Marcus J. Couch

Functional imaging of the lungs with gas agents

This review focuses on the state‐of‐the‐art of the three major classes of gas contrast agents used in magnetic resonance imaging (MRI)—hyperpolarized (HP) gas, molecular oxygen, and fluorinated gas—and their application to clinical pulmonary research. During the past several years there has been accelerated development of pulmonary MRI. This has been driven in part by concerns regarding ionizing radiation using multidetector computed tomography (CT). However, MRI also offers capabilities for fast multispectral and functional imaging using gas agents that are not technically feasible with CT. Recent improvements in gradient performance and radial acquisition methods using ultrashort echo time (UTE) have contributed to advances in these functional pulmonary MRI techniques. The relative strengths and weaknesses of the main functional imaging methods and gas agents are compared and applications to measures of ventilation, diffusion, and gas exchange are presented. Functional lung MRI methods using these gas agents are improving our understanding of a wide range of chronic lung diseases, including chronic obstructive pulmonary disease, asthma, and cystic fibrosis in both adults and children. J. Magn. Reson. Imaging 2016;43:295–315.

Inert fluorinated gas MRI: a new pulmonary imaging modality

Fluorine‐19 (19F) MRI of the lungs using inhaled inert fluorinated gases can potentially provide high quality images of the lungs that are similar in quality to those from hyperpolarized (HP) noble gas MRI. Inert fluorinated gases have the advantages of being nontoxic, abundant, and inexpensive compared with HP gases. Due to the high gyromagnetic ratio of 19F, there is sufficient thermally polarized signal for imaging, and averaging within a single breath‐hold is possible due to short longitudinal relaxation times. Therefore, the gases do not need to be hyperpolarized prior to their use in MRI. This eliminates the need for an expensive polarizer and expensive isotopes. Inert fluorinated gas MRI of the lungs has been previously demonstrated in animals, and more recently in healthy volunteers and patients with lung diseases. The ongoing improvements in image quality demonstrate the potential of 19F MRI for visualizing the distribution of ventilation in human lungs and detecting functional biomarkers. In this brief review, the development of inert fluorinated gas MRI, current progress, and future prospects are discussed. The current state of HP noble gas MRI is also briefly discussed in order to provide context to the development of this new imaging modality. Overall, this may be a viable clinical imaging modality that can provide useful information for the diagnosis and management of chronic respiratory diseases. Copyright

Hyperpolarized and Inert Gas MRI: The Future

Magnetic resonance imaging (MRI) is a potentially ideal imaging modality for noninvasive, nonionizing, and longitudinal assessment of disease. Hyperpolarized (HP) agents have been developed in the past 20 years for MR imaging, and they have the potential to vastly improve MRI sensitivity for the diagnosis and management of various diseases. The polarization of nuclear magnetic resonance (NMR)-sensitive nuclei other than 1H (e.g., 3He, 129Xe) can be enhanced by a factor of up to 100,000 times above thermal equilibrium levels, which enables direct detection of the HP agent with no background signal. In this review, a number of HP media applications in MR imaging are discussed, including HP 3He and 129Xe lung imaging, HP 129Xe brain imaging, and HP 129Xe biosensors. Inert fluorinated gas MRI, which is a new lung imaging technique that does not require hyperpolarization, is also briefly discussed. This technique will likely be an important future direction for the HP gas lung imaging community.

In vivo regional ventilation mapping using fluorinated gas MRI with an x-centric FGRE method.

Inert fluorinated gas lung MRI is a new and promising alternative to hyperpolarized gas lung MRI; it is less expensive and does not require expensive isotopes/polarizers. The thermally polarized nature of signal obtained from fluorinated gases makes it relatively easy to use for dynamic lung imaging and for obtaining lung ventilation maps. In this study, we propose that the sensitivity and resolution of fluorine‐19 (19F) in vivo images can be improved using the x‐centric pulse sequence, thereby achieving a short echo time/pulse repetition time. This study is a transitional step for converting to more sustainable gases for lung imaging.

Fractional ventilation mapping using inert fluorinated gas MRI in rat models of inflammation and fibrosis

The purpose of this study was to extend established methods for fractional ventilation mapping using 19F MRI of inert fluorinated gases to rat models of pulmonary inflammation and fibrosis. In this study, five rats were instilled with lipopolysaccharide (LPS) in the lungs two days prior to imaging, six rats were instilled with bleomycin in the lungs two weeks prior to imaging and an additional four rats were used as controls. 19F MR lung imaging was performed at 3 T with rats continuously breathing a mixture of sulfur hexafluoride and O2. Fractional ventilation maps were obtained using a wash‐out approach, by switching the breathing mixture to pure O2, and acquiring images following each successive wash‐out breath. The mean fractional ventilation (r) was 0.29 ± 0.05 for control rats, 0.23 ± 0.10 for LPS‐instilled rats and 0.19 ± 0.03 for bleomycin‐instilled rats. Bleomycin‐instilled rats had a significantly decreased mean r value compared with controls (P = 0.010). Although LPS‐instilled rats had a slightly reduced mean r value, this trend was not statistically significant (P = 0.556). Fractional ventilation gradients were calculated in the anterior/posterior (A/P) direction, and the mean A/P gradient was −0.005 ± 0.008 cm−1 for control rats, 0.013 ± 0.005 cm−1 for LPS‐instilled rats and 0.009 ± 0.018 cm−1 for bleomycin‐instilled rats. Fractional ventilation gradients were significantly different for control rats compared with LPS‐instilled rats only (P = 0.016). The ventilation gradients calculated from control rats showed the expected gravitational relationship, while ventilation gradients calculated from LPS‐ and bleomycin‐instilled rats showed the opposite trend. Histology confirmed that LPS‐instilled rats had a significantly elevated alveolar wall thickness, while bleomycin‐instilled rats showed signs of substantial fibrosis. Overall, 19F MRI may be able to detect the effects of pulmonary inflammation and fibrosis using a simple and inexpensive imaging approach that can potentially be translated to humans. Copyright

Hyperpolarized Gas Magnetic Resonance Imaging of Pediatric Cystic Fibrosis Lung Disease

Conventional pulmonary function tests appear normal in early cystic fibrosis (CF) lung disease. Therefore, new diagnostic approaches are required that can detect CF lung disease in children and monitor treatment response. Hyperpolarized (HP) gas (129Xe and 3He) magnetic resonance imaging (MRI) is a powerful, emergent tool for mapping regional lung function and may be well suited for studying pediatric CF. HP gas MRI is well tolerated, reproducible, and it can be performed longitudinally without the need for ionizing radiation. In particular, quantification of the distribution of ventilation, or ventilation defect percent (VDP), has been shown to be a sensitive indicator of CF lung disease and correlates well with pulmonary function tests. This article presents the current state of CF diagnosis and treatment and describes the potential role of HP gas MRI for detection of early CF lung disease and following the effects of interventions. The typical HP gas imaging workflow is described, along with a discussion of image analysis to calculate VDP, dosing considerations, and the reproducibility of VDP. The potential use of VDP as an outcome measure in CF is discussed, by considering the correlation with pulmonary function measures, preliminary interventional studies, and case studies involving longitudinal imaging and pulmonary exacerbations. Finally, emerging HP gas imaging techniques such as multiple breath washout imaging are introduced, followed by a discussion of future directions. Overall, HP gas MRI biomarkers are expected to provide sensitive outcome measures that can be used in disease surveillance as well as interventional studies involving novel CF therapies.

Chapter 22:Magnetic Resonance Imaging of the Brain using Hyperpolarized 129Xe

The use of laser-polarized xenon-129 (129Xe) as a novel contrast agent for magnetic resonance imaging (MRI) is quite useful for imaging the lungs and other organs such as the brain. From the earliest days of HP 129Xe MRI, the original interest of one of the co-inventors (Dr Mitchell Albert) was to use 129Xe to better understand the brain and directly image the effect of anaesthesia on brain function. Since xenon is a known anaesthetic and 129Xe is a spin 1/2 nucleus it was a logical choice to study the effects of anaesthesia on the brain using MRI. In this chapter, we will briefly review some historical advancements for functional brain imaging, such as functional magnetic resonance imaging (fMRI) and the use of 129Xe for animal and human brain imaging. The practical considerations for imaging the human brain using magnetic resonance will also be discussed. Considerations include: hyperpolarized gases, physical and chemical properties of xenon, routes and methods of delivery, physiological effects and patient safety. Finally, some basic ground-work and recent literature in the development of brain imaging using HP 129Xe in animals and humans will be discussed.

19F MRI of the Lungs Using Inert Fluorinated Gases: Challenges and New Developments: New Developments in 19F MRI of the Lungs

Fluorine‐19 (19F) MRI using inhaled inert fluorinated gases is an emerging technique that can provide functional images of the lungs. Inert fluorinated gases are nontoxic, abundant, relatively inexpensive, and the technique can be performed on any MRI scanner with broadband multinuclear imaging capabilities. Pulmonary 19F MRI has been performed in animals, healthy human volunteers, and in patients with lung disease. In this review, the technical requirements of 19F MRI are discussed, along with various imaging approaches used to optimize the image quality. Lung imaging is typically performed in humans using a gas mixture containing 79% perfluoropropane (PFP) or sulphur hexafluoride (SF6) and 21% oxygen. In lung diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), ventilation defects are apparent in regions that the inhaled gas cannot access. 19F lung images are typically acquired in a single breath‐hold, or in a time‐resolved, multiple breath fashion. The former provides measurements of the ventilation defect percent (VDP), while the latter provides measurements of gas replacement (ie, fractional ventilation). Finally, preliminary comparisons with other functional lung imaging techniques are discussed, such as Fourier decomposition MRI and hyperpolarized gas MRI. Overall, functional 19F lung MRI is expected to complement existing proton‐based structural imaging techniques, and the combination of structural and functional lung MRI will provide useful outcome measures in the future management of pulmonary diseases in the clinic.

Chapter 11:Medical Applications of Hyperpolarized and Inert Gases in MR Imaging and NMR Spectroscopy

MRI is a potentially ideal imaging modality for non-invasive, non-ionizing, and longitudinal assessment of disease. One notable disadvantage of MRI is its low sensitivity compared to other imaging modalities, and this drawback can be rectified with hyperpolarized (HP) agents that have been developed over the past 20 years. HP agents have the potential to vastly improve MRI sensitivity for the diagnosis and management of various diseases. The polarization of NMR-sensitive nuclei other than 1H (e.g. 3He, 129Xe) can be enhanced by a factor of up to 100 000 times above thermal equilibrium levels, thus enabling direct detection of the HP agent at low concentration and with no background signal. In this chapter, a number of HP media applications in MR imaging is discussed, including HP 3He and 129Xe lung imaging, HP 129Xe brain imaging, and HP 129Xe biosensors. Inert fluorinated gas MRI, which is a new lung imaging technique that does not require hyperpolarization, is also briefly discussed. These techniques will likely be important future directions for the HP gas lung imaging community.