Accurate quantification of brown adipose tissue mass by xenon-enhanced computed tomography.

Detection and quantification of brown adipose tissue (BAT) mass remains a major challenge, as current tomographic imaging techniques are either nonspecific or lack the necessary resolution to quantify BAT mass, especially in obese phenotypes, in which this tissue may be present but inactive. Here, we report quantification of BAT mass by xenon-enhanced computed tomography. We show that, during stimulation of BAT thermogenesis, the lipophilic gas xenon preferentially accumulates in BAT, leading to a radiodensity enhancement comparable to that seen in the lungs. This enhancement is mediated by a selective reduction in BAT vascular resistance, which greatly increases vascular perfusion of BAT. This enhancement enables precise identification and quantification of BAT mass not only in lean, but also in obese, mouse phenotypes, in which this tissue is invisible to conventional tomographic imaging techniques. The method is developed and validated in rodents and then applied in macaques to assess its feasibility in larger species.

Effect of microscopic susceptibility gradients on chemical-shift-based fat fraction quantification in supraclavicular fat.

BACKGROUND: Susceptibility differences between fat and water can cause changes in the water-fat frequency separation that can negatively affect the accuracy of fat fraction techniques. This may be especially relevant for brown adipose tissue, as MRI fat fraction techniques have been proposed for its detection. PURPOSE: To assess the effect of microscopic magnetic susceptibility gradients on the water-fat frequency separation and its impact on chemical-shift-based fat fraction quantification techniques in the supraclavicular fat, where brown adipose tissue is commonly found in humans. STUDY TYPE: Prospective. POPULATION/SUBJECTS/PHANTOM/SPECIMEN/ANIMAL MODEL: Subjects: 11 healthy volunteers, mean age of 26 and mean BMI of 23, three overweight volunteers, mean age of 38 and mean BMI of 33. Phantoms: bovine phantom and intralipid fat emulsion. Simulations: various water-fat distributions. FIELD STRENGTH/SEQUENCE: Six-echo gradient echo chemical-shift-encoded sequence at 3T. ASSESSMENT: Fat fraction values as obtained from a water-fat spectral model accounting for susceptibility-induced water-fat frequency variations were directly compared to traditional spectral models that assume constant water-fat frequency separation. STATISTICAL TESTS: Two-tail t-tests were used for significance testing (p < 0.05.) A Bayesian Information Criterion difference of 6 between fits was taken as strong evidence of an improved model. RESULTS: Phantom experiments and simulation results showed variations of the water-fat frequency separation up to 0.4 ppm and 0.6 ppm, respectively. In the supraclavicular area, the water-fat frequency separation produced by magnetic susceptibility gradients varied by as much as ±0.4 ppm, with a mean of 0.08 ± 0.14 ppm, producing a mean difference in fat fraction of -1.26 ± 5.26%. DATA CONCLUSION: In the supraclavicular fat depot, microscopic susceptibility gradients that exist within a voxel between water and fat compartments can produce variations in the water-fat frequency separation. These variations may produce fat fraction quantification errors of 5% when a spectral model with a fixed water-fat frequency separation is applied, which could impact MR brown fat techniques. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:141-151.

Simple and robust referencing system enables identification of dissolved-phase xenon spectral frequencies.

PURPOSE: To assess the effect of macroscopic susceptibility gradients on the gas-phase referenced dissolved-phase 129 Xe (DPXe) chemical shift (CS) and to establish the robustness of a water-based referencing system for in vivo DPXe spectra. METHODS: Frequency shifts induced by spatially varying magnetic susceptibility are calculated by finite-element analysis for the human head and chest. Their effect on traditional gas-phase referenced DPXe CS is then assessed theoretically and experimentally. A water-based referencing system for the DPXe resonances that uses the local water protons as reference is proposed and demonstrated in vivo in rats. RESULTS: Across the human brain, macroscopic susceptibility gradients can induce an apparent variation in the DPXe CS of up to 2.5 ppm. An additional frequency shift as large as 6.5 ppm can exist between DPXe and gas-phase resonances. By using nearby water protons as reference for the DPXe CS, the effect of macroscopic susceptibility gradients is eliminated and consistent CS values are obtained in vivo, regardless of shimming conditions, region of interest analyzed, animal orientation, or lung inflation. Combining in vitro and in vivo spectroscopic measurements finally enables confident assignment of some of the DPXe peaks observed in vivo. CONCLUSION: To use hyperpolarized xenon as a biological probe in tissues, the DPXe CS in specific organs/tissues must be reliably measured. When the gas-phase is used as reference, variable CS values are obtained for DPXe resonances. Reliable peak assignments in DPXe spectra can be obtained by using local water protons as reference. Magn Reson Med 80:431-441, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

A pilot study on the correlation between fat fraction values and glucose uptake values in supraclavicular fat by simultaneous PET/MRI.

PURPOSE: To assess the spatial correlation between MRI and 18F-fludeoxyglucose positron emission tomography (FDG-PET) maps of human brown adipose tissue (BAT) and to measure differences in fat fraction (FF) between glucose avid and non-avid regions of the supraclavicular fat depot using a hybrid FDG-PET/MR scanner. METHODS: In 16 healthy volunteers, mean age of 30 and body mass index of 26, FF, R2*, and FDG uptake maps were acquired simultaneously using a hybrid PET/MR system while employing an individualized cooling protocol to maximally stimulate BAT. RESULTS: Fourteen of the 16 volunteers reported BAT-positive FDG-PET scans. MR FF maps of BAT correlate well with combined FDG-PET/MR maps of BAT only in subjects with intense glucose uptake. The results indicate that the extent of the spatial correlation positively correlates with maximum FDG uptake in the supraclavicular fat depot. No consistent, significant differences were found in FF or R2* between FDG avid and non-avid supraclavicular fat regions. In a few FDG-positive subjects, a small but significant linear decrease in BAT FF was observed during BAT stimulation. CONCLUSION: MR FF, when used in conjunction with FDG uptake maps, can be seen as a valuable, radiation-free alternative to CT and can be used to measure tissue hydration and lipid consumption in some subjects. Magn Reson Med 78:1922-1932, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

Accurate MR thermometry by hyperpolarized 129 Xe.

PURPOSE: To investigate the temperature dependence of the resonance frequency of lipid-dissolved xenon (LDX) and to assess the accuracy of LDX-based MR thermometry. METHODS: The chemical shift temperature dependence of water protons, methylene protons, and LDX was measured from samples containing tissues with varying fat contents using a high-resolution NMR spectrometer. LDX results were then used to acquire relative and absolute temperature maps in vivo and the results were compared with PRF-based MR thermometry. RESULTS: The temperature dependence of proton resonance frequency (PRF) is strongly affected by the specific distribution of water and fat. A redistribution of water and fat compartments can reduce the apparent temperature dependence of the water chemical shift from -0.01 ppm/°C to -0.006 ppm, whereas the LDX chemical shift shows a consistent temperature dependence of -0.21 ppm/°C. The use of the methylene protons resonance frequency as internal reference improves the accuracy of LDX-based MR thermometry, but degrades that of PRF-based MR thermometry, as microscopic susceptibility gradients affected lipid and water spins differently. CONCLUSION: The LDX resonance frequency, with its higher temperature dependence, provides more accurate and precise temperature measurements, both in vitro and in vivo. More importantly, the resonance frequency of nearby methylene protons can be used to extract absolute temperature information. Magn Reson Med 78:1070-1079, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Detection of brown adipose tissue and thermogenic activity in mice by hyperpolarized xenon MRI.

The study of brown adipose tissue (BAT) in human weight regulation has been constrained by the lack of a noninvasive tool for measuring this tissue and its function in vivo. Existing imaging modalities are nonspecific and intrinsically insensitive to the less active, lipid-rich BAT of obese subjects, the target population for BAT studies. We demonstrate noninvasive imaging of BAT in mice by hyperpolarized xenon gas MRI. We detect a greater than 15-fold increase in xenon uptake by BAT during stimulation of BAT thermogenesis, which enables us to acquire background-free maps of the tissue in both lean and obese mouse phenotypes. We also demonstrate in vivo MR thermometry of BAT by hyperpolarized xenon gas. Finally, we use the linear temperature dependence of the chemical shift of xenon dissolved in adipose tissue to directly measure BAT temperature and to track thermogenic activity in vivo.

Remote detection of hyperpolarized 129Xe resonances via multiple distant dipolar field interactions with 1H.

A remote detection scheme utilizing the distant dipolar field interaction between two different spin species was proposed by Granwehr et al. [J. Magn. Reson. 176(2), 125 (2005)]. In that sequence 1H spins were detected indirectly via their dipolar field interaction with 129Xe spins, which served as the sensing spins. Here we propose a modification of the proposed detection scheme that takes advantage of the longer T1 relaxation time of xenon to create a long lasting dipolar field with which the fast relaxing 1H spins are allowed to interact many times during a single acquisition. This new acquisition scheme improves detection sensitivity, but it also presents some challenges.

Absolute thermometry of human brown adipose tissue by magnetic resonance with laser polarized 129Xe.

BACKGROUND: Absolute temperature measurements of tissues inside the human body are difficult to perform non-invasively. Yet, for brown adipose tissue (BAT), these measurements would enable direct monitoring of its thermogenic activity and its association with metabolic health. METHODS: Here, we report direct measurement of absolute BAT temperature in humans during cold exposure by magnetic resonance (MR) with laser polarized xenon gas. This methodology, which leverages on the sensitivity of the chemical shift of the 129Xe isotope to temperature-induced changes in fat density, is first calibrated in vitro and then tested in vivo in rodents. Finally, it is used in humans along with positron emission tomography (PET) scans with fluorine-18-fluorodeoxyglucose to detect BAT thermogenic activity during cold exposure. RESULTS: Absolute temperature measurements, obtained in rodents with an experimental error of 0.5 °C, show only a median deviation of 0.12 °C against temperature measurements made using a pre-calibrated optical temperature probe. In humans, enhanced uptake of 129Xe in BAT during cold exposure leads to background-free detection of this tissue by MR. Global measurements of supraclavicular BAT temperature, made over the course of four seconds and with an experimental error ranging from a minimum of 0.4 °C to more than 2 °C, in case of poor shimming, reveal an average BAT temperature of 38.8° ± 0.8 °C, significantly higher (p < 0.02 two-sided t test) than 37.7 °C. Hot BAT is also detected in participants with a PET scan negative for BAT. CONCLUSIONS: Non-invasive, radiation-free measurements of BAT temperature by MRI with hyperpolarized 129Xe may enable longitudinal monitoring of human BAT activity under various stimulatory conditions.

Brown adipose tissue (BAT) is a fat tissue specialized in heat production and considered a potential target for the treatment of obesity and diabetes. Detection of this tissue and its metabolic activity in adult humans is challenging as this tissue is often mixed with white fat, which makes up most of the fat in adult humans. Here we demonstrate that magnetic resonance imaging with laser-polarized xenon gas, a medical imaging technique used to assess lung ventilation function, can detect the presence of this tissue in humans and measure its temperature. These temperature measurements, which show that brown fat becomes significantly hotter than 37 °C when humans are exposed to cold, may be useful in future studies to assess the effects of drugs that aim to target BAT's heat-generating activity to regulate blood sugar level.

Effects of superparamagnetic iron oxide nanoparticles on the longitudinal and transverse relaxation of hyperpolarized xenon gas.

SuperParamagnetic Iron Oxide Nanoparticles (SPIONs) are often used in magnetic resonance imaging experiments to enhance Magnetic Resonance (MR) sensitivity and specificity. While the effect of SPIONs on the longitudinal and transverse relaxation time of 1H spins has been well characterized, their effect on highly diffusive spins, like those of hyperpolarized gases, has not. For spins diffusing in linear magnetic field gradients, the behavior of the magnetization is characterized by the relative size of three length scales: the diffusion length, the structural length, and the dephasing length. However, for spins diffusing in non-linear gradients, such as those generated by iron oxide nanoparticles, that is no longer the case, particularly if the diffusing spins experience the non-linearity of the gradient. To this end, 3D Monte Carlo simulations are used to simulate the signal decay and the resulting image contrast of hyperpolarized xenon gas near SPIONs. These simulations reveal that signal loss near SPIONs is dominated by transverse relaxation, with little contribution from T1 relaxation, while simulated image contrast and experiments show that diffusion provides no appreciable sensitivity enhancement to SPIONs.

Depolarization of nuclear spin polarized 129Xe gas by dark rubidium during spin-exchange optical pumping.

Continuous-flow spin-exchange optical pumping (SEOP) continues to serve as the most widespread method of polarizing 129Xe for magnetic resonance experiments. Unfortunately, continuous-flow SEOP still suffers from as-yet unidentified inefficiencies that prevent the production of large volumes of xenon with a nuclear spin polarization close to theoretically calculated values. In this work we use a combination of ultra-low field nuclear magnetic resonance spectroscopy and atomic absorption spectroscopy (AAS) measurements to study the effects of dark Rb vapor on hyperpolarized 129Xe in situ during continuous-flow SEOP. We find that dark Rb vapor in the optical cell outlet has negligible impact on the final 129Xe polarization at typical experimental conditions, but can become significant at higher oven temperatures and lower flow rates. Additionally, in the AAS spectra we also look for a signature of paramagnetic Rb clusters, previously identified as a source of xenon depolarization and a cause for SEOP inefficiency, for which we are able to set an upper limit of 8.3×1015 Rb dimers per cm3.

Diffusion-mediated 129Xe gas depolarization in magnetic field gradients during continuous-flow optical pumping.

The production of large volumes of highly polarized noble gases like helium and xenon is vital to applications of magnetic resonance imaging and spectroscopy with hyperpolarized (HP) gas in humans. In the past ten years, 129Xe has become the gas of choice due to its lower cost, higher availability, relatively high tissue solubility, and wide range of chemical shift values. Though near unity levels of xenon polarization have been achieved in-cell using stopped-flow Spin Exchange Optical Pumping (SEOP), these levels are currently unmatched by continuous-flow SEOP methods. Among the various mechanisms that cause xenon relaxation, such as persistent and transient xenon dimers, wall collisions, and interactions with oxygen, relaxation due to diffusion in magnetic field gradients, caused by rapidly changing magnetic field strength and direction, is often ignored. However, during continuous-flow SEOP production, magnetic field gradients may not have a negligible contribution, especially considering that this methodology requires the combined use of magnets with very different characteristics (low field for spin exchange optical pumping and high field for the reduction of xenon depolarization in the solid state during the freeze out phase) that, when placed together, inevitably create magnetic field gradients along the gas-flow-path. Here, a combination of finite element analysis and Monte Carlo simulations is used to determine the effect of such magnetic field gradients on xenon gas polarization with applications to a specific, continuous-flow hyperpolarization system.