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

Abstract

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 13 C, 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-tonoise ratio (SNR) 13 C MRI or MRSI data to be obtained following injection of a hyperpolarized 13 C agent. In this transgenic mouse study, this method was applied using a double spinecho (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 13 C pyruvate (pyr) and its metabolic products at 0.135 cm 3 nominal spatial resolution. The transgenic adenocarcinoma of mouse prostate (TRAMP) mouse is an established and well-studied murine model of prostate cancer (1,2). The histopathology of TRAMP mouse cancer tissue mimics that of human disease. TRAMP mice develop spontaneous progressive disease that begins with prostatic intraepithelial neoplasia (PIN) and then advances to frank carcinoma lesions in the prostatic lobes. The cancer also frequently metastasizes in this model to the lymph nodes (LN) and lungs, and, to a lesser extent, to the kidneys, adrenal glands, liver, and bone (2). The TRAMP model is being used in numerous laboratories to identify the molecular mechanisms associated with the initiation and progression of metastatic prostate cancer. Currently, almost all TRAMP studies use histopathology as the only parameter to evaluate the progression of the disease as well as the efficacy of the treatment agent being tested. Although this parameter is very useful and informative, the mouse has to be killed. Having a noninvasive, in vivo method would be valuable for following disease progression and treatment response in the same animal. TRAMP mice also serve as a good model system for testing new methods to characterize human prostate cancers.Combined proton MRI and MR spectroscopic imaging (MRSI) exams have become routine clinical procedures for characterizing prostate cancer in humans (3-6). In particular, proton MRSI allows identification of changes associated with prostate cancer biomarkers, such as an increase in choline and a reduction in citrate. Single-voxel proton MRS data have been demonstrated in the TRAMP model (7), but this required a 7T animal MR system and an extremely long acquisition time (ϳ2 hr for a single-voxel spectrum). Studying cellular bioenergetics in the TRAMP mouse would also benefit from in vivo MRS studies with non-proton nuclei, such as 13 C, but due to the low natural abundance of 13 C and its low sensitivity compared to the proton, the signal-to-noise ratio (SNR) is prohibitively low in small animals. With the recent development ...

Magnetization transfer measurements of exchange between hyperpolarized [1-13C]pyruvate and [1-13C]lactate in a murine lymphoma

“…Intravenous injection of such hyperpolarized molecules allows imaging of their distribution in vivo and their conversion into other metabolites (2)(3)(4)(5). Hyperpolarized [1- 13 C]pyruvate, in particular, has shown promise as a potential probe for the presence of disease and its response to treatment (3,(5)(6)(7)(8).…”

“…There could also be a combination of both exchange and net flux. In this study, we used magnetization transfer measurements to assess the contribution of exchange to the observed flux of 13 While a single-time point image of the lactate/pyruvate ratio allows detection of altered metabolism (2,3,5), it is sensitive to factors such as the timing of image acquisition, the time taken for pyruvate injection, and the time for inflow of labeled pyruvate into the tissue of interest. Therefore, in a previous study, a full dynamic data set was obtained and the pyruvate and lactate signal intensities were fit to a simple two-site exchange model in order to determine the apparent exchange rate constants (3).…”

In vivo single-shot 13C spectroscopic imaging of hyperpolarized metabolites by spatiotemporal encoding

“…Further developments are in progress to exploit additional benefits of spatiotemporal encoding, such as a built-in restricted FOV capability [24,26], multi-echo experiments and parallel imaging acquisition [34]. Representative metabolic images from a rat following injection of hyperpolarized [1][2][3][4][5][6][7][8][9][10][11][12][13] …”

“…Dissolution DNP has opened new horizons in dynamic metabolic imaging through 13 C spectral observations of hyperpolarized compounds in vivo [1][2]. DNP can result in signal enhancements >10,000 for 13 C; an unprecedented increase that is leading to new opportunities for imaging pathology and monitoring treatment [3][4][5][6][7]. Pyruvic acid has emerged as the principal 13 C-labeled agent in d-DNP, but there is significant on-going research to develop other compounds for dynamic imaging of metabolism [8][9][10].…”

Simultaneous in vivo assessment of cardiac and hepatic metabolism in the diabetic rat using hyperpolarized MRS

“…However, the use of the larger surface coil described here provides a suitable balance between sensitivity and The application of the two-slice approach detailed here was simple to implement and more efficient, in terms of the application of RF excitations that can reduce the reservoir of enhanced magnetization produced by the hyperpolarization process, than multi-shot 3D whole body approaches. 17 However, future studies that want to consider the involvement of other organs (e.g. the kidneys) may favour 3D approaches.…”