Pulmonary Structural MRI using Free-Breathing, Self-Gated Ultra-short Echo Time Imaging

High quality MRI of the lungs is challenged by low tissue density, fast MRI signal relaxation, and respiratory and cardiac motion. For these reasons, ...

University of Kansas Medical Center

Hyperpolarized (HP)  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 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  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.

Improved preclinical hyperpolarized  Xe ventilation imaging with constant flip angle 3D radial golden means acquisition and keyhole reconstruction.

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 (, 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* <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.

Preclinical MRI to Quantify Pulmonary Disease Severity and Trajectories in Poorly Characterized Mouse Models: A Pedagogical Example Using Data from Novel Transgenic Models of Lung Fibrosis.

Hyperpolarized (HP)  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  Xe MRI as outcome measures in multi-site clinical trials across a range of pulmonary disorders. Until recently, HP  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  Xe MRI more widely in translational research, multi-site trials, and ultimately clinical practice, this position paper from the  Xe MRI Clinical Trials Consortium (https://cpir.cchmc.org/XeMRICTC) recommends standard protocols to harmonize methods for image acquisition in HP  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  Xe dose volumes and breath-hold standardization to further foster consistency of imaging studies. The intention is that sites with HP  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  Xe MRI for multi-site pulmonary research.

Protocols for multi-site trials using hyperpolarized  Xe MRI for imaging of ventilation, alveolar-airspace size, and gas exchange: A position paper from the  Xe MRI clinical trials consortium.

To reduce scan duration in hyperpolarized  Xe 1-point Dixon gas exchange imaging by utilizing flip angle (FA)/TR equivalence.

Utilizing flip angle/TR equivalence to reduce breath hold duration in hyperpolarized  Xe 1-point Dixon gas exchange imaging.

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.

Imaging in Asthma Management.

Hyperpolarized  Xe MRI (Xe-MRI) is increasingly used to image the structure and function of the lungs. Because  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  Xe signal, which is interleaved with a 3D spiral ("FLORET") encoding pattern for gaseous  Xe. Thus, ventilation images are obtained at higher nominal spatial resolution (4.2 × 4.2 × 4.2 mm ) compared with gas-exchange images (6.25 × 6.25 × 6.25 mm ), both competitive with current standards within the Xe-MRI field. Moreover, the short 10 s Xe-MRI acquisition time allows for  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.

A single-breath-hold protocol for hyperpolarized  Xe ventilation and gas exchange imaging.

The interaction between  Xe atoms and pulmonary capillary red blood cells provides cardiogenic signal oscillations that display sensitivity to precapillary and postcapillary pulmonary hypertension. Recently, such oscillations have been spatially mapped, but little is known about optimal reconstruction or sensitivity to artifacts. In this study, we use digital phantom simulations to specifically optimize keyhole reconstruction for oscillation imaging. We then use this optimized method to re-establish healthy reference values and quantitatively evaluate microvascular flow changes in patients with chronic thromboembolic pulmonary hypertension (CTEPH) before and after pulmonary thromboendarterectomy (PTE).

Optimized quantitative mapping of cardiopulmonary oscillations using hyperpolarized  Xe gas exchange MRI: Digital phantoms and clinical evaluation in CTEPH.

Long COVID impacts ∼10% of people diagnosed with COVID-19, yet the pathophysiology driving ongoing symptoms is poorly understood. We hypothesised that 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.

Peter J. Niedbalski

Division of Pulmonary,
Critical Care,
and Sleep Medicine,
Hoglund Biomedical Imaging Center,
Division of Pulmonary, Critical Care, and Sleep Medicine, Hoglund Biomedical Imaging Center

University of Kansas Medical Center

Pulmonary Structural MRI using Free-Breathing, Self-Gated Ultra-short Echo Time Imaging

Peter J. Niedbalski

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Division of Pulmonary,Critical Care,and Sleep Medicine,Hoglund Biomedical Imaging Center,Division of Pulmonary, Critical Care, and Sleep Medicine, Hoglund Biomedical Imaging Center

University of Kansas Medical Center

Pulmonary Structural MRI using Free-Breathing, Self-Gated Ultra-short Echo Time Imaging

Division of Pulmonary,
Critical Care,
and Sleep Medicine,
Hoglund Biomedical Imaging Center,
Division of Pulmonary, Critical Care, and Sleep Medicine, Hoglund Biomedical Imaging Center