Mitchell S. Albert

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.

Pulmonary hyperpolarized noble gas MRI: recent advances and perspectives in clinical application.

The invention of hyperpolarized (HP) noble gas MRI using helium-3 ((3)He) or xenon-129 ((129)Xe) has provided a new method to evaluate lung function. Using HP (3)He or (129)Xe for inhalation into the lung air spaces as an MRI contrast agent significantly increases MR signal and makes pulmonary ventilation imaging feasible. This review focuses on important aspects of pulmonary HP noble gas MRI, including the following: (1) functional imaging types, (2) applications for major pulmonary diseases, (3) safety considerations, and (4) future directions. Although it is still challenging to use pulmonary HP noble gas MRI clinically, the technology offers promise for the investigation of the microstructure and function of the lungs.

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.

In vivo detection of cucurbit[6]uril, a hyperpolarized xenon contrast agent for a xenon magnetic resonance imaging biosensor

The Hyperpolarized gas Chemical Exchange Saturation Transfer (HyperCEST) Magnetic Resonance (MR) technique has the potential to increase the sensitivity of a hyperpolarized xenon-129 MRI contrast agent. Signal enhancement is accomplished by selectively depolarizing the xenon within a cage molecule which, upon exchange, reduces the signal in the dissolved phase pool. Herein we demonstrate the in vivo detection of the cucurbit[6]uril (CB6) contrast agent within the vasculature of a living rat. Our work may be used as a stepping stone towards using the HyperCEST technique as a molecular imaging modality.

Recent Progress in Alzheimer’s Disease Research, Part 3: Diagnosis and Treatment

The field of Alzheimer’s disease (AD) research has grown exponentially over the past few decades, especially since the isolation and identification of amyloid-β from postmortem examination of the brains of AD patients. Recently, the Journal of Alzheimer’s Disease (JAD) put forth approximately 300 research reports which were deemed to be the most influential research reports in the field of AD since 2010. JAD readers were asked to vote on these most influential reports. In this 3-part review, we review the results of the 300 most influential AD research reports to provide JAD readers with a readily accessible, yet comprehensive review of the state of contemporary research. Notably, this multi-part review identifies the “hottest” fields of AD research providing guidance for both senior investigators as well as investigators new to the field on what is the most pressing fields within AD research. Part 1 of this review covers pathogenesis, both on a molecular and macro scale. Part 2 review genetics and epidemiology, and part 3 covers diagnosis and treatment. This part of the review, diagnosis and treatment, reviews the latest diagnostic criteria, biomarkers, imaging, and treatments in AD.

HyperCEST detection of cucurbit[6]uril in whole blood using an ultrashort saturation Pre-pulse train.

Xenon based biosensors have the potential to detect and localize biomarkers associated with a wide variety of diseases. The development and nuclear magnetic resonance (NMR) characterization of cage molecules which encapsulate hyperpolarized xenon is imperative for the development of these xenon biosensors. We acquired (129) Xe NMR spectra, and magnetic resonance images and a HyperCEST saturation map of cucurbit[6]uril (CB6) in whole bovine blood. We observed a mean HyperCEST depletion of 84% (n = 5) at a concentration of 5 mM and 74% at 2.5 mM. Additionally, we collected these data using a pulsed HyperCEST saturation pre-pulse train with a SAR of 0.025 W/kg which will minimize any potential RF heating in animal or human tissue. Copyright

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

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.