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Based on the expanding set of applications for hyperpolarized carbon-13 (HP-13 C) MRI, this work aims to communicate standardized methodology implemented at the University of California, San Francisco, as a primer for conducting reproducible metabolic imaging studies of the prostate and brain. Current state-of-the-art HP-13 C acquisition, data processing/reconstruction and kinetic modeling approaches utilized in patient studies are presented together with the rationale underpinning their usage. Organized around spectroscopic and imaging-based methods, this guide provides an extensible framework for handling a variety of HP-13 C applications, which derives from two examples with dynamic acquisitions: 3D echo-planar spectroscopic imaging of the human prostate and frequency-specific 2D multislice echo-planar imaging of the human brain. Details of sequence-specific parameters and processing techniques contained in these examples should enable investigators to effectively tailor studies around individual-use cases. Given the importance of clinical integration in improving the utility of HP exams, practical aspects of standardizing data formats for reconstruction, analysis and visualization are also addressed alongside open-source software packages that enhance institutional interoperability and validation of methodology. To facilitate the adoption and further development of this methodology, example datasets and analysis pipelines have been made available in the supporting information.

Hyperpolarized 13 C MRI takes advantage of the unprecedented 50 000-fold signal-to-noise ratio enhancement to interrogate cancer metabolism in patients and animals. It can measure the pyruvate-to-lactate conversion rate, kPL , a metabolic biomarker of cancer aggressiveness and progression. Therefore, it is crucial to evaluate kPL reliably. In this study, three sequence components and parameters that modulate kPL estimation were identified and investigated in model simulations and through in vivo animal studies using several specifically designed pulse sequences. These factors included a magnetization spoiling effect due to RF pulses, a crusher gradient-induced flow suppression, and intrinsic image weightings due to relaxation. Simulation showed that the RF-induced magnetization spoiling can be substantially improved using an inputless kPL fitting. In vivo studies found a significantly higher apparent kPL with an additional gradient that leads to flow suppression (kPL,FID-Delay,Crush /kPL,FID-Delay  = 1.37 ± 0.33, P

MRI using hyperpolarized (HP) carbon-13 pyruvate is being investigated in clinical trials to provide non-invasive measurements of metabolism for cancer and cardiac imaging. In this project, we applied HP [1-13 C]pyruvate dynamic MRI in prostate cancer to measure the conversion from pyruvate to lactate, which is expected to increase in aggressive cancers. The goal of this work was to develop and test analysis methods for improved quantification of this metabolic conversion. In this work, we compared specialized kinetic modeling methods to estimate the pyruvate-to-lactate conversion rate, kPL , as well as the lactate-to-pyruvate area-under-curve (AUC) ratio. The kinetic modeling included an "inputless" method requiring no assumptions regarding the input function, as well as a method incorporating bolus characteristics in the fitting. These were first evaluated with simulated data designed to match human prostate data, where we examined the expected sensitivity of metabolism quantification to variations in kPL , signal-to-noise ratio (SNR), bolus characteristics, relaxation rates, and B1 variability. They were then applied to 17 prostate cancer patient datasets. The simulations indicated that the inputless method with fixed relaxation rates provided high expected accuracy with no sensitivity to bolus characteristics. The AUC ratio showed an undesired strong sensitivity to bolus variations. Fitting the input function as well did not improve accuracy over the inputless method. In vivo results showed qualitatively accurate kPL maps with inputless fitting. The AUC ratio was sensitive to bolus delivery variations. Fitting with the input function showed high variability in parameter maps. Overall, we found the inputless kPL fitting method to be a simple, robust approach for quantification of metabolic conversion following HP [1-13 C]pyruvate injection in human prostate cancer studies. This study also provided initial ranges of HP [1-13 C]pyruvate parameters (SNR, kPL , bolus characteristics) in the human prostate.

Introduction: The healthy heart has remarkable metabolic flexibility that permits rapid switching between mitochondrial glucose oxidation and fatty acid oxidation to generate ATP. Loss of metabolic flexibility has been implicated in the genesis of contractile dysfunction seen in cardiomyopathy. Metabolic flexibility has been imaged in experimental models, using hyperpolarized (HP) [2‐13C]pyruvate MRI, which enables interrogation of metabolites that reflect tricarboxylic acid (TCA) cycle flux in cardiac myocytes. This study aimed to develop methods, demonstrate feasibility for [2‐13C]pyruvate MRI in the human heart for the first time, and assess cardiac metabolic flexibility. Methods: Good manufacturing practice [2‐13C]pyruvic acid was polarized in a 5 T polarizer for 2.5–3 h. Following dissolution, quality control parameters of HP pyruvate met all safety and sterility criteria for pharmacy release, prior to administration to study subjects. Three healthy subjects each received two HP injections and MR scans, first under fasting conditions, followed by oral glucose load. A 5 cm axial slab‐selective spectroscopy approach was prescribed over the left ventricle and acquired at 3 s intervals on a 3 T clinical MRI scanner. Results: The study protocol, which included HP substrate injection, MR scanning, and oral glucose load, was performed safely without adverse events. Key downstream metabolites of [2‐13C]pyruvate metabolism in cardiac myocytes include the glycolytic derivative [2‐13C]lactate, TCA‐associated metabolite [5‐13C]glutamate, and [1‐13C]acetylcarnitine, catalyzed by carnitine acetyltransferase (CAT). After glucose load, 13C‐labeling of lactate, glutamate, and acetylcarnitine from 13C‐pyruvate increased by an average of 39.3%, 29.5%, and 114% respectively in the three subjects, which could result from increases in lactate dehydrogenase, pyruvate dehydrogenase, and CAT enzyme activity as well as TCA cycle flux (glucose oxidation). Conclusions: HP [2‐13C]pyruvate imaging is safe and permits noninvasive assessment of TCA cycle intermediates and the acetyl buffer, acetylcarnitine, which is not possible using HP [1‐13C]pyruvate. Cardiac metabolite measurement in the fasting/fed states provides information on cardiac metabolic flexibility and the acetylcarnitine pool. [ABSTRACT FROM AUTHOR]

Abstract Based on the expanding set of applications for hyperpolarized carbon‐13 (HP‐13C) MRI, this work aims to communicate standardized methodology implemented at the University of California, San Francisco, as a primer for conducting reproducible metabolic imaging studies of the prostate and brain. Current state‐of‐the‐art HP‐13C acquisition, data processing/reconstruction and kinetic modeling approaches utilized in patient studies are presented together with the rationale underpinning their usage. Organized around spectroscopic and imaging‐based methods, this guide provides an extensible framework for handling a variety of HP‐13C applications, which derives from two examples with dynamic acquisitions: 3D echo‐planar spectroscopic imaging of the human prostate and frequency‐specific 2D multislice echo‐planar imaging of the human brain. Details of sequence‐specific parameters and processing techniques contained in these examples should enable investigators to effectively tailor studies around individual‐use cases. Given the importance of clinical integration in improving the utility of HP exams, practical aspects of standardizing data formats for reconstruction, analysis and visualization are also addressed alongside open‐source software packages that enhance institutional interoperability and validation of methodology. To facilitate the adoption and further development of this methodology, example datasets and analysis pipelines have been made available in the supporting information. [ABSTRACT FROM AUTHOR]

Hyperpolarized 13C MRI takes advantage of the unprecedented 50 000‐fold signal‐to‐noise ratio enhancement to interrogate cancer metabolism in patients and animals. It can measure the pyruvate‐to‐lactate conversion rate, kPL, a metabolic biomarker of cancer aggressiveness and progression. Therefore, it is crucial to evaluate kPL reliably. In this study, three sequence components and parameters that modulate kPL estimation were identified and investigated in model simulations and through in vivo animal studies using several specifically designed pulse sequences. These factors included a magnetization spoiling effect due to RF pulses, a crusher gradient‐induced flow suppression, and intrinsic image weightings due to relaxation. Simulation showed that the RF‐induced magnetization spoiling can be substantially improved using an inputless kPL fitting. In vivo studies found a significantly higher apparent kPL with an additional gradient that leads to flow suppression (kPL,FID‐Delay,Crush/kPL,FID‐Delay = 1.37 ± 0.33, P < 0.01, N = 6), which agrees with simulation outcomes (12.5% kPL error with Δv = 40 cm/s), indicating that the gradients predominantly suppressed flowing pyruvate spins. Significantly lower kPL was found using a delayed free induction decay (FID) acquisition versus a minimum‐TE version (kPL,FID‐Delay/kPL,FID = 0.67 ± 0.09, P < 0.01, N = 5), and the lactate peak had broader linewidth than pyruvate (Δωlactate/Δωpyruvate = 1.32 ± 0.07, P < 0.000 01, N = 13). This illustrated that lactate's T2*, shorter than that of pyruvate, can affect calculated kPL values. We also found that an FID sequence yielded significantly lower kPL versus a double spin‐echo sequence that includes spin‐echo spoiling, flow suppression from crusher gradients, and more T2 weighting (kPL,DSE/kPL,FID = 2.40 ± 0.98, P < 0.0001, N = 7). In summary, the pulse sequence, as well as its interaction with pharmacokinetics and the tissue microenvironment, can impact and be optimized for the measurement of kPL. The data acquisition and analysis pipelines can work synergistically to provide more robust and reproducible kPL measures for future preclinical and clinical studies. This study investigated three pulse sequence components and parameters that can affect estimates of kPL in HP‐13C MRI. In vivo animal tumor studies showed significant impact on kPL with crusher‐gradient induced flow suppression, and intrinsic image weighting due to relaxation, corroborated by signal‐model simulations. RF‐induced magnetization spoiling can be substantially improved using an inputless kPL fitting. These outcomes suggested that the pulse sequence, as well as its interaction with pharmacokinetics and tissue microenvironment, can impact the measurement of kPL. [ABSTRACT FROM AUTHOR]

Introduction: The healthy heart has remarkable metabolic flexibility that permits rapid switching between mitochondrial glucose oxidation and fatty acid oxidation to generate ATP. Loss of metabolic flexibility has been implicated in the genesis of contractile dysfunction seen in cardiomyopathy. Metabolic flexibility has been imaged in experimental models, using hyperpolarized (HP) [2- 13 C]pyruvate MRI, which enables interrogation of metabolites that reflect tricarboxylic acid (TCA) cycle flux in cardiac myocytes. This study aimed to develop methods, demonstrate feasibility for [2- 13 C]pyruvate MRI in the human heart for the first time, and assess cardiac metabolic flexibility., Methods: Good manufacturing practice [2- 13 C]pyruvic acid was polarized in a 5 T polarizer for 2.5-3 h. Following dissolution, quality control parameters of HP pyruvate met all safety and sterility criteria for pharmacy release, prior to administration to study subjects. Three healthy subjects each received two HP injections and MR scans, first under fasting conditions, followed by oral glucose load. A 5 cm axial slab-selective spectroscopy approach was prescribed over the left ventricle and acquired at 3 s intervals on a 3 T clinical MRI scanner., Results: The study protocol, which included HP substrate injection, MR scanning, and oral glucose load, was performed safely without adverse events. Key downstream metabolites of [2- 13 C]pyruvate metabolism in cardiac myocytes include the glycolytic derivative [2- 13 C]lactate, TCA-associated metabolite [5- 13 C]glutamate, and [1- 13 C]acetylcarnitine, catalyzed by carnitine acetyltransferase (CAT). After glucose load, 13 C-labeling of lactate, glutamate, and acetylcarnitine from 13 C-pyruvate increased by an average of 39.3%, 29.5%, and 114% respectively in the three subjects, which could result from increases in lactate dehydrogenase, pyruvate dehydrogenase, and CAT enzyme activity as well as TCA cycle flux (glucose oxidation)., Conclusions: HP [2- 13 C]pyruvate imaging is safe and permits noninvasive assessment of TCA cycle intermediates and the acetyl buffer, acetylcarnitine, which is not possible using HP [1- 13 C]pyruvate. Cardiac metabolite measurement in the fasting/fed states provides information on cardiac metabolic flexibility and the acetylcarnitine pool., (© 2023 John Wiley & Sons, Ltd.)

Based on the expanding set of applications for hyperpolarized carbon-13 (HP- 13 C) MRI, this work aims to communicate standardized methodology implemented at the University of California, San Francisco, as a primer for conducting reproducible metabolic imaging studies of the prostate and brain. Current state-of-the-art HP- 13 C acquisition, data processing/reconstruction and kinetic modeling approaches utilized in patient studies are presented together with the rationale underpinning their usage. Organized around spectroscopic and imaging-based methods, this guide provides an extensible framework for handling a variety of HP- 13 C applications, which derives from two examples with dynamic acquisitions: 3D echo-planar spectroscopic imaging of the human prostate and frequency-specific 2D multislice echo-planar imaging of the human brain. Details of sequence-specific parameters and processing techniques contained in these examples should enable investigators to effectively tailor studies around individual-use cases. Given the importance of clinical integration in improving the utility of HP exams, practical aspects of standardizing data formats for reconstruction, analysis and visualization are also addressed alongside open-source software packages that enhance institutional interoperability and validation of methodology. To facilitate the adoption and further development of this methodology, example datasets and analysis pipelines have been made available in the supporting information., (© 2020 John Wiley & Sons, Ltd.)