James Tropp

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.

Very selective suppression pulses for clinical MRSI studies of brain and prostate cancer

Focal three‐dimensional magnetic resonance spectroscopic imaging (3D MRSI) methods based on conventional point resolved spectroscopy (PRESS) localization are compromised by the geometric restrictions in volume prescription and by chemical shift registration errors. Outer volume saturation (OVS) pulses have been applied to address the geometric limits, but conventional OVS pulses do little to overcome chemical shift registration error, are not particularly selective, and often leave substantial signals that can degrade the spectra of interest. In this paper, an optimized sequence of quadratic phase pulses is introduced to provide very selective spatial suppression with improved B1 and T1 insensitivity. This method was then validated in volunteer studies and in clinical 3D MRSI exams of brain tumors and prostate cancer. Magn Reson Med 43:23–33, 2000.

Detection of Inflammatory Arthritis by Using Hyperpolarized 13C-Pyruvate with MR Imaging and Spectroscopy

PURPOSE To examine the feasibility of using magnetic resonance (MR) spectroscopy with hyperpolarized carbon 13 ((13)C)-labeled pyruvate to detect inflammation. MATERIALS AND METHODS The animal care and use committee approved all work with animals. Arthritis was induced in the right hind paw of six rats; the left hind paw served as an internal control. The lactate dehydrogenase-catalyzed conversion of pyruvate to lactate was measured in inflamed and control paws by using (13)C MR spectroscopy. Clinical and histologic data were obtained to confirm the presence and severity of arthritis. Hyperpolarized (13)C-pyruvate was intravenously injected into the rats before simultaneous imaging of both paws with (13)C MR spectroscopy. The Wilcoxon signed rank test was used to test for differences in metabolites between the control and arthritic paws. RESULTS All animals showed findings of inflammation in the affected paws and no signs of arthritis in the control paws at both visible inspection (clinical index of 3 for arthritic paws and 0 for control paws) and histologic examination (histologic score of 3-5 for arthritic paws and 0 for control paws). Analysis of the spectroscopic profiles of (13)C-pyruvate and converted (13)C-lactate showed an increase in the amount of (13)C-lactate in inflamed paws (median lactate-to-pyruvate ratio, 0.50; mean lactate-to-pyruvate ratio ± standard deviation, 0.52 ± 0.16) versus control paws (median lactate-to-pyruvate ratio, 0.27; mean lactate-to-pyruvate ratio, 0.32 ± 0.11) (P < .03). The ratio of (13)C-lactate to total (13)C was also significantly increased in inflamed paws compared with control paws (P < .03). CONCLUSION These results suggest that alterations in the conversion of pyruvate to lactate as detected with (13)C-MR spectroscopy may be indicative of the presence of inflammatory arthritis.

In vivo hyperpolarization transfer in a clinical MRI scanner

The purpose of this study was to investigate the feasibility of in vivo 13C‐>1H hyperpolarization transfer, which has significant potential advantages for detecting the distribution and metabolism of hyperpolarized 13C probes in a clinical MRI scanner.

Sensitivity enhancement for detection of hyperpolarized 13C MRI probes with 1H spin coupling introduced by enzymatic transformation in vivo: HP13C MRI With 1H Spin Coupling

Although 1H spin coupling is generally avoided in probes for hyperpolarized (HP) 13C MRI, enzymatic transformations of biological interest can introduce large 13C‐1H couplings in vivo. The purpose of this study was to develop and investigate the application of 1H decoupling for enhancing the sensitivity for detection of affected HP 13C metabolic products.

Quantification of in vivo metabolic kinetics of hyperpolarized pyruvate in rat kidneys using dynamic 13C MRSI: QUANTIFICATION OF IN VIVO HYPERPOLARIZED 13C MRSI

With signal‐to‐noise ratio enhancements on the order of 10,000‐fold, hyperpolarized MRSI of metabolically active substrates allows the study of both the injected substrate and downstream metabolic products in vivo. Although hyperpolarized [1‐13C]pyruvate, in particular, has been used to demonstrate metabolic activities in various animal models, robust quantification and metabolic modeling remain important areas of investigation. Enzyme saturation effects are routinely seen with commonly used doses of hyperpolarized [1‐13C]pyruvate; however, most metrics proposed to date, including metabolite ratios, time‐to‐peak of metabolic products and single exchange rate constants, fail to capture these saturation effects. In addition, the widely used small‐flip‐angle excitation approach does not correctly model the inflow of fresh downstream metabolites generated proximal to the target slice, which is often a significant factor in vivo. In this work, we developed an efficient quantification framework employing a spiral‐based dynamic spectroscopic imaging approach. The approach overcomes the aforementioned limitations and demonstrates that the in vivo 13C labeling of lactate and alanine after a bolus injection of [1‐13C]pyruvate is well approximated by saturatable kinetics, which can be mathematically modeled using a Michaelis–Menten‐like formulation, with the resulting estimated apparent maximal reaction velocity Vmax and apparent Michaelis constant KM being unbiased with respect to critical experimental parameters, including the substrate dose, bolus shape and duration. Although the proposed saturatable model has a similar mathematical formulation to the original Michaelis–Menten kinetics, it is conceptually different. In this study, we focus on the 13C labeling of lactate and alanine and do not differentiate the labeling mechanism (net flux or isotopic exchange) or the respective contribution of various factors (organ perfusion rate, substrate transport kinetics, enzyme activities and the size of the unlabeled lactate and alanine pools) to the labeling process. Copyright

Quantitation of In Vivo Metabolic Kinetics of Hyperpolarized Pyruvate in Rat Kidneys using Dynamic 13C Magnetic Resonance Spectroscopic Imaging

With signal‐to‐noise ratio enhancements on the order of 10,000‐fold, hyperpolarized MRSI of metabolically active substrates allows the study of both the injected substrate and downstream metabolic products in vivo. Although hyperpolarized [1‐13C]pyruvate, in particular, has been used to demonstrate metabolic activities in various animal models, robust quantification and metabolic modeling remain important areas of investigation. Enzyme saturation effects are routinely seen with commonly used doses of hyperpolarized [1‐13C]pyruvate; however, most metrics proposed to date, including metabolite ratios, time‐to‐peak of metabolic products and single exchange rate constants, fail to capture these saturation effects. In addition, the widely used small‐flip‐angle excitation approach does not correctly model the inflow of fresh downstream metabolites generated proximal to the target slice, which is often a significant factor in vivo. In this work, we developed an efficient quantification framework employing a spiral‐based dynamic spectroscopic imaging approach. The approach overcomes the aforementioned limitations and demonstrates that the in vivo 13C labeling of lactate and alanine after a bolus injection of [1‐13C]pyruvate is well approximated by saturatable kinetics, which can be mathematically modeled using a Michaelis–Menten‐like formulation, with the resulting estimated apparent maximal reaction velocity Vmax and apparent Michaelis constant KM being unbiased with respect to critical experimental parameters, including the substrate dose, bolus shape and duration. Although the proposed saturatable model has a similar mathematical formulation to the original Michaelis–Menten kinetics, it is conceptually different. In this study, we focus on the 13C labeling of lactate and alanine and do not differentiate the labeling mechanism (net flux or isotopic exchange) or the respective contribution of various factors (organ perfusion rate, substrate transport kinetics, enzyme activities and the size of the unlabeled lactate and alanine pools) to the labeling process. Copyright