Jan Wolber

Detecting tumor response to treatment using hyperpolarized 13C magnetic resonance imaging and spectroscopy.

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 [1-13C]pyruvate that the lactate dehydrogenase–catalyzed flux of 13C label between the carboxyl groups of pyruvate and lactate in the tumor can be measured using 13C 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.

Diffusion MRI for prediction of response of rectal cancer to chemoradiation

Prediction of tumour response before onset of treatment could have considerable clinical benefit. Since the apparent diffusion coefficient (ADC) of a tumours water content can show the extent of necrosis, we looked for a possible correlation of ADC with response to treatment. We measured mean tumour water ADC before and after chemotherapy and chemoradiation in 14 patients with locally advanced rectal cancer, with a quantitative magnetic resonance diffusion imaging sequence. We found a strong negative correlation between mean pretreatment tumour water ADC and percentage size change of tumours after chemotherapy (r=-0.67, p=0.01) and chemoradiation (r=-0.83, p=0.001). Persistence of low ADC in responders after chemotherapy could represent loss of a non-viable fraction of the treated tumour.

In vivo 13carbon metabolic imaging at 3T with hyperpolarized 13C-1-pyruvate

We present for the first time dynamic spectra and spectroscopic images acquired in normal rats at 3T following the injection of 13C‐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 13C‐1‐pyruvate and its metabolic products 13C‐1‐alanine, 13C‐1‐lactate, and 13C‐bicarbonate. Dynamic spectra in rats were collected with a temporal resolution of 3 s from a 90‐mm axial slab using a dual 1H‐13C quadrature birdcage coil to observe the combined effects of metabolism, flow, and T1 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 1.5T, bicarbonate was routinely observed in skeletal muscle as well as the kidney and vasculature. Magn Reson Med 58:65–69, 2007.

Diffusion-Weighted Hyperpolarized 129Xe MRI in Healthy Volunteers and Subjects with Chronic Obstructive Pulmonary Disease

Given its greater availability and lower cost, 129Xe apparent diffusion coefficient (ADC) MRI offers an alternative to 3He ADC MRI. To demonstrate the feasibility of hyperpolarized 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 sec−1 for HV, 0.043 ± 0.006 cm2 sec−1 for AMC, and 0.056 ± 0.008 cm2 sec−1 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 because of 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 (forced expiratory volume in 1 sec, r = −0.77, P = 0.0002; forced expiratory volume in 1 sec/forced vital capacity, r = −0.77, P = 0.0002; diffusing capacity of carbon monoxide in the lung/alveolar volume (VA), r = −0.77, P = 0.0002). In healthy groups, ADC increased with age by 0.0002 cm2 sec−1 year−1 (r = 0.56, P = 0.02). This study shows that 129Xe ADC MRI is clinically feasible, sufficiently sensitive to distinguish HV from subjects with emphysema, and detects age‐ and posture‐dependent changes. Magn Reson Med, 2010.

Hyperpolarized 129Xe MR Imaging of Alveolar Gas Uptake in Humans

Background One 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 Findings Here 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. Conclusions The 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.

Characterization of diffusing capacity and perfusion of the rat lung in a lipopolysaccaride disease model using hyperpolarized 129Xe

The ability to quantify pulmonary diffusing capacity and perfusion using dynamic hyperpolarized 129Xe NMR spectroscopy is demonstrated. A model of alveolar gas exchange was developed, which, in conjunction with 129Xe 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 μm, LPS 9.9 ± 0.6 μm, P < 0.001), in capillary diffusion length (control 2.9 ± 0.4 μm, LPS 3.9 ± 1.0 μm, 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. Magn Reson Med 50:1170–1179, 2003.

Imaging Considerations for In Vivo 13C Metabolic Mapping Using Hyperpolarized 13C-Pyruvate

One of the challenges of optimizing signal‐to‐noise ratio (SNR) and image quality in 13C metabolic imaging using hyperpolarized 13C‐pyruvate is associated with the different MR signal time‐courses for pyruvate and its metabolic products, lactate and alanine. The impact of the acquisition time window, variation of flip angles, and order of phase encoding on SNR and image quality were evaluated in mathematical simulations and rat experiments, based on multishot fast chemical shift imaging (CSI) and three‐dimensional echo‐planar spectroscopic imaging (3DEPSI) sequences. The image timing was set to coincide with the peak production of lactate. The strategy of combining variable flip angles and centric phase encoding (cPE) improved image quality while retaining good SNR. In addition, two aspects of EPSI sampling strategies were explored: waveform design (flyback vs. symmetric EPSI) and spectral bandwidth (BW = 500 Hz vs. 267 Hz). Both symmetric EPSI and reduced BW trended toward increased SNR. The imaging strategies reported here can serve as guidance to other multishot spectroscopic imaging protocols for 13C metabolic imaging applications. Magn Reson Med, 2009.

Hyperpolarized 129Xe NMR as a probe for blood oxygenation

Optically enhanced NMR with 129Xe and 3He is emerging as a novel and promising technique for medical imaging of lungs and other tissues. Here it is shown that hyperpolarized 129Xe NMR provides a powerful means of measuring blood oxygenation quantitatively and noninvasively. The interaction of xenon with hemoglobin is responsible for an oxygen‐dependent NMR shift of 129Xe in red blood cells, in sharp contrast to the current model of xenon–hemoglobin binding. This effect could be exploited in brain functional studies, and in the assessment of conditions and diseases affected by blood oxygenation. Magn Reson Med 43:491–496, 2000.

Direct visualisation of collateral ventilation in COPD with hyperpolarised gas MRI

Background Collateral ventilation has been proposed as a mechanism of compensation of respiratory function in obstructive lung diseases but observations of it in vivo are limited. The assessment of collateral ventilation with an imaging technique might help to gain insight into lung physiology and assist the planning of new bronchoscopic techniques for treating emphysema. Objective To obtain images of delayed ventilation that might be related to collateral ventilation over the period of a single breath-hold in patients with chronic obstructive pulmonary disease (COPD). Methods Time-resolved breath-hold hyperpolarised 3He MRI was used to obtain images of the progressive influx of polarised gas into initially non-ventilated defects. Results A time-series of images showed that 3He moves into lung regions which were initially non-ventilated. Ventilation defects with delayed filling were observed in 8 of the 10 patients scanned. Conclusions A method for direct imaging of delayed ventilation within a single breath-hold has been demonstrated in patients with COPD. Images of what is believed to be collateral ventilation and slow filling of peripheral airspaces due to increased flow resistance are presented. The technique provides 3D whole-lung coverage with sensitivity to regional information, and is non-invasive and non-ionising.

Perfluorocarbon emulsions as intravenous delivery media for hyperpolarized xenon.

The use of perfluorooctyl bromide (PFOB) emulsions as delivery media for hyperpolarized xenon has been investigated. Emulsion droplet size was controlled by varying the content of egg yolk phospholipid (EYP), which served as an emulsifier. Hyperpolarized 129Xe nuclear magnetic resonance (NMR) spectra of the dissolved gas were obtained. The NMR spectra were found to be correlated strongly with the emulsion droplet size distribution. The NMR line width is determined by xenon exchange between the PFOB droplets and the aqueous environment. Our findings show that, in a 1.5‐Tesla field, relatively narrow 129Xe NMR spectra are obtained for droplet sizes larger than 5 μm. Preliminary results on animal models show that PFOB emulsions have potential as hyperpolarized 129Xe carriers for in vivo magnetic resonance applications. Magn Reson Med 41:442–449, 1999.