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.

In-vivo detection of white adipose tissue browning: a multimodality imaging approach.

Detection and differentiation of brown fat in humans poses several challenges, as this tissue is sparse and often mixed with white adipose tissue. Non-invasive detection of beige fat represents an even greater challenge as this tissue is structurally and functionally more like white fat than brown fat. Here we used positron emission tomography with 18F-fluorodeoxyglucose, computed tomography, xenon-enhanced computed tomography, and dynamic contrast-enhanced ultrasound, to non-invasively detect functional and structural changes associated with the browning process of inguinal white fat, induced in mice by chronic stimulation with the ß3-adrenergic receptor agonist CL-316243. These studies reveal a very heterogeneous increase in baseline tissue radiodensity and xenon-enhanced radiodensity, indicative of both an increase in adipocytes water and protein content as well as tissue perfusion, mostly in regions that showed enhanced norepinephrine-stimulated perfusion before CL-316243 treatment. No statistically significant increase in 18F-fluorodeoxyglucose uptake or norepinephrine-stimulated tissue perfusion were observed in the mice after the CL-316243 treatment. The increase in tissue-water content and perfusion, along with the negligible increase in the tissue glucose uptake and norepinephrine-stimulated perfusion deserve more attention, especially considering the potential metabolic role that this tissue may play in whole body metabolism.

Background-Free Detection of Spin-Exchange Dynamics at Ultra-Low Magnetic Field.

Ultra-low field nuclear magnetic resonance spectroscopy (NMR) and imaging (MRI) inherently suffer from a low signal-to-noise ratio due to the small thermal polarization of nuclear spins. Transfer of polarization from a pre-polarized spin system to a thermally polarized spin system via the Spin Polarization Induced Nuclear Overhauser Effect (SPINOE) could potentially be used to overcome this limitation. SPINOE is particularly advantageous at ultra-low magnetic field, where the transferred polarization can be several orders of magnitude higher than thermal polarization. Here we demonstrate direct detection of polarization transfer from highly polarized 129 Xe gas spins to 1 H spins in solution via SPINOE. At ultra-low field, where thermal nuclear spin polarization is close to background noise levels and where different nuclei can be simultaneously detected in a single spectrum, the dynamics of the polarization transfer can be observed in real time. We show that by simply bubbling hyperpolarized 129 Xe into solution, we can enhance 1 H polarization levels by a factor of up to 151-fold. While our protocol leads to lower enhancements than those previously reported under extreme Xe gas pressures, the methodology is easily repeatable and allows for on-demand enhanced spectroscopy. SPINOE at ultra-low magnetic field could also be employed to study 129 Xe interactions in solutions.

Enhanced 129 Xe T1 relaxation in whole blood and in the presence of SPIONs at low magnetic field strengths.

PURPOSE: To compare the effect of superparamagnetic iron oxide nanoparticles (SPIONs) on the T1 of 129 Xe and 1 H and to measure the relaxation of 129 Xe in blood at low and high magnetic field strengths. METHODS: 129 Xe and 1 H T1 relaxometry was performed at low- and high-field strengths in samples containing different SPION concentrations, while imaging was used to compare the contrast obtainable in these two field regimes. In vivo experiments at variable field strengths were performed to determine the depolarization of 129 Xe in blood and the feasibility of in vivo dissolved-phase spectroscopy and imaging at low field. RESULTS: The SPION relaxivity was substantially greater at low field for 1 H, increasing from 0.92 ± 0.06 mM s-1 at 11.7T to 31.5 ± 1.8 mM s-1 at 0.6 mT, and for 129 Xe, which increased from 0.13 ± 0.03 mM s-1 at 11.7T to 7.32 ± 0.71 mM s-1 at 2.1 mT. The additional MR signal loss increased from 0.7% at 9.4T to 20.6 ± 4.2% at 0.6 mT for 1 H and from -0.7 ± 3.4% at 9.4T to 12.7 ± 3.5% at 2.1 mT for 129 Xe. Blood was found to depolarize 129 Xe below 3T in a manner inversely proportional to the field strength. In vitro studies at 2.1 mT suggest 129 Xe relaxation times below 5 s in blood dilutions as low as 0.4% volume. CONCLUSION: SPIONs longitudinal relaxivity increases at low field both for 1 H and 129 Xe. The depolarization of xenon in blood, which is found to increase below 3T, effectively prevents in vivo dissolved-phase spectroscopy and imaging at low-field strengths.

In vivo imaging of brown adipose tissue vasculature reactivity during adrenergic stimulation of non-shivering thermogenesis in mice.

Brown adipose tissue (BAT) is a fat tissue specialized in heat production (non-shivering thermogenesis) and used by mammals to defend core body temperature when exposed to cold. Several studies have shown that during non-shivering thermogenesis the increase in BAT oxygen demand is met by a local and specific increase in tissue's blood flow. While the vasculature of BAT has been extensively studied postmortem in rodents using histology, optical and CT imaging techniques, vasculature changes during stimulation of non-shivering thermogenesis have never been directly detected in vivo. Here, by using computed tomography (CT) angiography with gold nanoparticles we investigate, non-invasively, changes in BAT vasculature during adrenergic stimulation of non-shivering thermogenesis by norepinephrine, a vasoconstrictor known to mediate brown fat heat production, and by CL 316,243, a specific ß3-adrenergic agonist also known to elicit BAT thermogenesis in rodents. We found that while CL 316,243 causes local vasodilation in BAT, with little impact on the rest of the vasculature throughout the body, norepinephrine leads to local vasodilation in addition to peripheral vasoconstriction. As a result, a significantly greater relative increase in BAT perfusion is observed following the injection of NE compared to CL. This study demonstrates the use of in vivo CT angiography as an effective tool in assessing vascular reactivity in BAT both qualitatively and quantitatively in preclinical studies.

Acute kidney injury after allogeneic hematopoietic stem cell transplantation - Predictors and survival impact: A single center retrospective study.

INTRODUCTION AND OBJECTIVES: Acute kidney injury (AKI) is a frequent complication of hematopoietic stem cell transplantation (HSCT) and appears to be linked to increased morbidity and mortality. The aim of this study was to evaluate the incidence, etiology, predictors and survival impact of early AKI in the post-allogeneic HSCT setting. PATIENTS AND METHODS: We performed a retrospective single center study that included 155 allogeneic transplant procedures from June 2017 through September 2019. RESULTS: AKI was observed in 50 patients (32%). In multivariate analysis, age (OR 31.55, 95% CI [3.42; 290.80], p=0.002), evidence of disease at the time of transplant (OR 2.54, 95% CI [1.12; 5.75], p=0.025), cytomegalovirus reactivation (OR 5.77, 95% CI [2.43; 13.72], p<0.001) and hospital stay >35 days (OR 2.66, 95% CI [1.08; 6.52], p=0.033) were independent predictors for AKI. Increasing age (HR 1.02, 95% CI [1.00; 1.04], p=0.029), increasing length of hospital stay (HR 1.02, 95% CI [1.01; 1.03], p=0.002), matched unrelated reduced intensity conditioning HSCT (HR 1.91, 95% CI [1.10; 3.33], p=0.022), occurrence of grade III/IV acute graft-versus-host disease (HR 2.41, 95% CI [1.15; 5.03], p=0.019) and need for mechanical ventilation (HR 3.49, 95% CI [1.54; 7.92], p=0.003) predicted an inferior survival in multivariate analysis. Early AKI from any etiology was not related to worse survival. CONCLUSION: Patients submitted to HSCT are at an increased risk for AKI, which etiology is often multifactorial. Due to AKI incidence, specialized nephrologist consultation as part of the multidisciplinary team might be of benefit.

Acute kidney injury after allogeneic hematopoietic stem cell transplantation – Predictors and survival impact: A single center retrospective study / Lesión renal aguda después de trasplante de células madre hematopoyéticas alogénicas, factores predictivos e impacto en la supervivencia: un estudio retrospectivo en un solo centro

Introduction and objectives: Acute kidney injury (AKI) is a frequent complication of hematopoietic stem cell transplantation (HSCT) and appears to be linked to increased morbidity and mortality. The aim of this study was to evaluate the incidence, etiology, predictors and survival impact of early AKI in the post-allogeneic HSCT setting. Patients and methods: We performed a retrospective single center study that included 155 allogeneic transplant procedures from June 2017 through September 2019. Results: AKI was observed in 50 patients (32%). In multivariate analysis, age (OR 31.55, 95% CI [3.42; 290.80], p=0.002), evidence of disease at the time of transplant (OR 2.54, 95% CI [1.12; 5.75], p=0.025), cytomegalovirus reactivation (OR 5.77, 95% CI [2.43; 13.72], p<0.001) and hospital stay >35 days (OR 2.66, 95% CI [1.08; 6.52], p=0.033) were independent predictors for AKI. Increasing age (HR 1.02, 95% CI [1.00; 1.04], p=0.029), increasing length of hospital stay (HR 1.02, 95% CI [1.01; 1.03], p=0.002), matched unrelated reduced intensity conditioning HSCT (HR 1.91, 95% CI [1.10; 3.33], p=0.022), occurrence of grade III/IV acute graft-versus-host disease (HR 2.41, 95% CI [1.15; 5.03], p=0.019) and need for mechanical ventilation (HR 3.49, 95% CI [1.54; 7.92], p=0.003) predicted an inferior survival in multivariate analysis. Early AKI from any etiology was not related to worse survival. Conclusion: Patients submitted to HSCT are at an increased risk for AKI, which etiology is often multifactorial. Due to AKI incidence, specialized nephrologist consultation as part of the multidisciplinary team might be of benefit. (AU)

Introducción y objetivos: La lesión renal aguda (LRA) es una complicación frecuente del trasplante de células madre hematopoyéticas (TCMH) y parece estar asociado a un incremento en la morbilidad y la mortalidad. El objetivo de este estudio fue evaluar la incidencia, la etiología, los factores predictivos y el impacto en la supervivencia de la LRA temprana en el contexto posterior al TCMH alogénico. Pacientes y métodos: Se realizó un estudio retrospectivo en un único centro que incluyó 155 procedimientos de trasplante alogénico desde junio de 2017 hasta septiembre de 2019. Resultados: Se observó LRA en 50 pacientes (32%). En el análisis de múltiples variables, la edad (OR 31,55, IC del 95% [3,42; 290,80], p=0,002), la evidencia de enfermedad en el momento del trasplante (OR 2,54, IC del 95% [1,12; 5,75], p=0,025), reactivación de citomegalovirus (OR 5,77, IC del 95% [2,43; 13,72], p<0,001) y estancia hospitalaria>35 días (OR 2,66, IC del 95% [1,08; 6,52], p=0,033) fueron los factores predictivos independientes para LRA. La mayor edad (HR 1,02, IC del 95% [1,00; 1,04], p=0,029), la mayor duración de la estancia hospitalaria (HR 1,02, IC del 95% [1,01; 1,03], p=0,002), TCMH con acondicionamiento de intensidad reducida no relacionados emparejados (HR 1,91, IC del 95% [1,10; 3,33], p=0,022), aparición de enfermedad injerto contra huésped aguda de grado iii/iv (HR 2,41, IC del 95% [1,15; 5,03], p=0,019) y necesidad de ventilación mecánica (HR 3,49, IC del 95% [1,54; 7,92], p=0,003) predijeron una supervivencia inferior en el análisis de múltiples variables. La LRA temprana de cualquier etiología no se asoció con una peor supervivencia. Conclusión: Los pacientes sometidos a TCMH presentan un mayor riesgo de LRA, cuya etiología es con frecuencia multifactorial. Debido a la incidencia de LRA, la consulta a un nefrólogo especializado como parte del equipo multidisciplinario podría ser beneficiosa. (AU)

Xenon-enhanced computed tomography assessment of brown adipose tissue distribution and perfusion in lean, obese, and diabetic primates.

OBJECTIVE: This study aimed to validate xenon-enhanced computed tomography (XECT) for the detection of brown adipose tissue (BAT) and to use XECT to assess differences in BAT distribution and perfusion between lean, obese, and diabetic nonhuman primates (NHPs). METHODS: Whole-body XECT imaging was performed in anesthetized rhesus and vervet monkeys during adrenergic stimulation of BAT thermogenesis. In XECT images, BAT was identified as fat tissue that, during xenon inhalation, underwent significant radiodensity enhancement compared with subcutaneous fat. To measure BAT blood flow, BAT radiodensity enhancement was measured over time on the six computed tomography scans acquired during xenon inhalation. Postmortem immunohistochemical staining was used to confirm imaging findings. RESULTS: XECT was able to correctly identify all BAT depots that were confirmed at necropsy, enabling construction of the first comprehensive anatomical map of BAT in NHPs. A significant decrease in BAT perfusion was found in diabetic animals compared with obese animals and healthy animals, as well as absence of axillary BAT and significant reduction of supraclavicular BAT in diabetic animals compared with obese and lean animals. CONCLUSIONS: The use of XECT in NHP models of obesity and diabetes allows the analysis of the impact of metabolic status on BAT mass and perfusion.

Low-boiling Point Perfluorocarbon Nanodroplets as Dual-Phase Dual-Modality MR/US Contrast Agent.

Detection of bare gas microbubbles by magnetic resonance (MR) at low concentrations typically used in clinical contrast-ultrasound studies was recently demonstrated using hyperCEST. Despite the enhanced sensitivity achieved with hyperCEST, in vivo translation is challenging as on-resonance saturation of the gas-phase core of microbubbles consequently results in saturation of the gas-phase hyperpolarized 129 Xe within the lungs. Alternatively, microbubbles can be condensed into the liquid phase to form perfluorocarbon nanodroplets, where 129 Xe resonates at a chemical shift that is separated from the gas-phase signal in the lungs. For ultrasound applications, nanodroplets can be acoustically reverted back into their microbubble form to act as a phase-change contrast agent. Here, we show that low-boiling point perfluorocarbons, both in their liquid and gas form, generate phase-dependent hyperCEST contrast. Magnetic resonance detection of ultrasound-mediated phase transition demonstrates that these perfluorocarbons could be used as a dual-phase dual-modality MR/US contrast agent.

Longitudinal nuclear spin relaxation of 129 Xe in solution and in hollow fiber membranes at low and high magnetic field strengths.

PURPOSE: To measure dissolved-phase 129 Xe T1 values at high and low magnetic fields and the field dependence of 129 Xe depolarization by hollow fiber membranes used to infuse hyperpolarized xenon in solution. METHODS: Dissolved-phase T1 measurements were made at 11.7T and 2.1 mT by bubbling xenon in solution and by using a variable delay to allow spins to partially relax back to thermal equilibrium before probing their magnetization. At high field, relaxation values were compared to those obtained by using the small flip angle method. For depolarization studies, we probed the magnetization of the polarized gas diffusing through an exchange membrane module placed at different field strengths. RESULTS: Total loss of polarization was observed for xenon diffusing through hollow fiber membranes at low field, while significant polarization loss (>20%) was observed at magnetic fields up to 2T. Dissolved-phase 129 Xe T1 values were found consistently shorter at 2.1 mT compared to 11.7T. In addition, both O2 and Xe gas concentrations in solution were found to significantly affect dissolved-phase 129 Xe T1 values. CONCLUSION: Dissolved-phase 129 Xe measurements are feasible at low field, but to assess the feasibility of in vivo dissolved-phase imaging and spectroscopy the T1 of xenon in blood will need to be measured. Both O2 and Xe concentrations in solution are found to greatly affect  dissolved-phase 129 Xe T1 values and may explain, along with RF miscalibration, the large discrepancy in previously reported results.

Allogeneic stem cell transplant in relapsed/ refractory Hodgkin lymphoma: A 21 years' experience.

Background: Allogenic stem cell transplant (alloSCT) has been used for several decades as a salvage strategy for relapsed/ refractory Hodgkin lymphoma (R/R HL), being a durable disease control method for some patients. Methods: A unicenter retrospective analysis was performed about alloSCT in R/R HL along 21 years. A survival analysis was made in search for prognostic factors with impact in overall survival (OS)/progression free survival (PFS). Results: Thirty-five patients were reviewed: median age 30years [17-46], 57.1% males, 82.9% had an esclero-nodular HL, 54.3% were in stage II of disease, and 42.9% achieved a complete response before the alloSCT. The donor type was matched-related in 54.3% and the stem cell source was peripheral blood in 97.1% of the grafts. All patients did a reduced intensity conditioning regimen. The overall response rate was 85.7% (complete in 68.6%, partial in 17.1%). Acute graft versus host disease grade II-IVwas seen in 45.7%. Transplant related mortality at day 360 was 17.9%. The median OS was 61 months (95% confidente interval: 33.6-88.3). The median PFS was 1Omonths (95% confidente interval: 3.1-16.9). Patients with >3Oyears at the alloSCT time and a previous autologous SCT showed better OS/PFS in the univariate analysis; having a matched donor and absence of infections along the alloSCT also improved PFS. Conclusions: AlloSCT is a feasible procedure in patients with R/R HL, being able to stabilize the disease in a large number of patients. However, it has a relevant toxicity in patients highly pre-treated.

In vivo hyperCEST imaging: Experimental considerations for a reliable contrast.

PURPOSE: HyperCEST contrast relies on the reduction of the solvent signal after selective saturation of the solute magnetization. The scope of this work is to outline the experimental conditions needed to obtain a reliable hyperCEST contrast in vivo, where the "solvent" signal (ie, the dissolved-phase signal) may change over time due to the increase in xenon (Xe) accumulation into tissue. METHODS: Hyperpolarized 129 Xe was delivered to mice at a constant volume and rate using a mechanical ventilator, which triggered the saturation, excitation, and acquisition of the MR signal during the exhale phase of the breath cycle-either every breath or every 2, 3, or 4 breaths. Serial Z-spectra and hyperCEST images were acquired before and after a bolus injection of cucurbit[6]uril to assess possible signal fluctuations and instabilities. RESULTS: The intensity of the dissolved-phase Xe signal was observed to first increase immediately after the beginning of the hyperpolarized gas inhalation and NMR acquisition, and then decrease before reaching a steady-state condition. Once a steady-state dissolved-phase magnetization was established, a reliable hyperCEST contrast, exceeding 40% signal reduction, was observed. CONCLUSION: A reliable hyperCEST contrast can only be obtained after establishing a steady-state dissolved phase 129 Xe magnetization. Under stable physiological conditions, a steady-state dissolved-phase Xe magnetization is only achieved after a series of Xe inhalations and RF excitations, and it requires synchronization of the breathing rate with the MR acquisition.

An open-source, low-cost NMR spectrometer operating in the mT field regime.

In recent years, low field and ultra-low field NMR spectrometers have gained interest due to their portability, lower cost, and reduced subject-induced magnetic field inhomogeneities. Here, we describe the design of a low-cost multinuclear NMR spectrometer operating in the ultra-low field regime (ULF), which possesses high spectral resolution and enables arbitrary pulse programming. An inexpensive multifunction input/output (I/O) device is used to handle waveform generation and digitization in the kHz operating range. A home-built radio frequency (RF) mixing circuit is used to down-mix the NMR signals, allowing for the slower sampling rates and lower memory requirements needed to enable minute-long acquisitions using a standard Windows PC. The LabVIEW code, along with a bill of materials for all components used in the spectrometer, is included. As proof of concept, 1H relaxation measurements and the simultaneous detection of 1H with gas phase and dissolved 129Xe frequencies using the described low field NMR spectrometer are demonstrated.

Genetic Variation in PFKFB3 Impairs Antifungal Immunometabolic Responses and Predisposes to Invasive Pulmonary Aspergillosis.

Activation of immune cells in response to fungal infection involves the reprogramming of their cellular metabolism to support antimicrobial effector functions. Although metabolic pathways such as glycolysis are known to represent critical regulatory nodes in antifungal immunity, it remains undetermined whether these are differentially regulated at the interindividual level. In this study, we identify a key role for 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in the immunometabolic responses to Aspergillus fumigatus. A genetic association study performed in 439 recipients of allogeneic hematopoietic stem cell transplantation (HSCT) and corresponding donors revealed that the donor, but not recipient, rs646564 variant in the PFKFB3 gene increased the risk of invasive pulmonary aspergillosis (IPA) after transplantation. The risk genotype impaired the expression of PFKFB3 by human macrophages in response to fungal infection, which was correlated with a defective activation of glycolysis and the ensuing antifungal effector functions. In patients with IPA, the risk genotype was associated with lower concentrations of cytokines in the bronchoalveolar lavage fluid samples. Collectively, these findings demonstrate the important contribution of genetic variation in PFKFB3 to the risk of IPA in patients undergoing HSCT and support its inclusion in prognostic tools to predict the risk of fungal infection in this clinical setting. IMPORTANCE The fungal pathogen Aspergillus fumigatus can cause severe and life-threatening forms of infection in immunocompromised patients. Activation of glycolysis is essential for innate immune cells to mount effective antifungal responses. In this study, we report the contribution of genetic variation in the key glycolytic activator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) to the risk of invasive pulmonary aspergillosis (IPA) after allogeneic hematopoietic stem cell transplantation. The PFKFB3 genotype associated with increased risk of infection was correlated with an impairment of the antifungal effector functions of macrophages in vitro and in patients with IPA. This work highlights the clinical relevance of genetic variation in PFKFB3 to the risk of IPA and supports its integration in risk stratification and preemptive measures for patients at high risk of IPA.

Magnetic Resonance Detection of Gas Microbubbles via HyperCEST: A Path Toward Dual Modality Contrast Agent.

Gas microbubbles are an established clinical ultrasound contrast agent. They could also become a powerful magnetic resonance (MR) intravascular contrast agent, but their low susceptibility-induced contrast requires high circulating concentrations or the addition of exogenous paramagnetic nanoparticles for MR detection. In order to detect clinical in vivo concentrations of raw microbubbles via MR, an alternative detection scheme must be used. HyperCEST is an NMR technique capable of indirectly detecting signals from very dilute molecules (concentrations well below the NMR detection threshold) that exchange hyperpolarized 129 Xe. Here, we use quantitative hyperCEST to show that microbubbles are very efficient hyperCEST agents. They can accommodate and saturate millions of 129 Xe atoms at a time, allowing for their indirect detection at concentrations as low as 10 femtomolar. The increased MR sensitivity to microbubbles achieved via hyperCEST can bridge the gap for microbubbles to become a dual modality contrast agent.

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.

Differences in [18F]FDG uptake in BAT of UCP1 -/- and UCP1 +/+ during adrenergic stimulation of non-shivering thermogenesis.

BACKGROUND: Brown adipose tissue (BAT) is a fat tissue found in most mammals that helps regulate energy balance and core body temperature through a sympathetic process known as non-shivering thermogenesis. BAT activity is commonly detected and quantified in [18F]FDG positron emission tomography/computed tomography (PET/CT) scans, and radiotracer uptake in BAT during adrenergic stimulation is often used as a surrogate measure for identifying thermogenic activity in the tissue. BAT thermogenesis is believed to be contingent upon the expression of the protein UCP1, but conflicting results have been reported in the literature concerning [18F]FDG uptake within BAT of mice with and without UCP1. Differences in animal handling techniques such as feeding status, type of anesthetic, type of BAT stimulation, and estrogen levels were identified as possible confounding variables for [18F]FDG uptake. In this study, we aimed to assess differences in BAT [18F]FDG uptake between wild-type and UCP1-knockout mice using a protocol that minimizes possible variations in BAT stimulation caused by different stress responses to mouse handling. RESULTS: [18F]FDG PET/CT scans were run on mice that were anesthetized with pentobarbital after stimulation of non-shivering thermogenesis by norepinephrine. While in wild-type mice [18F]FDG uptake in BAT increased significantly with norepinephrine stimulation of BAT, there was no consistent change in [18F]FDG uptake in BAT of mice lacking UCP1. CONCLUSIONS: [18F]FDG uptake within adrenergically stimulated BAT of wild-type and UCP1-knockout mice can significantly vary such that an [18F]FDG uptake threshold cannot be used to differentiate wild-type from UCP1-knockout mice. However, while an increase in BAT [18F]FDG uptake during adrenergic stimulation is consistently observed in wild-type mice, in UCP1-knockout mice [18F]FDG uptake in BAT seems to be independent of ß3-adrenergic stimulation of non-shivering thermogenesis.

Magnetic Resonance Imaging Techniques for Brown Adipose Tissue Detection.

Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) methods can non-invasively assess brown adipose tissue (BAT) structure and function. Recently, MRI and MRS have been proposed as a means to differentiate BAT from white adipose tissue (WAT) and to extract morphological and functional information on BAT inaccessible by other means. Specifically, proton MR (1H) techniques, such as proton density fat fraction mapping, diffusion imaging, and intermolecular multiple quantum coherence imaging, have been employed to access BAT microstructure; MR thermometry, relaxometry, and MRI and MRS with 31P, 2H, 13C, and 129Xe have shown to provide complementary information on BAT function. The purpose of the present review is to provide a comprehensive overview of MR imaging and spectroscopy techniques used to detect BAT in rodents and in humans. The present work discusses common challenges of current methods and provides an outlook on possible future directions of using MRI and MRS in BAT studies.

A Novel PET Probe for Brown Adipose Tissue Imaging in Rodents.

PURPOSE: Brown adipose tissue (BAT) has emerged as a promising target to counteract obesity and its associated metabolic disorders. However, the detection of this tissue remains one of the major roadblocks. PROCEDURES: In this study, we assess the use of BODIPY 1 as a positron emission tomography (PET) imaging agent to image BAT depots in vivo in two mouse phenotypes: obesity-resistant BALB/c mice and the obesity-prone C57BL/6 mice. [18F]BODIPY 1 is a radioactive dye that processed both radioactivity for PET imaging and fluorescence signal for in vitro mechanism study. RESULTS: Through the co-staining of cancer cells with BODIPY 1 and MitoTracker, we found BODIPY 1 mainly accumulated in cell mitochondria in vitro. Fluorescence imaging of primary brown and white adipocytes further confirmed BODIPY 1 had significantly higher accumulation in primary brown adipocytes compared with primary white adipocytes. We evaluated [18F]BODIPY 1 for BAT imaging in both obesity-resistant BALB/c mice and obesity-prone C57BL/6 mice. Indeed, [18F]BODIPY 1 was efficiently taken up by BAT in both mouse genotypes (6.40 ± 1.98 %ID/g in obesity-resistant BALB/c mice (n = 8) and 5.37 ± 0.82 %ID/g in obesity-prone C57BL/6 mice (n = 7)). Although norepinephrine stimulation could increase the absolute BAT uptake, the enhancement is not significant in both genotypes (p > 0.05) at current sample size. These results suggest BAT uptake of [18F]BODIPY 1 may be independent of BAT thermogenic activity. As a comparison, 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET imaging was performed in obesity-resistant BALB/c mice. Significantly increased uptake was observed in adrenergically activated BAT (10.08 ± 2.52 %ID/g, n = 3) but not in inactive BAT (3.803 ± 0.70 %ID/g; n = 3). Because [18F]BODIPY 1 maintained its fluorescent property, BAT tissue was excised and studied using fluorescence microscopy. Strong fluorescence signal was observed in BAT mouse that was injected with BODIPY 1. CONCLUSIONS: Unlike [18F]FDG, [18F]BODIPY 1 showed prominent accumulation in BAT under both inactive and stimulated status. [18F]BODIPY 1 may serve as a valuable BAT PET agent to possibly assess BAT mitochondria density, thus BAT thermogenic capacity after further evaluation.

Magnetic resonance imaging of obesity and metabolic disorders: Summary from the 2019 ISMRM Workshop.

More than 100 attendees from Australia, Austria, Belgium, Canada, China, Germany, Hong Kong, Indonesia, Japan, Malaysia, the Netherlands, the Philippines, Republic of Korea, Singapore, Sweden, Switzerland, the United Kingdom, and the United States convened in Singapore for the 2019 ISMRM-sponsored workshop on MRI of Obesity and Metabolic Disorders. The scientific program brought together a multidisciplinary group of researchers, trainees, and clinicians and included sessions in diabetes and insulin resistance; an update on recent advances in water-fat MRI acquisition and reconstruction methods; with applications in skeletal muscle, bone marrow, and adipose tissue quantification; a summary of recent findings in brown adipose tissue; new developments in imaging fat in the fetus, placenta, and neonates; the utility of liver elastography in obesity studies; and the emerging role of radiomics in population-based "big data" studies. The workshop featured keynote presentations on nutrition, epidemiology, genetics, and exercise physiology. Forty-four proffered scientific abstracts were also presented, covering the topics of brown adipose tissue, quantitative liver analysis from multiparametric data, disease prevalence and population health, technical and methodological developments in data acquisition and reconstruction, newfound applications of machine learning and neural networks, standardization of proton density fat fraction measurements, and X-nuclei applications. The purpose of this article is to summarize the scientific highlights from the workshop and identify future directions of work.