Matthew S. Freeman

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

Significance In recent years, there has been a growing interest in brown adipose tissue (BAT), a tissue specialized in nonshivering thermogenesis and considered to be the next therapeutic target against obesity and diabetes. However, the detection of this very sparse tissue still represents a major challenge. To our knowledge, we report the first in vivo detection of BAT and thermogenic activity by hyperpolarized xenon gas MRI. We show that during thermogenic activity a more than 15-fold enhancement in xenon uptake by BAT enables us to clearly differentiate this tissue from the surrounding tissue and to thereby overcome the major limitations of conventional imaging methods. We also use lipid-dissolved hyperpolarized xenon chemical shift to demonstrate direct in vivo MR thermometry of BAT. 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.

Single-breath clinical imaging of hyperpolarized (129)Xe in the airspaces, barrier, and red blood cells using an interleaved 3D radial 1-point Dixon acquisition.

We sought to develop and test a clinically feasible 1‐point Dixon, three‐dimensional (3D) radial acquisition strategy to create isotropic 3D MR images of 129Xe in the airspaces, barrier, and red blood cells (RBCs) in a single breath. The approach was evaluated in healthy volunteers and subjects with idiopathic pulmonary fibrosis (IPF).

Quantitative analysis of hyperpolarized 129Xe ventilation imaging in healthy volunteers and subjects with chronic obstructive pulmonary disease

In this study, hyperpolarized 129Xe MR ventilation and 1H anatomical images were obtained from three subject groups: young healthy volunteers (HVs), subjects with chronic obstructive pulmonary disease (COPD) and age‐matched controls (AMCs). Ventilation images were quantified by two methods: an expert reader‐based ventilation defect score percentage (VDS%) and a semi‐automated segmentation‐based ventilation defect percentage (VDP). Reader‐based values were assigned by two experienced radiologists and resolved by consensus. In the semi‐automated analysis, 1H anatomical images and 129Xe ventilation images were both segmented following registration to obtain the thoracic cavity volume and ventilated volume, respectively, which were then expressed as a ratio to obtain the VDP. Ventilation images were also characterized by generating signal intensity histograms from voxels within the thoracic cavity volume, and heterogeneity was analyzed using the coefficient of variation (CV). The reader‐based VDS% correlated strongly with the semi‐automatically generated VDP (r = 0.97, p < 0.0001) and with CV (r = 0.82, p < 0.0001). Both 129Xe ventilation defect scoring metrics readily separated the three groups from one another and correlated significantly with the forced expiratory volume in 1 s (FEV1) (VDS%: r = –0.78, p = 0.0002; VDP: r = –0.79, p = 0.0003; CV: r = –0.66, p = 0.0059) and other pulmonary function tests. In the healthy subject groups (HVs and AMCs), the prevalence of ventilation defects also increased with age (VDS%: r = 0.61, p = 0.0002; VDP: r = 0.63, p = 0.0002). Moreover, ventilation histograms and their associated CVs distinguished between subjects with COPD with similar ventilation defect scores, but visibly different ventilation patterns. Copyright

Dose and pulse sequence considerations for hyperpolarized 129Xe ventilation MRI

PURPOSE The aim of this study was to evaluate the effect of hyperpolarized (129)Xe dose on image signal-to-noise ratio (SNR) and ventilation defect conspicuity on both multi-slice gradient echo and isotropic 3D-radially acquired ventilation MRI. MATERIALS AND METHODS Ten non-smoking older subjects (ages 60.8±7.9years) underwent hyperpolarized (HP) (129)Xe ventilation MRI using both GRE and 3D-radial acquisitions, each tested using a 71ml (high) and 24ml (low) dose equivalent (DE) of fully polarized, fully enriched (129)Xe. For all images SNR and ventilation defect percentage (VDP) were calculated. RESULTS Normalized SNR (SNRn), obtained by dividing SNR by voxel volume and dose was higher for high-DE GRE acquisitions (SNRn=1.9±0.8ml(-2)) than low-DE GRE scans (SNRn=0.8±0.2ml(-2)). Radially acquired images exhibited a more consistent, albeit lower SNRn (High-DE: SNRn=0.5±0.1ml(-2), low-DE: SNRn=0.5±0.2ml(-2)). VDP was indistinguishable across all scans. CONCLUSIONS These results suggest that images acquired using the high-DE GRE sequence provided the highest SNRn, which was in agreement with previous reports in the literature. 3D-radial images had lower SNRn, but have advantages for visual display, monitoring magnetization dynamics, and visualizing physiological gradients. By evaluating normalized SNR in the context of dose-equivalent formalism, it should be possible to predict (129)Xe dose requirements and quantify the benefits of more efficient transmit/receive coils, field strengths, and pulse sequences.

Enabling hyperpolarized (129) Xe MR spectroscopy and imaging of pulmonary gas transfer to the red blood cells in transgenic mice expressing human hemoglobin.

Hyperpolarized (HP) 129Xe gas in the alveoli can be detected separately from 129Xe dissolved in pulmonary barrier tissues (blood plasma and parenchyma) and red blood cells (RBCs) of humans, allowing this isotope to probe impaired gas uptake. Unfortunately, mice, which are favored as lung disease models, do not display a unique RBC resonance, thus limiting the preclinical utility of 129Xe MR. Here we overcome this limitation using a commercially available strain of transgenic mice that exclusively expresses human hemoglobin.

In vivo MR imaging of pulmonary perfusion and gas exchange in rats via continuous extracorporeal infusion of hyperpolarized 129Xe

Background Hyperpolarized (HP) 129Xe magnetic resonance imaging (MRI) permits high resolution, regional visualization of pulmonary ventilation. Additionally, its reasonably high solubility (>10%) and large chemical shift range (>200 ppm) in tissues allow HP 129Xe to serve as a regional probe of pulmonary perfusion and gas transport, when introduced directly into the vasculature. In earlier work, vascular delivery was accomplished in rats by first dissolving HP 129Xe in a biologically compatible carrier solution, injecting the solution into the vasculature, and then detecting HP 129Xe as it emerged into the alveolar airspaces. Although easily implemented, this approach was constrained by the tolerable injection volume and the duration of the HP 129Xe signal. Methods and Principal Findings Here, we overcome the volume and temporal constraints imposed by injection, by using hydrophobic, microporous, gas-exchange membranes to directly and continuously infuse 129Xe into the arterial blood of live rats with an extracorporeal (EC) circuit. The resulting gas-phase 129Xe signal is sufficient to generate diffusive gas exchange- and pulmonary perfusion-dependent, 3D MR images with a nominal resolution of 2×2×2 mm3. We also show that the 129Xe signal dynamics during EC infusion are well described by an analytical model that incorporates both mass transport into the blood and longitudinal relaxation. Conclusions Extracorporeal infusion of HP 129Xe enables rapid, 3D MR imaging of rat lungs and, when combined with ventilation imaging, will permit spatially resolved studies of the ventilation-perfusion ratio in small animals. Moreover, EC infusion should allow 129Xe to be delivered elsewhere in the body and make possible functional and molecular imaging approaches that are currently not feasible using inhaled HP 129Xe.

Electron microscopic observations of Rb particles and pitting in 129Xe spin-exchange optical pumping cells

High-volume production of hyperpolarized 129Xe by spin-exchange optical pumping (SEOP) has historically fallen short of theoretical predictions. Recently, this shortfall was proposed to be caused by the formation of alkali metal clusters during optical pumping. However, this hypothesis has yet to be verified experimentally. Here, we seek to detect the presence of alkali particles using a combination of both transmission (TEM) and scanning (SEM) electron microscopy. From TEM studies, we observe the presence of particles exhibiting sizes ranging from approximately 0.2 to 1 μm and present at densities of order 10 s of particles per 100 square microns. Particle formation was more closely associated with extensive cell usage history than short-term ([Formula: see text]1 h) SEOP exposure. From the SEM studies, we observe pits on the cell surface. These pits are remarkably smooth, were frequently found adjacent to Rb particles, and located predominantly on the front face of the cells; they range in size from 1 to 5 μm. Together, these findings suggest that Rb particles do form during the SEOP process and at times can impart sufficient energy to locally alter the Pyrex surface.