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Purpose: Hyperpolarized 129 Xe MRI presents opportunities to assess regional pulmonary microstructure and function. Ongoing advancements in hardware, sequences, and image processing have helped it become increasingly adopted for both research and clinical use. As the number of applications and users increase, standardization becomes crucial. To that end, this study developed an executable, open-source 129 Xe image processing pipeline (XIPline) to provide a user-friendly, graphical user interface-based analysis pipeline to analyze and visualize 129 Xe MR data, including scanner calibration, ventilation, diffusion-weighted, and gas exchange images., Methods: The customizable XIPline is designed in MATLAB to analyze data from all three major scanner platforms. Calibration data is processed to calculate optimal flip angle and determine 129 Xe frequency offset. Data processing includes loading, reconstructing, registering, segmenting, and post-processing images. Ventilation analysis incorporates three common algorithms to calculate ventilation defect percentage and novel techniques to assess defect distribution and ventilation texture. Diffusion analysis features ADC mapping, modified linear binning to account for ADC age-dependence, and common diffusion morphometry methods. Gas exchange processing uses a generalized linear binning for data acquired using 1-point Dixon imaging., Results: The XIPline workflow is demonstrated using analysis from representative calibration, ventilation, diffusion, and gas exchange data., Conclusion: The application will reduce redundant effort when implementing new techniques across research sites by providing an open-source framework for developers. In its current form, it offers a robust and adaptable platform for 129 Xe MRI analysis to ensure methodological consistency, transparency, and support for collaborative research across multiple sites and MRI manufacturers., (© 2024 The Author(s). Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Modern pulmonary imaging can reveal underlying pathologic and pathophysiologic changes in the lungs of people with asthma, with important clinical implications. A multitude of imaging modalities, including computed tomography, magnetic resonance imaging, optical coherence tomography, and endobronchial ultrasound, are now being used to examine underlying structure-function relationships. Imaging-based biomarkers from these techniques, including airway dimensions, blood vessel volumes, mucus scores, extent of ventilation defect, and extent of air trapping, often have increased sensitivity compared with that of traditional lung function measurements and are increasingly being used as end points in clinical trials. Imaging has been crucial to recent improvements in our understanding of the relationships between type 2 inflammation, eosinophilia, and mucus extent. With the advent of effective anti-type 2 biologic therapies, computed tomography and magnetic resonance imaging techniques can identify not just which patients benefit from therapy but why they benefit. Clinical trials have begun to assess the utility of imaging to prospectively plan airway therapy targets in bronchial thermoplasty and have potential to direct future bronchoscopic therapies. Together, imaging techniques provide a diverse set of tools to investigate how spatially distributed airway, blood, and parenchymal abnormalities shape disease heterogeneity in patients with asthma., Competing Interests: Disclosure statement Disclosure of potential conflict of interest: P.J.N. and J.C.W. are consultants for Polarean Imaging, a company that develops and markets equipment for hyperpolarized 129XeMRI. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Chronic rhinosinusitis (CRS) and olfactory dysfunction (OD) are prevalent disease complications in people with cystic fibrosis. These understudied comorbidities significantly impact quality of life. The impact of highly effective modulator therapy (HEMT) in young children with cystic fibrosis (YCwCF) on these disease complications is unknown. This proposed study aims to characterise CRS and OD in YCwCF and assess the efficacy of HEMT in improving sinus and olfactory health in this young age group., Methods: This six-centre, prospective, observational study will enrol 80 YCwCF aged 2-8 years. Patients are divided into two groups: those receiving HEMT and those not on HEMT based on clinical indication. Both groups undergo sinus magnetic resonance imaging, psychophysical olfactory tests, and complete patient- or parent-reported quality of life surveys over 2 years. Outcomes will be compared before and after initiation of HEMT and between groups. Ethical approval has been obtained for all sites, and this study has been registered on ClinicalTrials.gov (NCT06191640)., Results: Enrolment began in April 2023. 21 participants have been enrolled as of October 2023 with ongoing enrolment at all sites., Conclusion: This investigation is expected to provide critical insights into the potential benefits of early HEMT initiation in managing CRS and OD in YCwCF. It will assist in developing targeted interventions and contribute to the understanding of HEMT's role in altering the disease course in this demographic., Competing Interests: Conflict of interest: C.M. Liu reports an NIDCD grant related to this work. Conflict of interest: J.L. Fischer has nothing to disclose. Conflict of interest: E.T. Zermaick reports that in the last 36 months, she has received grants to her institution from the Cystic Fibrosis Foundation, National Institutes of Health and Vertex Pharmaceuticals Incorporated; has received fees from the Cystic Fibrosis Foundation and Vertex Pharmaceuticals Incorporated related to consultation, participation on advisory boards, and grant review committees; she served as chair of the CFF Therapeutics Development Network steering committee, reviewed grants for CF Canada, and received travel support from the European CF Society Clinical Trials Network for speaking at their annual meeting. Conflict of interest: J.C. Woods reports that in the last 36 months, he has received grants to his institution from the Cystic Fibrosis Foundation, the National Institutes of Health, Vertex Pharmaceuticals Incorporated; and has received fees from Polarean LLC related to consultation on clinical and translational research. Conflict of interest: K.K. Markarian has nothing to disclose. Conflict of interest: S.B. Fain reports that in the last 36 months, he has served as a scientific advisor for Polarean LLC, and received research funding from Polarean LLC, Siemens Healthineers INC, and GE Healthcare INC for development of pulmonary CT and MRI methods. Conflict of interest: D. Froh reports that in the lasts 36 months, she has received grant support from the CF Foundation unrelated to this work, and from Vertex Pharmaceuticals Conflict of interest: S.L. Heltsche reports that in the last 36 months, they have received grant support from the Cystic Fibrosis Foundation; unrelated to this work they have has received grant support from National Institutes of Health and Boehringer Ingelheim, as well as service contracts from Calyx paid to their institution. Conflict of interest: L.R. Hoffman reports that in the past 36 months, they received grant funding from the CF Foundation and the NIH. Conflict of interest: S.M. Humphries declares grants from Boehringer Ingelheim and contracts from Calyx/Perceptive paid to their institution and unrelated to this work. E.L. Kramer reports that in the last 36 months, she has received grant support from the National Institutes of Health and the Cystic Fibrosis Foundation. Conflict of interest: K.L. Ode reports that in the last 36 months, she has received grant support from the National Institutes of Health, the Cystic Fibrosis Foundation, and Rhythm Pharmaceuticals, Inc. unrelated to this work Conflict of interest: M. Lewis participated in an advisory board serving as a consult for Pfizer to discuss RSV vaccines on 20 September 2023. Conflict of interest: D.A. Li reports that in the last 36 months, he has received grant support from the CF Foundation unrelated to this work. Conflict of interest: J. Mata reports that in the last 36 months, he has received grants to his institution from the Cystic Fibrosis Foundation, the National Institutes of Health, the Focused Ultrasound Foundation, iThriv and Polarean LLC; and fees from Polarean LLC related to consultation on clinical and translational research. Conflict of interest: S.S. Milla has nothing to disclose. Conflict of interest: P.J. Niedbalski reports that in the last 36 months, he has received grants from the National Institutes of Health, American Heart Association and Scleroderma Foundation. Conflict of interest: B.D. Sawatzky has nothing to disclose. Conflict of interest: M-S. Sim has nothing to disclose. Conflict of interest: J.S. Sullivan reports that in the last 36 months, she has received honoraria from the American Academy of Pediatrics to serve on the PREP-SA editorial board, unrelated to this work Conflict of interest: A.T. Trout reports that in the last 36 months, he has received grant to his institution from the Cystic Fibrosis Foundation, National Institutes of Health, GE Healthcare, Siemens Healthineers and Perspectum Inc.; and is a consultant for GE Healthcare and serves as an Assistant Editor for Pediatric Radiology. Conflict of interest: C.H. Gross reports that in the last 36 months, he has received grants from the National Institutes of Health, the Cystic Fibrosis Foundation, the Federal Drug Administration; has received fees from Enterprise Therapeutics for providing clinical trial design advice, honoraria from Gilead Sciences to serve as grant review committee chair and from Vertex Pharmaceuticals for speaking at the UK LEAD conference, served as a DSMB Chair for a trial supported by Novartis and the European Commission, and serves as the Deputy Editor of the Annals of the American Thoracic Society; he has stock in Air Therapeutics. Conflict of interest: J.L. Taylor-Cousar reports that faculty in an institution that is part of the CF TDN, she has been a site principal investigator on studies for Vertex, 4DMT, and Eloxx; has consulted/provided clinical trial design advice for Vertex and 4DMT; served as Chair of a Data Monitoring Committee for AbbVie (complete); and has received grant funding from the CFF and NIH; and is a member of the CFF Clinical Research Executive Committee, CFF TDN Sexual Health, Reproduction, and Gender Research Working Group (SHARING), and CFF Racial Justice Working Group, is ATS International Conference Committee Chair-Elect and Respiratory Health Awards Committee Member (Scientific Grant Review and Clinical Problems Programming Committee-complete), and is a member of the Emily's Entourage Scientific Advisory Board, and National Institutes of Health/National Heart, Blood, Lung Institute Clinical Trials Review Study Section. Conflict of interest: D.M. Beswick reports that in the last 36 months, he has received grant support from CF Foundation and American Rhinologic Society; and unrelated to this work, has received grant support from the International Society of Inflammation and Allergy of the Nose and the American Rhinologic Society; honoraria and consulting fees from Amgen and, on medicolegal cases, at Garner Health (equity)., (Copyright ©The authors 2025.)

Hyperpolarized (HP) xenon-129 ( 129 Xe) is an inhaled magnetic resonance imaging (MRI) contrast agent with unique spectral and physical properties that can be exploited to quantify pulmonary physiology, including ventilation, restricted diffusion (alveolar-airspace size), and gas exchange. In humans, it has been used to evaluate disease severity and progression in a variety of pulmonary disorders and is approved for clinical use in the United States and United Kingdom. Beyond its clinical applications, the ability of 129 Xe MRI to noninvasively assess pulmonary pathophysiology and provide spatially resolved information is valuable for preclinical research. Among animal models, mice are the most widely used due to the accessibility of genetically modified disease models. Here, 129 Xe MRI is promising as a minimally invasive, radiation-free, and sensitive technique to longitudinally monitor lung disease progression and therapy response (e.g., in drug discovery). This technique can extend to preclinical applications by incorporating an MRI-triggered, free-breathing apparatus or mechanical ventilator to deliver gas. Here, we describe the steps and provide checklists to ensure robust data collection and analysis, including creating a thermally polarized xenon gas phantom for quality control, optimizing polarization, animal handling (sedation, intubation, ventilation, and care for mice), and protocols for ventilation, restricted diffusion, and gas exchange data. While preclinical 129 Xe MRI can be applied in various animal models (e.g., rats, pigs, sheep), this protocol focuses on mice due to the challenges posed by their small anatomy, which are balanced by their affordability and the availability of many disease models.

High quality MRI of the lungs is challenged by low tissue density, fast MRI signal relaxation, and respiratory and cardiac motion. For these reasons, structural imaging of the lungs is performed almost exclusively using Computed Tomography (CT). However, CT imaging delivers ionizing radiation, and thus is less well suited for certain vulnerable populations (e.g., pediatrics) or for research applications. As an alternative, MRI using ultra-short echo times (UTE) is attracting interest. This technique can be performed during free-breathing over the course of a ~5-10 min scan. Respiratory motion information is encoded alongside images; this information can be used to "self-gate" images. Self-gating thus removes the requirement of advanced MRI pulse sequence programming or the use of respiratory bellows, which simplifies image acquisition. In this protocol, simple, robust, and computationally efficient acquisition and reconstruction methods for acquiring high quality UTE MRI of the lungs are presented. This protocol was developed for use on a 3T MRI scanner, but the same principles can be implemented at lower magnetic field strength. The protocol includes recommended parameter settings for 3D radial UTE image acquisition as well as directions for self-gated image reconstruction to generate images at distinct respiratory phases. Through the implementation of this protocol, users can generate high-resolution UTE images of the lungs with minimal to minimal-to-no motion artifacts. These images can be used to evaluate pulmonary structure, which can be implemented for research use in a variety of pulmonary conditions.

Lung diseases are almost invariably heterogeneous and progressive, making it imperative to capture temporally and spatially explicit information to understand the disease initiation and progression. Imaging the lung with MRI-particularly in the preclinical setting-has historically been challenging because of relatively low lung tissue density, rapid cardiac and respiratory motion, and rapid transverse (T 2 *) relaxation. These limitations can largely be mitigated using ultrashort-echo-time (UTE) sequences, which are intrinsically robust to motion and avoid significant T 2 * decay. A significant disadvantage of common radial UTE sequences is that they require inefficient, center-out k-space sampling, resulting in long acquisition times relative to conventional Cartesian sequences. Therefore, pulmonary images acquired with radial UTE are often undersampled to reduce acquisition time. However, undersampling reduces image SNR, introduces image artifacts, and degrades true image resolution. The level of undersampling is further increased if offline gating techniques like retrospective gating are employed, because only a portion (∼40-50%) of the data is used in the final image reconstruction. Here, we explore the impact of undersampling on SNR and T 2 * mapping in mouse lung imaging using simulation and in-vivo data. Increased scatter in both metrics was noticeable at around 50% sampling. Parenchymal apparent SNR only decreased slightly (average decrease ∼ 1.4) with as little as 10% sampling. Apparent T 2 * remained similar across undersampling levels, but it became significantly increased (p < 0.05) below 80% sampling. These trends suggest that undersampling can generate quantifiable, but moderate changes in the apparent value of T 2 *. Moreover, these approaches to assess the impact of undersampling are straightforward to implement and can readily be expanded to assess the quantitative impact of other MR acquisition and reconstruction parameters., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Long COVID impacts ∼10% of people diagnosed with coronavirus disease 2019 (COVID-19), yet the pathophysiology driving ongoing symptoms is poorly understood. We hypothesised that 129 Xe magnetic resonance imaging (MRI) could identify unique pulmonary phenotypic subgroups of long COVID. Therefore, we evaluated ventilation and gas exchange measurements with cluster analysis to generate imaging-based phenotypes., Methods: COVID-negative controls and participants who previously tested positive for COVID-19 underwent 129 Xe MRI ∼14 months post-acute infection across three centres. Long COVID was defined as persistent dyspnoea, chest tightness, cough, fatigue, nausea and/or loss of taste/smell at MRI; participants reporting no symptoms were considered fully recovered. 129 Xe MRI ventilation defect percent (VDP) and membrane-to-gas (Mem/Gas), red blood cell-to-membrane (RBC/Mem) and red blood cell-to-gas (RBC/Gas) ratios were used in k-means clustering for long COVID, and measurements were compared using ANOVA with post-hoc Bonferroni correction., Results: We evaluated 135 participants across three centres: 28 COVID-negative (mean±sd age 40±16 years), 34 fully recovered (42±14 years) and 73 long COVID (49±13 years). RBC/Mem (p=0.03) and forced expiratory volume in 1 s (FEV 1 ) (p=0.04) were different between long COVID and COVID-negative; FEV 1 and all other pulmonary function tests (PFTs) were within normal ranges. Four unique long COVID clusters were identified compared with recovered and COVID-negative. Cluster 1 was the youngest with normal MRI and mild gas trapping; Cluster 2 was the oldest, characterised by reduced RBC/Mem but normal PFTs; Cluster 3 had mildly increased Mem/Gas with normal PFTs; and Cluster 4 had markedly increased Mem/Gas with concomitant reduction in RBC/Mem and restrictive PFT pattern., Conclusions: We identified four 129 Xe MRI long COVID phenotypes with distinct characteristics. 129 Xe MRI can dissect pathophysiological heterogeneity of long COVID to enable personalised patient care., Competing Interests: Conflicts of interest: R.L. Eddy reports grants from Michael Smith Health Research BC, Canadian Respiratory Research Network, and Natural Sciences and Engineering Research Council Canada, consulting fees from VIDA Diagnostics Inc., payment or honoraria for lectures from Thorasys Thoracic Medical Systems Inc., support for attending meetings and/or travel from the Canadian Institutes of Health Research – Institute of Circulatory and Respiratory Health, and a leadership or fiduciary role for the Xenon MRI Clinical Trials Consortium (Steering Committee Member). D. Mummy reports consultancy fees from Polarean Imaging Plc. F.V. Gerayeli reports grants from MITACS Accelerate. J.A. Leipsic reports grants from GE Healthcare, consultancy fees and support for attending meetings and/or travel from Heartflow, and owns stock/stock options in Heartflow. J.M. Leung reports grants from the Canadian Institutes of Health Research and BC Lung Foundation, payment or honoraria for lectures, presentations, manuscript writing or educational events from the BC Lung Foundation, participation on a data safety monitoring board or advisory board for Enhance Quality Safety, and Patient Experience in Chronic Obstructive Pulmonary Disorder (EQuiP COPD), and leadership or fiduciary roles for the Canadian Respiratory Research Network and CanCOLD Study. B. Driehuys reports grants from Translating Duke Health (Duke Internal Award), royalties or licenses from Polarean Imaging, a leadership or fiduciary role with Polarean Imaging, and owns stock/stock options in Polarean Imaging. L.G. Que reports grants from Translating Duke Health (Duke Internal Award) and a leadership or fiduciary role as a member of the Xe MRI Consortium. M. Castro reports grants from the NIH, ALA, PCORI, AstraZeneca, Gala Therapeutics, Genentech, GSK, Novartis, Pulmatrix, Sanofi-Aventis, Shionogi and Theravance, consulting fees from Genentech, Teva, Sanofi-Aventis, Merck, Novartis, Arrowhead Pharmaceuticals, Allakos, Amgen, OM Pharma, Pfizer, Pioneering Medicines and GSK, payment or honoraria for lectures, presentations, manuscript writing or educational events from Amgen, AstraZeneca, Genentech, Regeneron, Sanofi-Aventis and Teva, and owns stock/stock options in Aer Therapeutics. D.D. Sin reports payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK, AstraZeneca and Boehringer Ingelheim, and participation on a data safety monitoring board or advisory board for the NHLBI. P.J. Niedbalski reports grants from the Scleroderma Foundation (New Investigator Grant) and American Heart Association (CDA 930177), and consultancy fees, payment or honoraria for lectures, and support for attending meetings and/or travel from Polarean Imaging Plc. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Hyperpolarized 129 Xe MRI (Xe-MRI) is increasingly used to image the structure and function of the lungs. Because 129 Xe imaging can provide multiple contrasts (ventilation, alveolar airspace size, and gas exchange), imaging often occurs over several breath-holds, which increases the time, expense, and patient burden of scans. We propose an imaging sequence that can be used to acquire Xe-MRI gas exchange and high-quality ventilation images within a single, approximately 10 s, breath-hold. This method uses a radial one-point Dixon approach to sample dissolved 129 Xe signal, which is interleaved with a 3D spiral ("FLORET") encoding pattern for gaseous 129 Xe. Thus, ventilation images are obtained at higher nominal spatial resolution (4.2 × 4.2 × 4.2 mm 3 ) compared with gas-exchange images (6.25 × 6.25 × 6.25 mm 3 ), both competitive with current standards within the Xe-MRI field. Moreover, the short 10 s Xe-MRI acquisition time allows for 1 H "anatomic" images used for thoracic cavity masking to be acquired within the same breath-hold for a total scan time of about 14 s. Images were acquired using this single-breath method in 11 volunteers (N = 4 healthy, N = 7 post-acute COVID). For 11 of these participants, a separate breath-hold was used to acquire a "dedicated" ventilation scan and five had an additional "dedicated" gas exchange scan. The images acquired using the single-breath protocol were compared with those from dedicated scans using Bland-Altman analysis, intraclass correlation (ICC), structural similarity, peak signal-to-noise ratio, Dice coefficients, and average distance. Imaging markers from the single-breath protocol showed high correlation with dedicated scans (ventilation defect percent, ICC = 0.77, p = 0.01; membrane/gas, ICC = 0.97, p = 0.001; red blood cell/gas, ICC = 0.99, p < 0.001). Images showed good qualitative and quantitative regional agreement. This single-breath protocol enables the collection of essential Xe-MRI information within one breath-hold, simplifying scanning sessions and reducing costs associated with Xe-MRI., (© 2023 John Wiley & Sons Ltd.)

Background: 129 Xe gas-transfer MRI provides regional measures of pulmonary gas exchange in adults and separates xenon in interstitial lung tissue/plasma (barrier) from xenon in red blood cells (RBCs). The technique has yet to be demonstrated in pediatric populations or conditions., Purpose/hypothesis: To perform an exploratory analysis of 129 Xe gas-transfer MRI in children., Study Type: Prospective., Population: Seventy-seven human volunteers (38 males, age = 17.7 ± 15.1 years, range 5-68 years, 16 healthy). Four pediatric disease cohorts., Field Strength/sequence: 3-T, three-dimensional-radial one-point Dixon Fast Field Echo (FFE) Ultrashort Echo Time (UTE)., Assessment: Breath hold compliance was assessed by quantitative signal-to-noise and dynamic metrics. Whole-lung means and standard deviations were extracted from gas-transfer maps. Gas-transfer metrics were investigated with respect to age and lung disease. Clinical pulmonary function tests were retrospectively acquired for reference lung disease severity., Statistical Tests: Wilcoxon rank-sum tests to compare age and disease cohorts, Wilcoxon signed-rank tests to compare pre- and post-breath hold vitals, Pearson correlations between age and gas-transfer metrics, and limits of normal with a binomial exact test to compare fraction of subjects with abnormal gas-transfer. P ≤ 0.05 was considered significant., Results: Eighty percentage of pediatric subjects successfully completed 129 Xe gas-transfer MRI. Gas-transfer parameters differed between healthy children and adults, including ventilation (0.75 and 0.67) and RBC:barrier ratio (0.31 and 0.46) which also correlated with age (ρ = -0.76, 0.57, respectively). Bone marrow transplant subjects had impaired ventilation (90% of reference) and increased dissolved 129 Xe standard deviation (242%). Bronchopulmonary dysplasia subjects had decreased barrier-uptake (69%). Cystic fibrosis subjects had impaired ventilation (91%) and increased RBC-transfer (146%). Lastly, childhood interstitial lung disease subjects had increased ventilation heterogeneity (113%). Limits of normal provided detection of abnormalities in additional gas-transfer parameters., Data Conclusion: Pediatric 129 Xe gas-transfer MRI was adequately successful and gas-transfer metrics correlated with age. Exploratory analysis revealed abnormalities in a variety of pediatric obstructive and restrictive lung diseases., Level of Evidence: 2 TECHNICAL EFFICACY STAGE: 2., (© 2022 International Society for Magnetic Resonance in Medicine.)

Asthma is a heterogeneous disease characterized by chronic airway inflammation that affects more than 300 million people worldwide. Clinically, asthma has a widely variable presentation and is defined based on a history of respiratory symptoms alongside airflow limitation. Imaging is not needed to confirm a diagnosis of asthma, and thus the use of imaging in asthma has historically been limited to excluding alternative diagnoses. However, significant advances continue to be made in novel imaging methodologies, which have been increasingly used to better understand respiratory impairment in asthma. As a disease primarily impacting the airways, asthma is best understood by imaging methods with the ability to elucidate airway impairment. Techniques such as computed tomography, magnetic resonance imaging with gaseous contrast agents, and positron emission tomography enable assessment of the small airways. Others, such as optical coherence tomography and endobronchial ultrasound enable high-resolution imaging of the large airways accessible to bronchoscopy. These imaging techniques are providing new insights in the pathophysiology and treatments of asthma and are poised to impact the clinical management of asthma., Competing Interests: None declared., (Thieme. All rights reserved.)

Purpose: To reduce scan duration in hyperpolarized 129 Xe 1-point Dixon gas exchange imaging by utilizing flip angle (FA)/TR equivalence., Methods: Images were acquired in 12 subjects (n = 3 radiation therapy, n = 1 unexplained dyspnea, n = 8 healthy) using both standard (TR = 15 ms, FA = 20°, duration = 15 s, 998 projections) and "fast" (TR = 5.4 ms, FA = 12°, duration = 11.3 s, 2100 projections) acquisition parameters. For the fast acquisition, 3 image sets were reconstructed using subsets of 1900, 1500, and 1000 projections. From the resulting ventilation, tissue ("barrier"), and red blood cell (RBC) images, image metrics and biomarkers were compared to assess agreement between methods., Results: Images acquired using both FA/TR settings had similar qualitative appearance. There were no significant differences in SNR, image mean, or image SD between images. Moreover, the percentage of the lungs in "defect", "normal", and "high" bins for each image (ventilation, RBC, barrier) was not significantly different among the acquisition types. After registration, comparison of 3D image metrics (Dice, volume similarity, average distance) agreed well between bins. Images using 1000 projections for reconstruction had no significant differences from images using all projections., Conclusion: Using flip angle/TR equivalence, hyperpolarized 129 Xe gas exchange images can be acquired via the 1-point Dixon technique in as little as 6 s, compared to ~15 s for previously reported parameter settings. The resulting images from this accelerated scan have no significant differences from the standard method in qualitative appearance or quantitative metrics., (© 2021 International Society for Magnetic Resonance in Medicine.)

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 (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 that 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 < 5%) for estimating ADC. The whole-lung mean 129 Xe ADC of healthy subjects increased with age at a rate of 1.75 × 10 -4  cm 2 /s/yr (p = 0.001)., Conclusions: HP 129 Xe diffusion MRI can be improved by minimizing the uncertainty of ADC measurements via uncertainty propagation. Doing so will improve experimental accuracy when measuring lung microstructure in vivo and should allow improved monitoring of regional disease progression and assessment of therapy response in a range of lung diseases., (© 2021 John Wiley & Sons, Ltd.)

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., (© 2021 International Society for Magnetic Resonance in Medicine.)

Structural remodeling in lung disease is progressive and heterogeneous, making temporally and spatially explicit information necessary to understand disease initiation and progression. While mouse models are essential to elucidate mechanistic pathways underlying disease, the experimental tools commonly available to quantify lung disease burden are typically invasive ( e.g. , histology). This necessitates large cross-sectional studies with terminal endpoints, which increases experimental complexity and expense. Alternatively, magnetic resonance imaging (MRI) provides information noninvasively, thus permitting robust, repeated-measures statistics. Although lung MRI is challenging due to low tissue density and rapid apparent transverse relaxation (T 2 * <1 ms), various imaging methods have been proposed to quantify disease burden. However, there are no widely accepted strategies for preclinical lung MRI. As such, it can be difficult for researchers who lack lung imaging expertise to design experimental protocols-particularly for novel mouse models. Here, we build upon prior work from several research groups to describe a widely applicable acquisition and analysis pipeline that can be implemented without prior preclinical pulmonary MRI experience. Our approach utilizes 3D radial ultrashort echo time (UTE) MRI with retrospective gating and lung segmentation is facilitated with a deep-learning algorithm. This pipeline was deployed to assess disease dynamics over 255 days in novel, transgenic mouse models of lung fibrosis based on disease-associated, loss-of-function mutations in Surfactant Protein-C. Previously identified imaging biomarkers (tidal volume, signal coefficient of variation, etc.) were calculated semi-automatically from these data, with an objectively-defined high signal volume identified as the most robust metric. Beyond quantifying disease dynamics, we discuss common pitfalls encountered in preclinical lung MRI and present systematic approaches to identify and mitigate these challenges. While the experimental results and specific pedagogical examples are confined to lung fibrosis, the tools and approaches presented should be broadly useful to quantify structural lung disease in a wide range of mouse models., Competing Interests: Conflicts of Interest: The authors declare that there are no conflicts of interest regarding the publication of this paper.

Purpose: Diffusion and lung morphometry imaging using hyperpolarized gases are promising tools to quantify pulmonary microstructure noninvasively in humans and in animal models. These techniques assume the motion encoded is exclusively diffusive gas displacement, but the impact of cardiac motion on measurements has never been explored. Furthermore, although diffusion morphometry has been validated against histology in humans and mice using 3 He, it has never been validated in mice for 129 Xe. Here, we examine the effect of cardiac motion on diffusion imaging and validate 129 Xe diffusion morphometry in mice., Theory and Methods: Mice were imaged using gradient-echo-based diffusion imaging, and apparent diffusion-coefficient (ADC) maps were generated with and without cardiac gating. Diffusion-weighted images were fit to a previously developed theoretical model using Bayesian probability theory, producing morphometric parameters that were compared with conventional histology., Results: Cardiac gating had no significant impact on ADC measurements (dual-gating: ADC = 0.020 cm 2 /s, single-gating: ADC = 0.020 cm 2 /s; P = .38). Diffusion-morphometry-generated maps of ADC (mean, 0.0165 ± 0.0001 cm 2 /s) and acinar dimensions (alveolar sleeve depth [h] = 44 µm, acinar duct radii [R] = 99 µm, mean linear intercept [L m ] = 74 µm) that agreed well with conventional histology (h = 45 µm, R = 108 µm, L m = 63 µm)., Conclusion: Cardiac motion has negligible impact on 129 Xe ADC measurements in mice, arguing its impact will be similarly minimal in humans, where relative cardiac motion is reduced. Hyperpolarized 129 Xe diffusion morphometry accurately and noninvasively maps the dimensions of lung microstructure, suggesting it can quantify the pulmonary microstructure in mouse models of lung disease., (© 2020 International Society for Magnetic Resonance in Medicine.)

Hyperpolarized (HP) 129 Xe MRI is increasingly used to noninvasively probe regional lung structure and function in the preclinical setting. As in human imaging, the primary barrier to quantitative imaging with HP gases is nonequilibrium magnetization, which is depleted by T 1 relaxation and radio frequency excitation. Preclinical HP gas imaging commonly involves mechanically ventilating small animals and encoding k-space over tens or hundreds of breaths, with small subsets of k-space data collected within each breath. Breath-to-breath magnetization renewal enables the use of large flip angles, but the resulting magnetization decay generates large view-to-view differences in within-breath signal intensity, leading to artifacts and degraded image quality. This deleterious signal decay has motivated the use of variable flip angle (VFA) sampling schemes, in which the flip angle is progressively increased to maintain constant view-to-view signal intensity. However, VFA imaging complicates data acquisition and provides only a global correction that fails to compensate for regional differences in signal dynamics. When constant flip angle (CFA) imaging is used alongside 3D radial golden means acquisition, the center of k-space is sampled with every excitation, thereby encoding signal dynamics alongside imaging data. Here, keyhole reconstruction is used to generate multiple images to capture in-breath HP 129 Xe signal dynamics in mice and thus provide flip angle maps to quantitatively correct images without extra data collection. These CFA images display SNR that is not significantly different from VFA images, and further, high frequency k-space scaling can be used to mitigate decay-induced image artifacts. Results are supported by point spread function calculations and simulations of radial imaging with preclinical signal dynamics. Together, these results show that CFA 3D radial golden means ventilation imaging provides comparable image quality with VFA in small animals and allows for keyhole reconstruction, which can be used to generate flip angle maps and correct images for signal depletion., (© 2020 John Wiley & Sons, Ltd.)

Magnetic resonance (MR) imaging and spectroscopy using dissolved hyperpolarized (HP) 129 Xe have expanded the ability to probe lung function regionally and noninvasively. In particular, HP 129 Xe imaging has been used to quantify impaired gas uptake by the pulmonary tissues. Whole-lung spectroscopy has also been used to assess global cardiogenic oscillations in the MR signal intensity originating from 129 Xe dissolved in the red blood cells of pulmonary capillaries. Herein, we show that the magnitude of these cardiogenic dynamics can be mapped three dimensionally using radial MRI, because dissolved 129 Xe dynamics are encoded directly in the raw imaging data. Specifically, 1-point Dixon imaging is combined with postacquisition keyhole image reconstruction to assess regional blood volume fluctuations within the pulmonary microvasculature throughout the cardiac cycle. This "oscillation mapping" was applied in healthy subjects (mean amplitude 9% of total RBC signal) and patients with pulmonary arterial hypertension (PAH; mean 4%) and idiopathic pulmonary fibrosis (IPF; mean 14%). Whole-lung mean values from these oscillation maps correlated strongly with spectroscopy and clinical pulmonary function testing, but exhibited significant regional heterogeneity, including gravitationally dependent gradients in healthy subjects. Moreover, regional oscillations were found to be sensitive to disease state. Greater percentages of the lungs exhibit low-amplitude oscillations in PAH patients, and longitudinal imaging shows high-amplitude oscillations increase significantly over time (4-14 mo, P = 0.02) in IPF patients. This technique enables regional dynamics within the pulmonary capillary bed to be measured, and in doing so, provides insight into the origin and progression of pathophysiology within the lung microvasculature. NEW & NOTEWORTHY Spatially heterogeneous abnormalities within the lung microvasculature contribute to pathology in various cardiopulmonary diseases but are difficult to assess noninvasively. Hyperpolarized 129 Xe MRI is a noninvasive method to probe lung function, including regional gas exchange between pulmonary air spaces and capillaries. We show that cardiogenic oscillations in the raw dissolved 129 Xe MRI signal from pulmonary capillary red blood cells can be imaged using a postacquisition reconstruction technique, providing a new means of assessing regional lung microvasculature function and disease state.

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 sequences). This is especially true in preclinical studies, where high magnetic fields lead to shorter relaxation times than are typically seen in human studies. However, the 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 7 T 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 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 10 healthy C57Bl/6 J mice and found T 2 * ~ 5 ms in the lung airspaces. Interestingly, T 2 * was relatively constant over all experimental conditions, and varied significantly with sex, but not age, 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., (© 2020 John Wiley & Sons, Ltd.)

Purpose: Hyperpolarized 129 Xe MRI characterizes regional lung ventilation in a variety of disease populations, with high sensitivity to airway obstruction in early disease. However, ventilation images are usually limited to a single breath-hold and most-often acquired using gradient-recalled echo sequences with thick slices (~10-15 mm), which increases partial-volume effects, limits ability to observe small defects, and suffers from imperfect slice selection. We demonstrate higher-resolution ventilation images, in shorter breath-holds, using FLORET (Fermat Looped ORthogonally Encoded Trajectories), a center-out 3D-spiral UTE sequence., Methods: In vivo human adult (N = 4; 2 healthy, 2 with cystic fibrosis) 129 Xe images were acquired using 2D gradient-recalled echo, 3D radial, and FLORET. Each sequence was acquired at its highest possible resolution within a 16-second breath-hold with a minimum voxel dimension of 3 mm. Images were compared using 129 Xe ventilation defect percentage, SNR, similarity coefficients, and vasculature cross-sections., Results: The FLORET sequence obtained relative normalized SNR, 40% greater than 2D gradient-recalled echo (P = .012) and 26% greater than 3D radial (P = .067). Moreover, the FLORET images were acquired with 3-fold-higher nominal resolution in a 15% shorter breath-hold. Finally, vasculature was less prominent in FLORET, likely due to diminished susceptibility-induced dephasing at shorter TEs afforded by UTE sequences., Conclusion: The FLORET sequence yields higher SNR for a given resolution with a shorter breath-hold than traditional ventilation imaging techniques. This sequence more accurately measures ventilation abnormalities and enables reduced scan times in patients with poor compliance and severe lung disease., (© 2019 International Society for Magnetic Resonance in Medicine.)

Purpose: Hyperpolarized (HP) media enable biomedical imaging applications that cannot be achieved with conventional MRI contrast agents. Unfortunately, quantifying HP images is challenging, because relaxation and radio-frequency pulsing generate spatially varying signal decay during acquisition. We demonstrate that, by combining center-out k-space sampling with postacquisition keyhole reconstruction, voxel-by-voxel maps of regional HP magnetization decay can be generated with no additional data collection., Theory and Methods: Digital phantom, HP 129 Xe phantom, and in vivo 129 Xe human (N = 4 healthy; N = 2 with cystic fibrosis) imaging was performed using radial sampling. Datasets were reconstructed using a postacquisition keyhole approach in which 2 temporally resolved images were created and used to generate maps of regional magnetization decay following a simple analytical model., Results: Mean, keyhole-derived decay terms showed excellent agreement with the decay used in simulations (R 2 = 0.996) and with global attenuation terms in HP 129 Xe phantom imaging (R 2 > 0.97). Mean regional decay from in vivo imaging agreed well with global decay values and displayed spatial heterogeneity that matched expected variations in flip angle and oxygen partial pressure. Moreover, these maps could be used to correct variable signal decay across the image volume., Conclusions: We have demonstrated that center-out trajectories combined with keyhole reconstruction can be used to map regional HP signal decay and to quantitatively correct images. This approach may be used to improve the accuracy of quantitative measures obtained from hyperpolarized media. Although validated with gaseous HP 129 Xe in this work, this technique can be generalized to any hyperpolarized agent., (© 2019 International Society for Magnetic Resonance in Medicine.)