Yi-Fen Yen

Hyperpolarized 13C Lactate, Pyruvate, and Alanine: Noninvasive Biomarkers for Prostate Cancer Detection and Grading

An extraordinary new technique using hyperpolarized (13)C-labeled pyruvate and taking advantage of increased glycolysis in cancer has the potential to improve the way magnetic resonance imaging is used for detection and characterization of prostate cancer. The aim of this study was to quantify, for the first time, differences in hyperpolarized [1-(13)C] pyruvate and its metabolic products between the various histologic grades of prostate cancer using the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Fast spectroscopic imaging techniques were used to image lactate, alanine, and total hyperpolarized carbon (THC = lactate + pyruvate + alanine) from the entire abdomen of normal mice and TRAMP mice with low- and high-grade prostate tumors in 14 s. Within 1 week, the mice were dissected and the tumors were histologically analyzed. Hyperpolarized lactate SNR levels significantly increased (P < 0.05) with cancer development and progression (41 +/- 11, 74 +/- 17, and 154 +/- 24 in normal prostates, low-grade primary tumors, and high-grade primary tumors, respectively) and had a correlation coefficient of 0.95 with the histologic grade. In addition, there was minimal overlap in the lactate levels between the three groups with only one of the seven normal prostates overlapping with the low-grade primary tumors. The amount of THC, a possible measure of substrate uptake, and hyperpolarized alanine also increased with tumor grade but showed more overlap between the groups. In summary, elevated hyperpolarized lactate and potentially THC and alanine are noninvasive biomarkers of prostate cancer presence and histologic grade that could be used in future three-dimensional (13)C spectroscopic imaging studies of prostate cancer patients.

Deactivation of Sensory-Specific Cortex by Cross-Modal Stimuli

Visual and auditory cortices traditionally have been considered to be modality-specific. Thus, their activity has been thought to be unchanged by information in other sensory modalities. However, using functional magnetic resonance imaging (fMRI), the present experiments revealed that ongoing activity in the visual cortex could be modulated by auditory information and ongoing activity in the auditory cortex could be modulated by visual information. In both cases, this cross-modal modulation of activity took the form of deactivation. Yet, the deactivation response was not evident in either cortical area during the paired presentation of visual and auditory stimuli. These data suggest that cross-modal inhibitory processes operate within traditional modality-specific cortices and that these processes can be switched on or off in different circumstances.

Hyperpolarized C-13 spectroscopic imaging of the TRAMP mouse at 3T—Initial experience

The transgenic adenocarcinoma of mouse prostate (TRAMP) mouse is a well‐studied murine model of prostate cancer with histopathology and disease progression that mimic the human disease. To investigate differences in cellular bioenergetics between normal prostate epithelial cells and prostate tumor cells, in vivo MR spectroscopic (MRS) studies with non‐proton nuclei, such as 13C, in the TRAMP model would be extremely useful. The recent development of a method for retaining dynamic nuclear polarization (DNP) in solution permits high signal‐to‐noise ratio (SNR) 13C MRI or MRSI data to be obtained following injection of a hyperpolarized 13C agent. In this transgenic mouse study, this method was applied using a double spin‐echo (DSE) pulse sequence with a small‐tip‐angle excitation RF pulse, hyperbolic‐secant refocusing pulses, and a flyback echo‐planar readout trajectory for fast (10–14 s) MRSI of 13C pyruvate (pyr) and its metabolic products at 0.135 cm3 nominal spatial resolution. Elevated 13C lactate (lac) was observed in both primary and metastatic tumors, demonstrating the feasibility of studying cellular bioenergetics in vivo with DNP hyperpolarized 13C MRSI. Magn Reson Med, 2007.

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.

Kinetic modeling of hyperpolarized 13C1-pyruvate metabolism in normal rats and TRAMP mice

PURPOSE To investigate metabolic exchange between (13)C(1)-pyruvate, (13)C(1)-lactate, and (13)C(1)-alanine in pre-clinical model systems using kinetic modeling of dynamic hyperpolarized (13)C spectroscopic data and to examine the relationship between fitted parameters and dose-response. MATERIALS AND METHODS Dynamic (13)C spectroscopy data were acquired in normal rats, wild type mice, and mice with transgenic prostate tumors (TRAMP) either within a single slice or using a one-dimensional echo-planar spectroscopic imaging (1D-EPSI) encoding technique. Rate constants were estimated by fitting a set of exponential equations to the dynamic data. Variations in fitted parameters were used to determine model robustness in 15 mm slices centered on normal rat kidneys. Parameter values were used to investigate differences in metabolism between and within TRAMP and wild type mice. RESULTS The kinetic model was shown here to be robust when fitting data from a rat given similar doses. In normal rats, Michaelis-Menten kinetics were able to describe the dose-response of the fitted exchange rate constants with a 13.65% and 16.75% scaled fitting error (SFE) for k(pyr-->lac) and k(pyr-->ala), respectively. In TRAMP mice, k(pyr-->lac) increased an average of 94% after up to 23 days of disease progression, whether the mice were untreated or treated with casodex. Parameters estimated from dynamic (13)C 1D-EPSI data were able to differentiate anatomical structures within both wild type and TRAMP mice. CONCLUSIONS The metabolic parameters estimated using this approach may be useful for in vivo monitoring of tumor progression and treatment efficacy, as well as to distinguish between various tissues based on metabolic activity.

Dietary caffeine consumption modulates fMRI measures.

Caffeine is the most widely used stimulant in the world. The stimulant effects of caffeine are mediated through its antagonistic properties on neuronal adenosine receptors. In addition, caffeine blocks neurovascular adenosine receptors and decreases cerebral perfusion. Although the effects of caffeine on blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging measures are extremely important, there are few studies addressing this issue in the literature. Because chronic caffeine use causes an upregulation of adenosine receptors, the differential effects of caffeine in low and high users is of particular interest. The present study was designed to test the hypothesis that caffeine has differential effects on the BOLD signal in high and low caffeine users. We demonstrated that the BOLD signal change in visual cortex was significantly greater in high users than in low users in the presence of caffeine. In addition, the magnitude of the BOLD signal was significantly correlated with caffeine consumption. We propose that the outcome observed here was due to an upregulation of adenosine receptors in high users, resulting in differential contributions of the neural and vascular effects of adenosine in the two study populations.

Test-retest reproducibility of quantitative CBF measurements using FAIR perfusion MRI and acetazolamide challenge.

The reproducibility of quantitative cerebral blood flow (CBF) measurements using MRI with arterial spin labeling and acetazolamide challenge was assessed in 12 normal subjects, each undergoing the identical experimental procedure on two separate days. CBF was measured on a 1.5T scanner using a flow‐sensitive alternating inversion recovery (FAIR) pulse sequence, performed both at baseline and 12 min after intravenous administration of acetazolamide. T1 was measured in conjunction with the FAIR scan in order to calculate quantitative CBF. The CBF maps were segmented to separate gray matter (GM) from white matter (WM) for region‐of‐interest (ROI) analyses. Post‐ acetazolamide CBF values (ml/100 g/min, mean ± SD) of 87.5 ± 12.5 (GM) and 46.1 ± 10.8 (WM) represented percent increases of 37.7% ± 24.4% (GM) and 40.1% ± 24.4% (WM). Day‐to‐day differences in baseline CBF were −1.7 ± 6.9 (GM) and –1.4 ± 4.7 (WM) or, relative to the mean CBF over both days for each subject, −2.5% ± 11.7% (GM) and −3.8% ± 13.6% (WM) Day‐ to‐day differences in absolute post‐ACZ CBF increase were −2.5 ± 6.8 (GM) and 2.7 ± 9.4 (WM) or, relative to the mean CBF increase over both days for each subject, –4.7% ± 13.3% (GM) and 9.1% ± 26.2% (WM). Thus, FAIR‐ based CBF measurements show satisfactory reproducibility from day to day, but with sufficient variation to warrant caution in interpreting longitudinal data. The hemispheric asymmetry of baseline CBF and post‐acetazolamide CBF increases varied within a narrower range and should be sensitive to small changes related to disease or treatment. Magn Reson Med 47:921–928, 2002.

Application of subsecond spiral chemical shift imaging to real-time multislice metabolic imaging of the rat in vivo after injection of hyperpolarized 13C1-pyruvate.

Dynamic nuclear polarization can create hyperpolarized compounds with MR signal‐to‐noise ratio enhancements on the order of 10,000‐fold. Both exogenous and normally occurring endogenous compounds can be polarized, and their initial concentration and downstream metabolic products can be assessed using MR spectroscopy. Given the transient nature of the hyperpolarized signal enhancement, fast imaging techniques are a critical requirement for real‐time metabolic imaging. We report on the development of an ultrafast, multislice, spiral chemical shift imaging sequence, with subsecond acquisition time, achieved on a clinical MR scanner. The technique was used for dynamic metabolic imaging in rats, with measurement of time‐resolved spatial distributions of hyperpolarized 13C1‐pyruvate and metabolic products 13C1‐lactate and 13C1‐alanine, with a temporal resolution of as fast as 1 s. Metabolic imaging revealed different signal time courses in liver from kidney. These results demonstrate the feasibility of real‐time, hyperpolarized metabolic imaging and highlight its potential in assessing organ‐specific kinetic parameters. Magn Reson Med, 2009.

Metabolic imaging in the anesthetized rat brain using hyperpolarized [1-13C] pyruvate and [1-13C] ethyl pyruvate.

Formulation, polarization, and dissolution conditions were developed to obtain a stable hyperpolarized solution of [1‐13C]‐ethyl pyruvate. A maximum tolerated concentration and injection rate were determined, and 13C spectroscopic imaging was used to compare the uptake of hyperpolarized [1‐13C]‐ethyl pyruvate relative to hyperpolarized [1‐13C]‐pyruvate into anesthetized rat brain. Hyperpolarized [1‐13C]‐ethyl pyruvate and [1‐13C]‐pyruvate metabolic imaging in normal brain is demonstrated and quantified in this feasibility and range‐finding study. Magn Reson Med 63:1137–1143, 2010.

Least‐squares chemical shift separation for 13C metabolic imaging

To describe a new least‐squares chemical shift (LSCSI) method for separation of chemical species with widely spaced peaks in a sparse spectrum. The ability to account for species with multiple peaks is addressed.