denoising strategies including: filtering, total variation denoising and higher-order singular value decomposition. Structural similarity between the denoised and original images was assessed. In a prospective study, the feasibility of using SNR gains from DL reconstruction to allow natural-abundance xenon MRI was evaluated in healthy volunteers. RESULTS:129Xe ventilation image SNR was improved with DL reconstruction when compared with conventionally reconstructed images. In patients with asthma and/or COPD, DL-reconstructed images exhibited a slight positive bias in ventilation defect percentage (1.3% at 75% denoising) and ventilation heterogeneity index (˜1.4) when compared with conventionally reconstructed images. Additionally, DL-reconstructed images preserved structural similarity more effectively than data denoised using alternative approaches. DL reconstruction greatly improved image SNR (greater than threefold), to a level that 129Xe ventilation imaging using natural-abundance xenon appears feasible. CONCLUSION:DL-based image reconstruction significantly improves 129Xe ventilation image SNR, preserves structural similarity, and leads to a minor bias in ventilation metrics that can be attributed to differences in the image sharpness. This tool should help facilitate cost-effective 129Xe ventilation imaging with natural-abundance xenon in the future.

PURPOSE:To characterize the dependence of Xe-MRI gas transfer metrics upon age, sex, and lung volume in a group of healthy volunteers. METHODS:Sixty-five subjects with no history of chronic lung disease were assessed with 129Xe-MRI using a four-echo 3D radial spectroscopic imaging sequence and a dose of xenon titrated according to subject height that was inhaled from a lung volume of functional residual capacity (FRC). Imaging was repeated in 34 subjects at total lung capacity (TLC). Regional maps of the fractions of dissolved xenon in red blood cells (RBC), membrane (M), and airspace (Gas) were acquired at an isotropic resolution of 2 cm, from which global averages of the ratios RBC:M, RBC:Gas, and M:Gas were computed. RESULTS:Data from 26 males and 36 females with a median age of 43 y (range: 20-69 y) were of sufficient quality to analyze. Age (p = 0.0006) and sex (p < 0.0001) were significant predictors for RBC:M, and a linear regression showed higher values and steeper decline in males: RBC:M(Males) = -0.00362 × Age + 0.60 (p = 0.01, R2 = 0.25); RBC:M(Females) = -0.00170 × Age + 0.44 (p = 0.02, R2 = 0.15). Similarly, age and sex were significant predictors for RBC:Gas but not for M:Gas. RBC:M, M:Gas and RBC:Gas were significantly lower at TLC than at FRC (plus inhaled volume), with an average 9%, 30% and 35% decrease, respectively. CONCLUSION:Expected age and sex dependence of pulmonary function concurs with 129Xe RBC:M imaging results, demonstrating that these variables must be considered when reporting Xe-MRI metrics. Xenon doses and breathing maneuvers should be controlled due to the strong dependence of Xe-MRI metrics upon lung volume.

PURPOSE:To assess the regional amplitude and phase of dissolved 129Xe red blood cell (RBC) signal oscillations in the lung vasculature with keyhole spectroscopic imaging and to compare with previous methodology, which does not account for oscillation phase. METHODS:129Xe gas transfer was measured with a four-echo 3D radial spectroscopic imaging sequence. Keyhole reconstruction-based RBC signal oscillation amplitude mapping was applied retrospectively to data acquired from 28 healthy volunteers, 4 chronic thromboembolic pulmonary hypertension (CTEPH) patients, and 5 patients who were hospitalized due to COVID-19 pneumonia and had residual lung abnormalities. Using a sliding window keyhole reconstruction, maps of RBC oscillation amplitude were corrected for regional phase difference. Repeatability of the phase-adjusted oscillation amplitude was assessed in 8 healthy volunteers across three scans. RESULTS:With sliding window keyhole reconstruction, regional phase differences were observed in the RBC signal oscillations: mean phase = (0.27 ± 0.19) rad in healthy volunteers, (0.24 ± 0.13) rad in CTEPH patients, and (0.33 ± 0.19) rad in patients with post-COVID-19 residual lung abnormality. The oscillation amplitude and phase maps were more heterogeneous (i.e., they showed increased coefficient of variation) for the CTEPH patients. The RBC oscillation amplitude was repeatable, and the mean three-scan coefficient of variation was smaller when the phase adjustment was made (0.07 ± 0.04 compared with 0.16 ± 0.05). CONCLUSION:Sliding window keyhole reconstruction of radial dissolved 129Xe imaging reveals regional phase differences in the RBC oscillations, which are not captured when performing two phase keyhole reconstruction. This regional phase information may reflect the hemodynamic effect of the cardiac pulse wave in the pulmonary microvasculature.