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PurposeTo test the hypothesis that lactate shuttling contributes to the13C-lactate and13C-bicarbonate signal observed in the awake human brain using hyperpolarized13C MRI.MethodsHealthy human volunteers (n = 6) were scanned twice using hyperpolarized13C-MRI, with reduced radiofrequency saturation of13C-lactate on one set of scans.13C-lactate,13C-bicarbonate, and13C-pyruvate signals for 132 brain regions across each set of scans were compared using a clustered Wilcoxon sum rank test.ResultsReduced13C-lactate radiofrequency saturation resulted in a significantly greater13C-bicarbonate signal (p= 0.04). These changes were observed across the majority of brain regions.ConclusionRadiofrequency saturation of13C-lactate leads to a decrease in13C-bicarbonate signal, demonstrating that the13C-lactate generated from the injected13C-pyruvate is being converted back to13C-pyruvate and oxidized throughout the human brain.

Background Stereotactic radiosurgery (SRS) is used to manage intracranial metastases in a significant fraction of patients. Local progression after SRS can often only be detected with increased volume of enhancement on serial MRI scans which may lag true progression by weeks or months. Methods Patients with intracranial metastases (N = 11) were scanned using hyperpolarized $$^{13}$$ 13 C MRI prior to treatment with stereotactic radiosurgery (SRS). The status of each lesion was then recorded at six months post-treatment follow-up (or at the time of death). Results The positive predictive value of $$^{13}$$ 13 C-lactate signal, measured pre-treatment, for prediction of progression of intracranial metastases at six months post-treatment with SRS was 0.8 $$p < 0.05$$ p < 0.05 , and the AUC from an ROC analysis was 0.77 $$p < 0.05$$ p < 0.05 . The distribution of $$^{13}$$ 13 C-lactate z-scores was different for intracranial metastases from different primary cancer types (F = 2.46, $$p = 0.1$$ p = 0.1 ). Conclusions Hyperpolarized $$^{13}$$ 13 C imaging has potential as a method for improving outcomes for patients with intracranial metastases, by identifying patients at high risk of treatment failure with SRS and considering other therapeutic options such as surgery.

Purpose Asymmetric in-plane k-space sampling of EPI can reduce the minimum achievable TE in hyperpolarized 13 C with spectral-spatial radio frequency pulses, thereby reducing T 2 * weighting and signal-losses. Partial Fourier image reconstruction exploits the approximate Hermitian symmetry of k-space data and can be applied to asymmetric data sets to synthesize unmeasured data. Here we tested whether the application of partial Fourier image reconstruction would improve spatial resolution from hyperpolarized [1- 13 C ]pyruvate scans in the human brain. Methods Fifteen healthy control subjects were imaged using a volumetric dual-echo echo-planar imaging sequence with spectral-spatial radio frequency excitation. Images were reconstructed by zero-filling as well as with the partial Fourier reconstruction algorithm projection-on-convex-sets. Resulting images were quantitatively evaluated with a no-reference image quality assessment. Results The no-reference image sharpness metric agreed with perceived improvements in image resolution and contrast. The [1- 13 C ]lactate images benefitted most, followed by the [1- 13 C ]pyruvate images. The 13 C -bicarbonate images were improved by the smallest degree, likely owing to relatively lower SNR. Conclusions Partial Fourier imaging and reconstruction were shown to improve the sharpness and contrast of human HP 13 C brain data and is a viable method for enhancing resolution.

Molecular imaging techniques have rapidly progressed over recent decades providing unprecedented in vivo characterization of metabolic pathways and molecular biomarkers. Many of these new techniques have been successfully applied in the field of neuro-oncological imaging to probe tumor biology. Targeting specific signaling or metabolic pathways could help to address several unmet clinical needs that hamper the management of patients with brain tumors. This review aims to provide an overview of the recent advances in brain tumor imaging using molecular targeting with positron emission tomography and magnetic resonance imaging, as well as the role in patient management and possible therapeutic implications.

Hyperpolarized (HP) [1-13 C]lactate is an attractive alternative to [1-13 C]pyruvate as a substrate to investigate cardiac metabolism in vivo: it can be administered safely at a higher dose and can be polarized to a degree similar to pyruvate via dynamic nuclear polarization. While 13 C cardiac experiments using HP lactate have been performed in small animal models, they have not been demonstrated in large animal models or humans. Utilizing the same hardware and data acquisition methods as the first human HP 13 C cardiac study, 13 C metabolic images were acquired following injections of HP [1-13 C]lactate in porcine hearts. Data were also acquired using HP [1-13 C]pyruvate for comparison. The 13 C bicarbonate signal was localized to the myocardium and had a similar appearance with both substrates for all animals. No 13 C pyruvate signal was detected in the experiments following injection of HP 13 C lactate. The signal-to-noise ratio (SNR) of injected lactate was 88 ± 4% of the SNR of injected pyruvate, and the SNR of bicarbonate in the experiments using lactate as the substrate was 52 ± 19% of the SNR in the experiments using pyruvate as the substrate. The lower SNR was likely due to the shorter T1 of [1-13 C]lactate as compared with [1-13 C]pyruvate and the additional enzyme-catalyzed metabolic conversion step before the 13 C nuclei from [1-13 C]lactate were detected as 13 C bicarbonate. While challenges remain, the potential of HP lactate as a substrate for clinical metabolic imaging of human heart has been demonstrated.

This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) 13C magnetic resonance imaging’s (MRI’s) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolarized 13C MRI in 2011, preclinical studies involving [1-13C]pyruvate as well a number of other 13C labeled metabolic substrates have demonstrated this technology's capacity to provide unique metabolic information. A dose-ranging study of HP [1-13C]pyruvate in patients with prostate cancer established safety and feasibility of this technique. Additional studies are ongoing in prostate, brain, breast, liver, cervical, and ovarian cancer. Technology for generating and delivering hyperpolarized agents has evolved, and new MR data acquisition sequences and improved MRI hardware have been developed. It will be important to continue investigation and development of existing and new probes in animal models. Improved polarization technology, efficient radiofrequency coils, and reliable pulse sequences are all important objectives to enable exploration of the technology in healthy control subjects and patient populations. It will be critical to determine how HP 13C MRI might fill existing needs in current clinical research and practice, and complement existing metabolic imaging modalities. Financial sponsorship and integration of academia, industry, and government efforts will be important factors in translating the technology for clinical research in oncology. This white paper is intended to provide recommendations with this goal in mind.

Background Stereotactic radiosurgery (SRS) is used to manage intracranial metastases in a significant fraction of patients. Local progression after SRS can often only be detected with increased volume of enhancement on serial MRI scans which may lag true progression by weeks or months. Methods Patients with intracranial metastases (N = 11) were scanned using hyperpolarized \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{13}$$\end{document}13C MRI prior to treatment with stereotactic radiosurgery (SRS). The status of each lesion was then recorded at six months post-treatment follow-up (or at the time of death). Results The positive predictive value of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{13}$$\end{document}13C-lactate signal, measured pre-treatment, for prediction of progression of intracranial metastases at six months post-treatment with SRS was 0.8 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$p < 0.05$$\end{document}p

Hyperpolarized [1-13C]lactate is an attractive alternative to [1-13C]pyruvate as a substrate to investigate cardiac metabolism in vivo; it can be administered safely at a higher dose and can be polarized to a similar degree as pyruvate via dynamic nuclear polarization. While 13C cardiac experiments using HP lactate have been performed in small animal models, it has not been demonstrated in large animal models or humans. Utilizing the same hardware and data acquisition methods used in the first human HP 13C cardiac study, 13C metabolic images were acquired following injections of HP [1-13C]lactate in porcine hearts. Data were also acquired using HP [1-13C]pyruvate for comparison. The 13C bicarbonate signal was localized to the myocardium and had a similar appearance with both substrates for all animals. No 13C pyruvate signal was detected in the experiments following injection of hyperpolarized 13C lactate. The SNR of injected lactate was 88 +/-14% of the SNR of injected pyruvate, and the SNR of bicarbonate in the experiments using lactate as the substrate was 52+/-19% of the SNR in the experiments using pyruvate as the substrate. The lower SNR was likely due to the shorter T1 of [1-13C]lactate as compared to [1-13C]pyruvate and the additional enzyme-catalyzed metabolic conversion step before the 13C nuclei from [1-13C]lactate were detected as 13C bicarbonate. While challenges remain, the potential of HP lactate as a substrate for clinical metabolic imaging of human heart was demonstrated.

PurposeStereotactic radiosurgery (SRS) is used to manage intracranial metastases in a significant fraction of patients. Local progression after SRS can often only be detected with increased volume of enhancement on serial MRI scans which may lag true progression by weeks or months.Experimental DesignPatients with intracranial metastases (N = 11) were scanned using hyperpolarized 13C MRI prior to treatment with stereotactic radiosurgery (SRS). The status of each lesion was then recorded at six months post-treatment follow-up (or at the time of death).ResultsThe positive predictive value of 13C-lactate signal, measured pre-treatment, for prediction of progression of intracranial metastases at six months post-treatment with SRS was 0.8 p < 0.05, and the AUC from an ROC analysis was 0.77 p < 0.05. The distribution of 13C-lactate z-scores was different for intracranial metastases from different primary cancer types (F = 2.46, p = 0.1).ConclusionsHyperpolarized 13C imaging has potential as a method for improving outcomes for patients with intracranial metastases, by identifying patients at high risk of treatment failure with SRS and considering other therapeutic options such as surgery.

Hyperpolarized (HP) 13 C MRI provides the means to monitor lactate metabolism noninvasively in tumours. Since 13 C -lactate signal levels obtained from HP 13 C imaging depend on multiple factors, such as the rate of 13 C substrate delivery via the vasculature, the expression level of monocarboxylate transporters (MCTs) and lactate dehydrogenase (LDH), and the local lactate pool size, the interpretation of HP 13 C metabolic images remains challenging. In this study, ex vivo tissue extract measurements (i.e., NMR isotopomer analysis, western blot analysis) derived from an MDA-MB-231 xenograft model in nude rats were used to test for correlations between the in vivo 13 C data and the ex vivo measures. The lactate-to-pyruvate ratio from HP 13 C MRI was strongly correlated with [1- 13 C ]lactate concentration measured from the extracts using NMR (R = 0.69, p 0.05), as well as negatively correlated with tumour wet weight (R = - 0.60, p 0.05). In this tumour model, both MCT1 and MCT4 expressions were positively correlated with wet weight ( ρ = 0.78 and 0.93, respectively, p 0.01). Lactate pool size and the lactate-to-pyruvate ratio were not significantly correlated.

Lactate is now recognized as an important intermediate in brain metabolism, but its role is still under investigation. In this work we mapped the distribution of lactate and bicarbonate produced from intravenously injected 13C-pyruvate over the whole brain using a new imaging method, hyperpolarized 13C MRI (N = 14, ages 23 to 77). Segmenting the 13C-lactate images into brain atlas regions revealed a pattern of lactate that was preserved across individuals. Higher lactate signal was observed in cortical grey matter compared to white matter and was highest in the precuneus, cuneus and lingual gyrus. Bicarbonate signal, indicating flux of [1–13C]pyruvate into the TCA cycle, also displayed consistent spatial distribution. One-way ANOVA to test for significant differences in lactate among atlas regions gave F = 87.6 and p

This review will highlight recent advances in hyperpolarized (13)C MR spectroscopic imaging, which can be used to noninvasively interrogate tumor metabolism. After providing an overview of MR and hyperpolarization, we will discuss the latest advances in data acquisition techniques. Next, we will shift our focus to hyperpolarized probe design and provide an overview of the latest hyperpolarized (13)C MR spectroscopic imaging probes developed in the last several years.

PURPOSE To provide built-in off-resonance correction in time-resolved, volumetric hyperpolarized 13 C metabolic imaging by implementing a novel dual-echo 3D echo-planar imaging (EPI) sequence and reconstruction. METHODS A spectral-spatial pulse for single-resonance excitation followed by a dual-echo 3D EPI readout was implemented to provide 64 × 8 × 6 cm3 coverage at 5 × 5 × 5 mm3 nominal resolution. Multiple sources of EPI distortions were encoded using a multi-echo 1 H EPI reference scan. Phase maps computed from the reference scans were combined with a bulk 13 C frequency offset encoded in the dual-echo [1-13 C]pyruvate images to correct geometric distortion and improve spatial registration. The proposed scheme was validated in a phantom study, and in vivo [1-13 C]pyruvate and [1-13 C]lactate rat images were acquired with intentional transmit frequency deviations to assess the dual-echo 3D EPI sequence. RESULTS The phantom study demonstrated improved spatial registration in off-resonance corrected images. Close agreement was observed between metabolic kidney signal and the underlying anatomy in rat imaging experiments. Relative to a single-echo acquisition, the coherent addition of the two corrected echoes provided the expected increase in signal-to-noise ratio by approximately 2. CONCLUSION A novel dual-echo 3D EPI acquisition sequence for integrated off-resonance correction in hyperpolarized 13 C imaging was developed and demonstrated. The proposed sequence offers clear advantages over flyback EPI for time-resolved metabolic mapping. Magn Reson Med 79:643-653, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Purpose To develop a novel diffusion-weighted magnetic resonance spectroscopy (DW-MRS) technique in conjunction with J-resolved spatially localized spectroscopy (JPRESS) to measure the apparent diffusion coefficients (ADCs) of brain metabolites beyond N-acetylaspartic acid (NAA), creatine (Cr), and choline (Cho) at 3T. This technique will be useful to probe tissue microstructures in vivo, as the various metabolites have different physiological characteristics. Methods Two JPRESS spectra were collected (high b-value and low b-value), and the ADCs of 16 different metabolites were estimated. Two analysis pipelines were developed: 1) a 2D pipeline that uses ProFit software to extract ADCs from metabolites not typically accessible at 3T and 2) a 1D pipeline that uses TARQUIN software to extract the metabolite concentrations from each line in the 2D dataset, allowing for scaling as well as validation. Results The ADCs of 16 different metabolites were estimated from within six subjects in parietal white matter. There was excellent agreement between the results obtained from the 1D and 2D pipelines for NAA, Cr, and Cho. Conclusion The proposed technique provided consistent estimates for the ADCs of NAA, Cr, Cho, glutamate + glutamine, and myo-inositol in all subjects and additionally glutathione and scyllo-inositol in all but one subject. Magn Reson Med, 2016. © 2016 International Society for Magnetic Resonance in Medicine.

Asymmetric in-plane k-space sampling of EPI can reduce the minimum achievable TE in hyperpolarizedFifteen healthy control subjects were imaged using a volumetric dual-echo echo-planar imaging sequence with spectral-spatial radio frequency excitation. Images were reconstructed by zero-filling as well as with the partial Fourier reconstruction algorithm projection-on-convex-sets. Resulting images were quantitatively evaluated with a no-reference image quality assessment.The no-reference image sharpness metric agreed with perceived improvements in image resolution and contrast. The [1-Partial Fourier imaging and reconstruction were shown to improve the sharpness and contrast of human HP

Lactate is now recognized as an important intermediate in brain metabolism, but its role is still under investigation. In this work we mapped the distribution of lactate and bicarbonate produced from intravenously injected

Hyperpolarized (HP)

The aim of this study was to develop a time-efficient inversion technique to measure the T1 relaxation time of the methyl group of lactate (Lac) in the presence of contaminating lipids and to measure T1 at 3 T in a cohort of primary high-grade gliomas. Three numerically optimized inversion times (TIs) were chosen to minimize the expected error in T1 estimates for a given input total scan duration (set to be 30 min). A two-cycle spectral editing scheme was used to suppress contaminating lipids. The T1 values were then estimated from least-squares fitting of signal measurements versus TI. Lac T1 was estimated as 2000 ± 280 ms. After correcting for T1 (and T2 from literature values), the mean absolute Lac concentration was estimated as 4.3 ± 2.6 mm. The technique developed agrees with the results obtained by standard inversion recovery and can be used to provide rapid T1 estimates of other spectral components as required. Lac T1 exhibits similar variations to other major metabolites observable by MRS in high-grade gliomas. The T1 estimate provided here will be useful for future MRS studies wishing to report relaxation-corrected estimates of Lac concentration as an objective tumor biomarker. Copyright © 2016 John Wiley & Sons, Ltd.

In this study, a mixture of pyruvic acid and the perfusion agent HP001 was co-polarized for simultaneous assessment of perfusion and metabolism in vivo. The pre-polarized mixture was administered to rats with subcutaneous MDA-MB-231 breast cancer xenografts and imaged using an interleaved sequence with designed spectral-spatial pulses and flyback echo-planar readouts. Voxel-by-voxel signal correlations from 10 animals (15 data sets) were analyzed for tumour, kidney, and muscle regions of interest. The relationship between perfusion and hyperpolarized signal was explored on a voxel-by-voxel basis in various metabolically active tissues, including tumour, healthy kidneys, and skeletal muscle. Positive pairwise correlations between lactate, pyruvate, and HP001 observed in all 10 tumours suggested that substrate delivery was the dominant factor limiting the conversion of pyruvate to lactate in the tumour model used in this study. On the other hand, in cases where conversion is the limiting factor, such as in healthy kidneys, both pyruvate and lactate can act as excellent perfusion markers. In intermediate cases between the two limits, such as in skeletal muscle, some perfusion information may be inferred from the (pyruvate + lactate) signal distribution. Co-administration of pyruvate with a dynamic nuclear polarization (DNP) perfusion agent is an effective approach for distinguishing between slow metabolism and poor perfusion and a practical strategy for lactate signal normalization to account for substrate delivery, especially in cases of rapid pyruvate-to-lactate conversion and in poorly perfused regions with inadequate pyruvate signal-to-noise ratio for reliable determination of the lactate-to-pyruvate ratio. Copyright © 2016 John Wiley & Sons, Ltd.

PURPOSE 1 H MRI is an established diagnostic method that generally relies on detection of water. Imaging specific macromolecules is normally accomplished only indirectly through the use of paramagnetic tags, which alter the water signal in their vicinity. We demonstrate a new approach in which macromolecular constituents, such as proteins and drug delivery systems, are observed directly and quantitatively in vivo using 1 H MRI of 13 C-labeled poly(ethylene glycol) (13 C-PEG) tags. METHODS Molecular imaging of 13 C-PEG-labeled species was accomplished by incorporating a modified heteronuclear multiple quantum coherence filter into a gradient echo imaging sequence. We demonstrate the approach by monitoring the real-time distribution of 13 C-PEG and 13 C-PEGylated albumin injected into the hind leg of a mouse. RESULTS Filtering the 1 H PEG signal through the directly coupled 13 C nuclei largely eliminates background water and fat signals, thus enabling the imaging of molecules using 1 H MRI. CONCLUSION PEGylation is widely employed to enhance the performance of a multitude of macromolecular therapeutics and drug delivery systems, and 13 C-filtered 1 H MRI of 13 C-PEG thus offers the possibility of imaging and quantitating their distribution in living systems in real time. Magn Reson Med 77:1553-1561, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

PURPOSE To enable large field-of-view, time-resolved volumetric coverage in hyperpolarized 13 C metabolic imaging by implementing a novel data acquisition and image reconstruction method based on the compressed sensing framework. METHODS A spectral-spatial pulse for single-resonance excitation followed by a symmetric echo-planar imaging (EPI) readout was implemented for encoding a 72 × 18 cm2 field of view at 5 × 5 mm2 resolution. Random undersampling was achieved with blipped z-gradients during the ramp portion of the echo-planar imaging readout. The sequence and reconstruction were tested with phantom studies and consecutive in vivo hyperpolarized 13 C scans in rats. Retrospectively and prospectively undersampled data were compared on the basis of structural similarity in the reconstructed images and the quantification of the lactate-to-pyruvate ratio in rat kidneys. RESULTS No artifacts or loss of resolution are evident in the compressed sensing reconstructed images acquired with the proposed sequence. Structural similarity analysis indicate that compressed sensing reconstructions can accurately recover spatial features in the metabolic images evaluated. CONCLUSION A novel z-blip acquisition sequence for compressed sensing accelerated hyperpolarized 13 C 3D echo-planar imaging was developed and demonstrated. The close agreement in lactate-to-pyruvate ratios from both retrospectively and prospectively undersampled data from rats shows that metabolic information is preserved with acceleration factors up to 3-fold with the developed method. Magn Reson Med 77:538-546, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Purpose Develop and test an analytic correction method to correct the signal intensity variation caused by the inhomogeneous reception profile of an eight-channel phased array for hyperpolarized 13C imaging. Theory and Methods Fiducial markers visible in anatomical images were attached to the individual coils to provide three dimensional localization of the receive hardware with respect to the image frame of reference. The coil locations and dimensions were used to numerically model the reception profile using the Biot-Savart Law. The accuracy of the coil sensitivity estimation was validated with images derived from a homogenous 13C phantom. Numerical coil sensitivity estimates were used to perform intensity correction of in vivo hyperpolarized 13C cardiac images in pigs. Results In comparison to the conventional sum-of-squares reconstruction, improved signal uniformity was observed in the corrected images. Conclusion The analytical intensity correction scheme was shown to improve the uniformity of multichannel image reconstruction in hyperpolarized [1-13C]pyruvate and 13C-bicarbonate cardiac MRI. The method is independent of the pulse sequence used for 13C data acquisition, simple to implement and does not require additional scan time, making it an attractive technique for multichannel hyperpolarized 13C MRI. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

PURPOSE To develop an accurate technique for simultaneously measuring the position and orientation of interventional devices using a projection-based spectrally selective refocusing pulse sequence. METHODS Projections along physical axes using spectrally selective excitation were acquired to track a catheter. A 9F passive tracking device capable of generating controllable susceptibility artifacts using susceptibility materials (titanium and graphite) was attached to the catheter. A library of projections for different orientations of the device with respect to the main magnetic field were simulated offline. Cross-correlations with these templates were computed to determine the orientation and position of the device. A phantom study was performed to evaluate the accuracy of the tracking technique. The tracking technique was also evaluated in vivo in the carotid artery of a pig. RESULTS Simultaneous and accurate measurement of position and orientation of the tracking device was obtained in the phantom and in vivo studies with reasonable temporal resolution. For the phantom study, the average of absolute errors in the Z-, Y-, and X-axes are 0.37, 0.76, and 0.85 mm, respectively. The mean absolute error and standard deviation of orientation measurement are 1.5 and 1.1 degrees, respectively. CONCLUSION This positioning technique, in conjunction with a controllable tracking device, can provide accurate tracking of interventional devices in MR-guided interventions. Magn Reson Med 76:1563-1573, 2016. © 2015 International Society for Magnetic Resonance in Medicine.

Previous studies have demonstrated that using hyperpolarized [2-13C]pyruvate as a contrast agent can reveal 13C signals from metabolites associated with the tricarboxylic acid (TCA) cycle. However, the metabolites detectable from TCA cycle-mediated oxidation of [2-13C]pyruvate are the result of several metabolic steps. In the instance of the [5-13C]glutamate signal, the amplitude can be modulated by changes to the rates of pyruvate dehydrogenase (PDH) flux, TCA cycle flux and metabolite pool size. Also key is the malate–aspartate shuttle, which facilitates the transport of cytosolic reducing equivalents into the mitochondria for oxidation via the malate–α-ketoglutarate transporter, a process coupled to the exchange of cytosolic malate for mitochondrial α-ketoglutarate. In this study, we investigated the mechanism driving the observed changes to hyperpolarized [2-13C]pyruvate metabolism. Using hyperpolarized [1,2-13C]pyruvate with magnetic resonance spectroscopy (MRS) in the porcine heart with different workloads, it was possible to probe 13C–glutamate labeling relative to rates of cytosolic metabolism, PDH flux and TCA cycle turnover in a single experiment non-invasively. Via the [1-13C]pyruvate label, we observed more than a five-fold increase in the cytosolic conversion of pyruvate to [1-13C]lactate and [1-13C]alanine with higher workload. 13C–Bicarbonate production by PDH was increased by a factor of 2.2. Cardiac cine imaging measured a two-fold increase in cardiac output, which is known to couple to TCA cycle turnover. Via the [2-13C]pyruvate label, we observed that 13C–acetylcarnitine production increased 2.5-fold in proportion to the 13C–bicarbonate signal, whereas the 13C–glutamate metabolic flux remained constant on adrenergic activation. Thus, the 13C–glutamate signal relative to the amount of 13C–labeled acetyl-coenzyme A (acetyl-CoA) entering the TCA cycle was decreased by 40%. The data strongly suggest that NADH (reduced form of nicotinamide adenine dinucleotide) shuttling from the cytosol to the mitochondria via the malate–aspartate shuttle is limited on adrenergic activation. Changes in [5-13C]glutamate production from [2-13C]pyruvate may play an important future role in non-invasive myocardial assessment in patients with cardiovascular diseases, but careful interpretation of the results is required.

Current cardiovascular clinical imaging techniques offer only limited assessment of innate immune cell-driven inflammation, which is a potential therapeutic target in myocardial infarction (MI) and other diseases. Hyperpolarized magnetic resonance (MR) is an emerging imaging technology that generates contrast agents with 10- to 20 000-fold improvements in MR signal, enabling cardiac metabolite mapping.To determine whether hyperpolarized MR using [1-We performed hyperpolarized [1-Hyperpolarized MR using [1

The PRESS technique has been widely used to achieve voxel localization for in vivo(1)H MRS acquisitions. However, for dynamic hyperpolarized (13)C MRS experiments, the transition bands of the refocusing pulses may saturate the pre-polarized substrate spins flowing into the voxel. This limitation may be overcome by designing refocusing pulses that do not perturb the resonance of the hyperpolarized substrate, but selectively refocuses the spins of the metabolic products. In this study, a PRESS pulse sequence incorporating spectral-spatial refocusing pulses that have a stop band ('notch') at the substrate resonance is tested in vivo using hyperpolarized [1-(13)C]pyruvate. Higher metabolite SNR was observed in experiments using the spectral-spatial refocusing pulses as compared to conventional refocusing pulses.

Previous studies have demonstrated that using hyperpolarized [2

Purpose Hyperpolarized [1-13C]lactate in solution may be a clinically relevant and safe substrate for real time MR investigations of key metabolic pathways. The potential of using hyperpolarized [1-13C]lactate for magnetic resonance studies of cardiac metabolism in vivo was explored. Methods Neat [1-13C]lactic acid was hyperpolarized using the dynamic nuclear polarization process. Cardiac MR spectroscopy experiments were performed in vivo using hyperpolarized [1-13C]lactate and [1-13C]pyruvate in solutions. Results A high degree of polarization was achieved for [1-13C]lactate in solution (16.7%). 13C-bicarbonate was observed in rat hearts in vivo after either hyperpolarized [1-13C]lactate or hyperpolarized [1-13C]pyruvate was infused, but lower 13C-bicarbonate to substrate ratio was observed with hyperpolarized [1-13C]lactate infusions. The response of 13C-bicarbonate signal as a function of hyperpolarized [1-13C]lactate doses was also investigated and a saturation of 13C-bicarbonate signal was observed at the highest dose of [1-13C]lactate used (0.69 mmol/kg). Conclusion This study demonstrated that the use of neat [1-13C]lactic acid as the DNP sample is a potential alternative to [1-13C]pyruvic acid for cardiac hyperpolarized 13C MR studies. Hyperpolarized [1-13C]lactate may enable noninvasive assessment of cardiac PDH flux in cardiac patients in the near future. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc. Magn Reson Med 73:2087–2093, 2015. © 2014 Wiley Periodicals, Inc.

Blip-reversed echo-planar imaging (EPI) is investigated as a method for measuring and correcting the spatial shifts that occur due to bulk frequency offsets in 13C metabolic imaging in vivo. By reversing the k-space trajectory for every other time point, the direction of the spatial shift for a given frequency is reversed. Here, mutual information is used to find the ‘best’ alignment between images and thereby measure the frequency offset. Time-resolved 3D images of pyruvate/lactate/urea were acquired with 5 s temporal resolution over a 1 min duration in rats (N = 6). For each rat, a second injection was performed with the demodulation frequency purposely mis-set by +35 Hz, to test the correction for erroneous shifts in the images. Overall, the shift induced by the 35 Hz frequency offset was 5.9 ± 0.6 mm (mean ± standard deviation). This agrees well with the expected 5.7 mm shift based on the 2.02 ms delay between k-space lines (giving 30.9 Hz per pixel). The 0.6 mm standard deviation in the correction corresponds to a frequency-detection accuracy of 4 Hz. A method was presented for ensuring the spatial registration between 13C metabolic images and conventional anatomical images when long echo-planar readouts are used. The frequency correction method was shown to have an accuracy of 4 Hz. Summing the spatially corrected frames gave a signal-to-noise ratio (SNR) improvement factor of 2 or greater, compared with the highest single frame. Copyright © 2013 John Wiley & Sons, Ltd.

Purpose A proof-of-concept study was performed to assess the technical feasibility of using magnetic materials to generate spatial encoding fields. Theory and Methods Spatially varying magnetic fields were generated by the placement of markers with different volume susceptibilities within the imaging volume. No linear gradients were used for spatial encoding during the signal acquisition. A signal-encoding model is described for reconstructing the images encoded with these field perturbations. Simulation and proof-of-concept experimental results are presented. Experiments were performed using field perturbations from a cylindrical marker as an example of the new encoding fields. Based on this experimental setup, annular rings were reconstructed from signals encoded with the new fields. Results Simulation results were presented for different acquisition parameters. Proof-of-concept was supported by the correspondence of regions in an image reconstructed from experimental data compared to those in a conventional gradient-echo image. Experimental results showed that inclusions of dimensions 1.5 mm in size could be resolved with the experimental setup. Conclusion This study shows the technical feasibility of using magnetic markers to produce encoding fields. Magnetic materials will allow generating spatial encoding fields, which can be tailored to an imaging application with less complexity and at lower cost compared to the use of gradient inserts. Magn Reson Med 72:399–408, 2014. © 2013 Wiley Periodicals, Inc.

Purpose To design and demonstrate a new susceptibility-based tracking device with an artifact that can be mechanically turned on and off, thus permitting tracking and imaging at the device tip with limited artifact. Methods The magnetic susceptibilities of readily obtainable grades of titanium and graphite were measured. Using numerical optimization, layer thicknesses for three concentric cylinders were found where the field from the graphite layer maximally cancelled the fields from titanium layers. The tracking elements were fabricated for an outer diameter of 3 mm and attached to a catheter to show feasibility of detection in phantoms and in vivo. Results The device was successfully integrated into a 9F catheter, and its use with conventional guidewires under fluoroscopy was demonstrated by guiding the catheter through the bifurcation into the carotid artery. MR images including the catheter tip were acquired with the device in both the “on” and “off” positions. Conclusion A new passive tracking device with a susceptibility effect that can be enabled and disabled by sliding one of the components was designed, fabricated, and demonstrated in phantoms and in vivo. The device may also be integrated into many different interventional MR devices such as needles, ultrasound transducers for prostate biopsy, or any catheter-based devices. Magn Reson Med 72:269–275, 2014. © 2013 Wiley Periodicals, Inc.

Purpose To demonstrate the capability of incorporating independent shims into a dual-band spectral-spatial excitation and to compare fat suppression between standard global shims and independent shims for in vivo bilateral breast imaging at 1.5T. Methods A dual-band spectral-spatial excitation pulse was designed by interleaving two flyback spectral-spatial pulses, playing one during positive gradient lobes and the other during negative gradient lobes. Each slab was enabled to have an independent spatial offset, spectral offset, and slab-phase modulation by modulating radiofrequency phase, and independent linear shims were incorporated by playing extra shim gradients. Phantom experiments were performed to demonstrate the functionality of the pulse, and in vivo experiments were performed for 10 healthy volunteers to compare fat suppression between standard shims and independent shims. Results The phantom experiments confirmed that the dual-band pulse can provide independent spectral and spatial offsets and linear shims to the two slabs. Independent shims provided qualitatively more homogeneous fat suppression than standard shims in seven out of 10 subjects, with equivalent fat suppression in two of the other three subjects. Conclusion Incorporating independent shims into the dual-band spectral-spatial excitation can provide homogeneous fat suppression in bilateral breast imaging. Magn Reson Med 71:1511–1517, 2014. © 2013 Wiley Periodicals, Inc.

Noninvasive identification and assessment of functional brown adipose tissue in rodents using hyperpolarized 13 C imaging

A calibration-based technique for real-time measurement of pyruvate polarization by partial integral analysis of the doublet from the neighbouring J-coupled carbon is presented. In vitro calibration data relating the C2 and C1 asymmetries to the instantaneous C1 and C2 polarizations, respectively, were acquired in blood. The feasibility of using the in vitro calibration data to determine the instantaneous in vivo C1 and C2 polarizations was demonstrated in the analysis of rat kidney and pig heart spectral data. An approach for incorporating this technique into in vivo protocols is proposed. Copyright © 2013 John Wiley & Sons, Ltd.

To provide built-in off-resonance correction in time-resolved, volumetric hyperpolarizedA spectral-spatial pulse for single-resonance excitation followed by a dual-echo 3D EPI readout was implemented to provide 64 × 8 × 6 cmThe phantom study demonstrated improved spatial registration in off-resonance corrected images. Close agreement was observed between metabolic kidney signal and the underlying anatomy in rat imaging experiments. Relative to a single-echo acquisition, the coherent addition of the two corrected echoes provided the expected increase in signal-to-noise ratio by approximately 2.A novel dual-echo 3D EPI acquisition sequence for integrated off-resonance correction in hyperpolarized

Rationale: Altered cardiac energetics is known to play an important role in the progression toward heart failure. A noninvasive method for imaging metabolic markers that could be used in longitudinal studies would be useful for understanding therapeutic approaches that target metabolism. Objective: To demonstrate the first hyperpolarized 13 C metabolic magnetic resonance imaging of the human heart. Methods and Results: Four healthy subjects underwent conventional proton cardiac magnetic resonance imaging followed by 13 C imaging and spectroscopic acquisition immediately after intravenous administration of a 0.1 mmol/kg dose of hyperpolarized [1- 13 C]pyruvate. All subjects tolerated the procedure well with no adverse effects reported ≤1 month post procedure. The [1- 13 C]pyruvate signal appeared within the chambers but not within the muscle. Imaging of the downstream metabolites showed 13 C-bicarbonate signal mainly confined to the left ventricular myocardium, whereas the [1- 13 C]lactate signal appeared both within the chambers and in the myocardium. The mean 13 C image signal:noise ratio was 115 for [1- 13 C]pyruvate, 56 for 13 C-bicarbonate, and 53 for [1- 13 C]lactate. Conclusions: These results represent the first 13 C images of the human heart. The appearance of 13 C-bicarbonate signal after administration of hyperpolarized [1- 13 C]pyruvate was readily detected in this healthy cohort (n=4). This shows that assessment of pyruvate metabolism in vivo in humans is feasible using current technology. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02648009.

[1-(13)C] pyruvate pre-polarized via DNP has been used in animal models to probe changes in metabolic enzyme activities in vivo. To more accurately assess the metabolic state and its change from disease progression or therapy in a specific region or tissue in vivo, it may be desirable to separate the downstream (13)C metabolite signals resulting from the metabolic activity within the tissue of interest and those brought into the tissue by perfusion. In this study, a spectral-spatial saturation pulse that selectively saturates the signal from the metabolic products [1-(13)C] lactate and [1-(13)C] alanine was designed and implemented as outer volume suppression for localized MRSI acquisition. Preliminary in vivo results showed that the suppression pulse did not prevent the pre-polarized pyruvate from being delivered throughout the animal while it saturated the metabolites within the targeted saturation region.

Hyperpolarization of spins via dynamic nuclear polarization (DNP) has been explored as a method to non-invasively study real-time metabolic rocesses occurring in vivo using 13C-labeled substrates. Recently, hyperpolarized 13C pyruvate has been used to characterize in vivo cardiac metabolism in the rat and pig. Conventional 3D spectroscopic imaging methods require in excess of 100 excitations, making it challenging to acquire a full cardiac-gated, breath-held, whole-heart volume. In this article, the development of a rapid multislice cardiac-gated spiral 13C imaging pulse sequence consisting of a large flip-angle spectral-spatial excitation RF pulse combined with a single-shot spiral k-space trajectory for rapid imaging of cardiac metabolism is described. This sequence permits whole-heart coverage (6 slices, 8.8-mm in-plane resolution) in any plane, allowing imaging of the metabolites of interest, [1- 13C] pyruvate, [1- 13C] lactate, and 13C bicarbonate, within a single breathhold. Pyruvate and bicarbonate cardiac volumes were acquired, while lactate images were not acquired due to low lactate levels in the animal model studied. The sequence was demonstrated with phantom experiments and in vivo testing in a pig model. Magn Reson Med, 2010. © 2010 Wiley-Liss, Inc.

To develop a novel diffusion-weighted magnetic resonance spectroscopy (DW-MRS) technique in conjunction with J-resolved spatially localized spectroscopy (JPRESS) to measure the apparent diffusion coefficients (ADCs) of brain metabolites beyond N-acetylaspartic acid (NAA), creatine (Cr), and choline (Cho) at 3T. This technique will be useful to probe tissue microstructures in vivo, as the various metabolites have different physiological characteristics.Two JPRESS spectra were collected (high b-value and low b-value), and the ADCs of 16 different metabolites were estimated. Two analysis pipelines were developed: 1) a 2D pipeline that uses ProFit software to extract ADCs from metabolites not typically accessible at 3T and 2) a 1D pipeline that uses TARQUIN software to extract the metabolite concentrations from each line in the 2D dataset, allowing for scaling as well as validation.The ADCs of 16 different metabolites were estimated from within six subjects in parietal white matter. There was excellent agreement between the results obtained from the 1D and 2D pipelines for NAA, Cr, and Cho.The proposed technique provided consistent estimates for the ADCs of NAA, Cr, Cho, glutamate + glutamine, and myo-inositol in all subjects and additionally glutathione and scyllo-inositol in all but one subject. Magn Reson Med 78:1235-1245, 2017. © 2016 International Society for Magnetic Resonance in Medicine.