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.

Comparison of single breath hyperpolarized 129 Xe MRI with dynamic 19 F MRI in cystic fibrosis lung disease.

PURPOSE: To quantitatively compare dynamic 19 F and single breath hyperpolarized 129 Xe MRI for the detection of ventilation abnormalities in subjects with mild cystic fibrosis (CF) lung disease. METHODS: Ten participants with stable CF and a baseline FEV1 > 70% completed a single imaging session where dynamic 19 F and single breath 129 Xe lung ventilation images were acquired on a 3T MRI scanner. Ventilation defect percentages (VDP) values between 19 F early-breath, 19 F maximum-ventilation, 129 Xe low-resolution, and 129 Xe high-resolution images were compared. Dynamic 19 F images were used to determine gas wash-in/out rates in regions of ventilation congruency and mismatch between 129 Xe and 19 F. RESULTS: VDP values from high-resolution 129 Xe images were greater than from low-resolution images (P = .001), although these values were significantly correlated (r = 0.68, P = .03). Early-breath 19 F VDP and max-vent 19 F VDP also showed significant correlation (r = 0.75, P = .012), with early-breath 19 F VDP values being significantly greater (P < .001). No correlation in VDP values were detected between either 19 F method or high-res 129 Xe images. In addition, the location and volume of ventilation defects were often different when comparing 129 Xe and 19 F images from the same subject. Areas of ventilation congruence displayed the expected ventilation kinetics, while areas of ventilation mismatch displayed abnormally slow gas wash-in and wash-out. CONCLUSION: In CF subjects, ventilation abnormalities are identified by both 19 F and HP 129 Xe imaging. However, these ventilation abnormalities are not entirely congruent. 19 F and HP 129 Xe imaging provide complementary information that enable differentiation of normally ventilated, slowly ventilated, and non-ventilated regions in the lungs.

Direct detection of brown adipose tissue thermogenesis in UCP1-/- mice by hyperpolarized 129Xe MR thermometry.

Brown adipose tissue (BAT) is a type of fat specialized in non-shivering thermogenesis. While non-shivering thermogenesis is mediated primarily by uncoupling protein 1 (UCP1), the development of the UCP1 knockout mouse has enabled the study of possible UCP1-independent non-shivering thermogenic mechanisms, whose existence has been shown so far only indirectly in white adipose tissue and still continues to be a matter of debate in BAT. In this study, by using magnetic resonance thermometry with hyperpolarized xenon, we produce the first direct evidence of UCP1-independent BAT thermogenesis in knockout mice. We found that, following adrenergic stimulation, the BAT temperature of knockout mice increases more and faster than rectal temperature. While with this study we cannot exclude or separate the physiological effect of norepinephrine on core body temperature, the fast increase of iBAT temperature seems to suggest the existence of a possible UCP1-independent thermogenic mechanism responsible for this temperature increase.

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.

Correlation distance dependence of the resonance frequency of intermolecular zero quantum coherences and its implication for MR thermometry.

PURPOSE: Because the resonance frequency of water-fat intermolecular zero-quantum coherences (iZQCs) reflects the water-fat frequency separation at the microscopic scale, these frequencies have been proposed and used as a mean to obtain more accurate temperature information. The purpose of this work was to investigate the dependence of the water-fat iZQC resonance frequency on sample microstructure and on the specific choice of the correlation distance. METHODS: The effect of water-fat susceptibility gradients on the water-methylene iZQC resonance frequency was first computed and then measured for different water-fat emulsions and for a mixture of porcine muscle and fat. Similar measurements were also performed for mixed heteronuclear spin systems. RESULTS: A strong dependence of the iZQC resonance frequency on the sample microstructure and on the specific choice of the correlation distance was found for spin systems like water and fat that do not mix, but not for spin systems that mix at the molecular level. CONCLUSIONS: Because water and fat spins do not mix at the molecular level, the water-fat iZQC resonance frequency and its temperature coefficient are not only affected by sample microstructure but also by the specific choice of the correlation distance. Magn Reson Med 79:1429-1438, 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.