Martin A. Janich

IDEAL spiral CSI for dynamic metabolic MR imaging of hyperpolarized [1‐13C]pyruvate

Metabolic imaging with hyperpolarized [1‐13C]pyruvate offers the unique opportunity for a minimally invasive detection of cellular metabolism. Efficient and robust acquisition and reconstruction techniques are required for capturing the wealth of information present for the limited duration of the hyperpolarized state (∼1 min). In this study, the Dixon/IDEAL type of water–fat separation is expanded toward spectroscopic imaging of [1‐13C]pyruvate and its down‐stream metabolites. For this purpose, the spectral–spatial encoding is based on single‐shot spiral image encoding and echo‐time shifting in between excitations for the chemical‐shift encoding. In addition, also a free‐induction decay spectrum is acquired and the obtained chemical‐shift prior knowledge is efficiently used in the reconstruction. The spectral–spatial reconstruction problem is found to efficiently separate into a chemical‐shift inversion followed by a spatial reconstruction. The method is successfully demonstrated for dynamic, multislice [1‐13C]pyruvate metabolic MR imaging in phantom and in vivo rat experiments. Magn Reson Med, 2012.

Saturation-recovery metabolic-exchange rate imaging with hyperpolarized [1-13C] pyruvate using spectral-spatial excitation.

Within the last decade hyperpolarized [1‐13C] pyruvate chemical‐shift imaging has demonstrated impressive potential for metabolic MR imaging for a wide range of applications in oncology, cardiology, and neurology. In this work, a highly efficient pulse sequence is described for time‐resolved, multislice chemical shift imaging of the injected substrate and obtained downstream metabolites. Using spectral‐spatial excitation in combination with single‐shot spiral data acquisition, the overall encoding is evenly distributed between excitation and signal reception, allowing the encoding of one full two‐dimensional metabolite image per excitation. The signal‐to‐noise ratio can be flexibly adjusted and optimized using lower flip angles for the pyruvate substrate and larger ones for the downstream metabolites. Selectively adjusting the excitation of the down‐stream metabolites to 90° leads to a so‐called “saturation‐recovery” scheme with the detected signal content being determined by forward conversion of the available pyruvate. In case of repetitive excitations, the polarization is preserved using smaller flip angles for pyruvate. Metabolic exchange rates are determined spatially resolved from the metabolite images using a simplified two‐site exchange model. This novel contrast is an important step toward more quantitative metabolic imaging. Goal of this work was to derive, analyze, and implement this “saturation‐recovery metabolic exchange rate imaging” and demonstrate its capabilities in four rats bearing subcutaneous tumors. Magn Reson Med, 2013.

Robust slice-selective broadband refocusing pulses

Slice-selective broadband refocusing pulses are of great interest in localized MR spectroscopy for improving spatial selectivity, reducing chemical-shift displacement errors, and reducing anomalous J modulation. In practice the bandwidth of RF pulses is limited by the maximum available B1 amplitude. The goal of the present work is to design slice-selective and broadband refocusing pulses which are tolerant against B1 deviations. Pulse design is performed by numerical optimization based on optimal control theory. A comprehensive study of different cost functions and their effect on the optimization is given. The optimized slice-selective broadband refocusing pulses are compared to conventional Shinnar-Le Roux (SLR), broadband SLR, and hyperbolic secant pulses. In simulations and experiments optimized pulses were shown to fulfill broadband slice specifications over a range of ±20% B1 scalings. Experimental validation showed a reduction of chemical-shift displacement error by a factor of 3 compared to conventional SLR pulses.

In vivo measurement of apparent diffusion coefficients of hyperpolarized 13C‐labeled metabolites

The combination of hyperpolarized MRS with diffusion weighting (dw) allows for determination of the apparent diffusion coefficient (ADC), which is indicative of the intra‐ or extracellular localization of the metabolite. Here, a slice‐selective pulsed‐gradient spin echo sequence was implemented to acquire a series of dw spectra from rat muscle in vivo to determine the ADCs of multiple metabolites after a single injection of hyperpolarized [1‐13C]pyruvate. An optimal control optimized universal‐rotation pulse was used for refocusing to minimize signal loss caused by B1 imperfections.

Apparent rate constant mapping using hyperpolarized [1- 13 C]pyruvate

Hyperpolarization of [1‐13C]pyruvate in solution allows real‐time measurement of uptake and metabolism using MR spectroscopic methods. After injection and perfusion, pyruvate is taken up by the cells and enzymatically metabolized into downstream metabolites such as lactate, alanine, and bicarbonate. In this work, we present comprehensive methods for the quantification and interpretation of hyperpolarized 13C metabolite signals. First, a time‐domain spectral fitting method is described for the decomposition of FID signals into their metabolic constituents. For this purpose, the required chemical shift frequencies are automatically estimated using a matching pursuit algorithm. Second, a time‐discretized formulation of the two‐site exchange kinetic model is used to quantify metabolite signal dynamics by two characteristic rate constants in the form of (i) an apparent build‐up rate (quantifying the build‐up of downstream metabolites from the pyruvate substrate) and (ii) an effective decay rate (summarizing signal depletion due to repetitive excitation, T1‐relaxation and backward conversion). The presented spectral and kinetic quantification were experimentally verified in vitro and in vivo using hyperpolarized [1‐13C]pyruvate. Using temporally resolved IDEAL spiral CSI, spatially resolved apparent rate constant maps are also extracted. In comparison to single metabolite images, apparent build‐up rate constant maps provide improved contrast by emphasizing metabolically active tissues (e.g. tumors) and suppression of high perfusion regions with low conversion (e.g. blood vessels). Apparent build‐up rate constant mapping provides a novel quantitative image contrast for the characterization of metabolic activity. Its possible implementation as a quantitative standard will be subject to further studies. Copyright

Quantified pH imaging with hyperpolarized (13) C-bicarbonate.

Because pH plays a crucial role in several diseases, it is desirable to measure pH in vivo noninvasively and in a spatially localized manner. Spatial maps of pH were quantified in vitro, with a focus on method‐based errors, and applied in vivo.

Effects of pyruvate dose on in vivo metabolism and quantification of hyperpolarized 13C spectra

Real‐time in vivo measurements of metabolites are performed by signal enhancement of [1‐13C]pyruvate using dynamic nuclear polarization, rapid dissolution and intravenous injection, acquisition of free induction decay signals and subsequent quantification of spectra. The commonly injected dose of hyperpolarized pyruvate is larger than typical tracer doses, with measurement before complete dilution of the injected bolus. Pyruvate is in exchange with its downstream metabolites lactate, alanine and bicarbonate. A transient exposure to high pyruvate blood concentrations may cause the saturation of cellular uptake and metabolic conversion. The goal of this study was to examine the effects of a [1‐13C]pyruvate bolus on metabolic conversion in vivo.

Multimodal Assessment of In Vivo Metabolism with Hyperpolarized [1-13C]MR Spectroscopy and 18F-FDG PET Imaging in Hepatocellular Carcinoma Tumor–Bearing Rats

Abnormalities of tumor metabolism can be exploited for molecular imaging. PET imaging of 18F-FDG is a well-established method using the avid glucose uptake of tumor cells. 13C MR spectroscopic imaging (MRSI) of hyperpolarized [1-13C]pyruvate and its metabolites, meanwhile, represents a new method to study energy metabolism by visualizing, for example, the augmented lactate dehydrogenase activity in tumor cells. Because of rapid signal loss, this method underlies strict temporal limitations, and the acquisition of data—encoding spatial, temporal, and spectral information within this time frame—is challenging. The object of our study was to compare spectroscopic images with 18F-FDG PET images for visualizing tumor metabolism in a rat model. Methods: 13C MRSI with IDEAL (Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation) chemical shift imaging in combination with single-shot spiral acquisition was used to obtain dynamic data from 23 rats bearing a subcutaneous hepatocellular carcinoma and from reference regions of the same animals. Static and dynamic analysis of 18F-FDG PET images of the same animals was performed. The data were analyzed qualitatively (visual assessment) and quantitatively (magnitude and dynamics of 18F-FDG uptake, 13C MRSI dynamics, and physiologic parameters). Results: In most animals increased [1-13C]lactate signals in the tumor could be detected by simple display of integrated [1-13C]lactate images with corresponding enhanced 18F-FDG uptake. Low [1-13C]pyruvate or [1-13C]lactate signals did not correlate with histologic or physiologic parameters. Significantly less pyruvate reached the tumors than the gastrointestinal tract, but in tumors a significantly higher amount of pyruvate was converted to lactate and alanine within seconds after intravenous administration. Conclusion: This study reveals that PET and 13C MRSI can be used to visualize increased glycolytic flux in malignant tissue. The combination of signals will allow the quantitative dissection of substrate metabolism, with respect to uptake and downstream metabolic pathways. Although hyperpolarized [1-13C]pyruvate increases the sensitivity of MR imaging, signal-to-noise ratio constraints still apply for spatially and temporally resolved 13C MRSI, emphasizing the need for further MR methodologic development. These first imaging data suggest the feasibility of 13C MRSI for future clinical use.

Transmit gain calibration for nonproton MR using the Bloch–Siegert shift

Transmit gain (B  1+ ) calibration is necessary for the adjustment of radiofrequency (RF) power levels to the desired flip angles. In proton MRI, this is generally an automated process before the actual scan without any user interaction. For other nuclei, it is usually time consuming and difficult, especially in the case of hyperpolarised MR. In the current work, transmit gain calibration was implemented on the basis of the Bloch–Siegert phase shift. From the same data, the centre frequency, line broadening and SNR could also be determined. The T1 and B0 insensitivity, and the wide range of B  1+ over which this technique is effective, make it well suited for nonproton applications. Examples are shown for hyperpolarised 13C and 3He applications. Copyright

Bolus tracking for improved metabolic imaging of hyperpolarised compounds.

Dynamic nuclear polarisation has enabled real-time metabolic imaging of pyruvate and its metabolites. Conventional imaging sequences rely on predefined settings and do not account for intersubject variations in biological parameters such as perfusion. We present a fully automatic real-time bolus tracking sequence for hyperpolarised substrates which starts the imaging acquisition at a defined point on the bolus curve. This reduces artefacts due to signal change and allows for a more efficient use of hyperpolarised magnetisation. For single time point imaging methods, bolus tracking enables a more reliable and consistent quantification of metabolic activity. An RF excitation with a small flip angle is used to obtain slice-selective pyruvate tracking information in rats. Moreover, in combination with a copolarised urea and pyruvate injection, spectrally selective tracking on urea allows obtaining localised bolus tracking information without depleting the pyruvate signal. Particularly with regard to clinical application, the bolus tracking technique could provide an important step towards a routine assessment protocol which removes operator dependencies and ensures comparable results.