Measurements of early tumor responses to therapy have been shown, in some cases, to predict treatment outcome. We show in lymphoma-bearing mice injected intravenously with hyperpolarized [1-(13)C]pyruvate that the lactate dehydrogenase-catalyzed flux of (13)C label between the carboxyl groups of pyruvate and lactate in the tumor can be measured using (13)C magnetic resonance spectroscopy and spectroscopic imaging, and that this flux is inhibited within 24 h of chemotherapy. The reduction in the measured flux after drug treatment and the induction of tumor cell death can be explained by loss of the coenzyme NAD(H) and decreases in concentrations of lactate and enzyme in the tumors. The technique could provide a new way to assess tumor responses to treatment in the clinic.

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We present for the first time dynamic spectra and spectroscopic images acquired in normal rats at 3T following the injection of 13 C-1-pyruvate that was hyperpolarized by the dynamic nuclear polarization (DNP) method. Spectroscopic sampling was optimized for signal-to-noise ratio (SNR) and for spectral resolution of 13 C-1-pyruvate and its metabolic products 13 C-1-alanine, 13 C-1-lactate, and 13 C-bicarbonate. Dynamic spectra in rats were collected with a temporal resolution of 3 s from a 90-mm axial slab using a dual 1 H-13 C quadrature birdcage coil to observe the combined effects of metabolism, flow, and T 1 relaxation. In separate experiments, spectroscopic imaging data were obtained during a 17-s acquisition of a 20-mm axial slice centered on the rat kidney region to provide information on the spatial distribution of the metabolites. Conversion of pyruvate to lactate, alanine, and bicarbonate occurred within a minute of injection. Alanine was observed primarily in skeletal muscle and liver, while pyruvate, lactate, and bicarbonate concentrations were relatively high in the vasculature and kidneys. In contrast to earlier work at 1. Historically, magnetic resonance (MR) has been a technique associated with low sensitivity, limited by small differences in energy-state populations dictated by the Boltzmann distribution. Increases in magnetic field strength provide modest improvements in the population distribution and thus the sensitivity, but the polarization at thermal equilibrium is fundamentally limited by the low nuclear gyromagnetic ratios. Applications of MRI have thus been focused on imaging the 1 H nucleus occurring in very high concentrations in fat and water in vivo. Clinical 1 H spectroscopy has been possible for metabolites in relatively high concentrations, while spectroscopy of nuclei with lower gyromagnetic ratios, and thus less favorable population distributions, has been difficult at best.Methods to produce substantially altered population distributions or "hyperpolarization" by dynamic nuclear polarization (DNP) and other techniques have been known for a long time (1-6), but have not been applicable to in vivo studies due to the necessity of polarization at very low temperatures (1.2 K) and high fields. The recent development of techniques to achieve high polarization in the solid state and retain a high degree of polarization through fast dissolution procedures (7-9) has provided a mechanism to produce enhancements of MR signals by up to five orders of magnitude compared to thermal equilibrium at typical MR field strengths, thus providing the possibility of directly imaging metabolites of low concentration in vivo. In addition, the potential now exists for directly observing low concentrations of 13 C-labeled compounds in vivo and following their metabolism over short periods of time. Prior studies performed at 1.5T (10,11) have demonstrated the use of hyperpolarized 13 C-labeled pyruvate to directly monitor metabolism in vivo, and to observe the conversion of pyruvate to lactate and alanin...

129Xe apparent diffusion coefficient (ADC) MRI offers an alternative to 3He ADC MRI, given its greater availability and lower cost. To demonstrate the feasibility of HP 129Xe ADC MRI, we present results from healthy volunteers (HV), chronic obstructive pulmonary disease (COPD) subjects, and age-matched healthy controls (AMC). The mean parenchymal ADC was 0.036±0.003 cm2/s for HV, 0.043±0.006 cm2/s for AMC, and 0.056±0.008 cm2/s for COPD subjects with emphysema. In healthy individuals, but not the COPD group, ADC decreased significantly in the anterior-posterior direction by ~22% (p = 0.006, AMC; 0.0059, HV), likely due to gravity-induced tissue compression. The COPD group exhibited a significantly larger superior-inferior ADC reduction (~28%) than the healthy groups (~24%) (p = 0.00018 HV; p = 3.45×10-5 AMC), consistent with smoking-related tissue destruction in the superior lung. Superior-inferior gradients in healthy subjects may result from regional differences in xenon concentration. ADC was significantly correlated with pulmonary function tests (FEV1, r=-0.77, p=0.0002; FEV1/FVC, r=-0.78, p=0.0002; DLCO/VA, r=-0.77, p=0.0002), and in healthy groups, increased with age by 0.0002 cm2/s/yr (r=0.56, p=0.02). This study shows 129Xe ADC MRI is clinically feasible, sufficiently sensitive to distinguish HV from subjects with emphysema, and detects age and posture-dependent changes.

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The ability to quantify pulmonary diffusing capacity and perfusion using dynamic hyperpolarized 129 Xe NMR spectroscopy is demonstrated. A model of alveolar gas exchange was developed, which, in conjunction with 129 Xe NMR, enables quantification of average alveolar wall thickness, pulmonary perfusion, capillary diffusion length, and mean transit time. The technique was employed to compare a group of naïve rats (n ‫؍‬ 10) with a group of rats with acute inflammatory lung injury (n ‫؍‬ 10), caused by instillation of lipopolysaccaride (LPS). The measured structural and perfusion-related parameters were in agreement with reported values from studies using non-NMR methods. Significant differences between the groups were found in total diffusion length (control 8.5 ؎ 0.5 m, LPS 9.9 ؎ 0.6 m, P < 0.001), in capillary diffusion length (control 2.9 ؎ 0.4 m, LPS 3.9 ؎ 1.0 m, P < 0.05), and in pulmonary hematocrit (control 0.55 ؎ 0.06, LPS 0.43 ؎ 0.08, P < 0.01), whereas no differences were observed in alveolar wall thickness, pulmonary perfusion, and mean transit time. These results demonstrate the ability of the method to distinguish two main aspects of lung function, namely, diffusing capacity and pulmonary perfusion. Key words: hyperpolarized gas NMR; xenon-129; lung function; diffusing capacity; pulmonary perfusion Gas transfer from ambient air to the blood involves different transport mechanisms. Alveolar ventilation is accomplished by convective transport. Gas transfer within the alveolus and from the alveolus into the blood stream occurs by diffusion along concentration gradients. The blood is then transported from the lungs to peripheral tissues by the pulmonary circulation. These transport processes are affected by a number of lung diseases. Convective transport in the airways is impaired in obstructive lung diseases (1). Diffusion impairment occurs in interstitial lung diseases as well as in pulmonary edema (2). The pulmonary vasculature is affected by both primary lung disease and by left heart failure, causing abnormalities in blood flow (3).The most common method of assessment of diffusion in the alveolar-capillary unit is measurement of the diffusing capacity for carbon monoxide, DL CO (4). The diffusing capacity is defined as the total rate of gas passage across the alveolar-capillary membrane per unit of partial pressure difference of the gas. The tracer gas carbon monoxide diffuses across the alveolar-capillary barrier and is tightly bound to hemoglobin in the erythrocytes. In addition to factors determining diffusion, e.g., the available surface area and the diffusion path length, DL CO therefore depends also on the availability of binding sites, i.e., on hemoglobin concentration and on perfusion. DL CO provides information about diffusion properties of the lung as a whole, but no regional information about function is obtained. By measurement at different partial pressures for oxygen, DL CO can be subdivided into the membrane conductance and a term reflecting the availability of binding sites. This is...

BackgroundOne of the central physiological functions of the lungs is to transfer inhaled gases from the alveoli to pulmonary capillary blood. However, current measures of alveolar gas uptake provide only global information and thus lack the sensitivity and specificity needed to account for regional variations in gas exchange.Methods and Principal FindingsHere we exploit the solubility, high magnetic resonance (MR) signal intensity, and large chemical shift of hyperpolarized (HP) 129Xe to probe the regional uptake of alveolar gases by directly imaging HP 129Xe dissolved in the gas exchange tissues and pulmonary capillary blood of human subjects. The resulting single breath-hold, three-dimensional MR images are optimized using millisecond repetition times and high flip angle radio-frequency pulses, because the dissolved HP 129Xe magnetization is rapidly replenished by diffusive exchange with alveolar 129Xe. The dissolved HP 129Xe MR images display significant, directional heterogeneity, with increased signal intensity observed from the gravity-dependent portions of the lungs.ConclusionsThe features observed in dissolved-phase 129Xe MR images are consistent with gravity-dependent lung deformation, which produces increased ventilation, reduced alveolar size (i.e., higher surface-to-volume ratios), higher tissue densities, and increased perfusion in the dependent portions of the lungs. Thus, these results suggest that dissolved HP 129Xe imaging reports on pulmonary function at a fundamental level.

Purpose:To evaluate the safety and tolerability of inhaling multiple 1-L volumes of undiluted hyperpolarized xenon 129 ( 129 Xe) followed by up to a 16-second breath hold and magnetic resonance (MR) imaging. Materials and Methods:This study was approved by the institutional review board and was HIPAA compliant. Written informed consent was obtained. Forty-four subjects (19 men, 25 women; mean age, 46.1 years 6 18.8 [standard deviation ]) were enrolled, consisting of 24 healthy volunteers, 10 patients with chronic obstructive pulmonary disease (COPD), and 10 age-matched control subjects. All subjects received three or four 1-L volumes of undiluted hyperpolarized 129 Xe, followed by breath-hold MR imaging. Oxygen saturation, heart rate and rhythm, and blood pressure were continuously monitored. These parameters, along with respiratory rate and subjective symptoms, were assessed after each dose. Subjects' serum biochemistry and hematology were recorded at screening and at 24-hour follow-up. A 12-lead electrocardiogram (ECG) was obtained at these times and also within 2 hours prior to and 1 hour after 129 Xe MR imaging. Xenon-related symptoms were evaluated for relationship to subject group by using a x 2 test and to subject age by using logistic regression. Changes in vital signs were tested for signifi cance across subject group and time by using a repeated-measures multivariate analysis of variance test.