Magnetic resonance imaging of hyperpolarized (HP) [1-13C]pyruvate allows in-vivo assessment of metabolism and has translated into human studies across diseases at 15 centers worldwide. Consensus on best practice for multi-center studies is required to develop clinical applications. This paper presents the results of a 2-round formal consensus building exercise carried out by experts with HP [1-13C]pyruvate human study experience. Twenty-nine participants from 13 sites brought together expertise in pharmacy methods, MR physics, translational imaging, and data-analysis; with the goal of providing recommendations and best practice statements on conduct of multi-center human studies of HP [1-13C]pyruvate MRI. Overall, the group reached consensus on approximately two-thirds of 246 statements in the questionnaire, covering 'HP 13C-Pyruvate Preparation', 'MRI System Setup, Calibration, and Phantoms', 'Acquisition and Reconstruction', and 'Data Analysis and Quantification'. Consensus was present across categories, examples include that: (i) different HP pyruvate preparation methods could be used in human studies, but that the same release criteria have to be followed; (ii) site qualification and quality assurance must be performed with phantoms and that the same field strength must be used, but that the rest of the system setup and calibration methods could be determined by individual sites; (iii) the same pulse sequence and reconstruction methods were preferable, but the exact choice should be governed by the anatomical target; (iv) normalized metabolite area-under-curve (AUC) values and metabolite AUC were the preferred metabolism metrics. The work confirmed areas of consensus for multi-center study conduct and identified where further research is required to ascertain best practice.

Magnetic resonance imaging (MRI) of hyperpolarized (HP) [1-13C]pyruvate is a promising method for measuring cerebral energy metabolism in vivo. The substantial increase in signal provided by HP makes it possible to dynamically monitor the conversion of [1-13C]pyruvate to [1-13C]lactate and [13C]bicarbonate. The HP [1-13C]lactate signal is commonly associated with glycolic activity, whereas [13C]bicarbonate, a by-product of the reaction that forms acetyl-CoA, is linked to oxidative metabolism. However, there is compelling evidence that other factors, such as the concentration of monocarboxylate transporters, influence the production of HP [1-13C]lactate. To clarify the processes responsible for producing the topography of HP [1-13C]pyruvate and its metabolites, we spatially correlated group-average HP 13C MRI images with [18F]FDG, [15O]H2O, [15O]O2, and [15O]CO positron emission topography (PET) images from a separate group of 35 age- and sex-matched adults. We found that [1-13C]pyruvate correlated best with cerebral blood volume (CBV), whereas [1-13C]lactate and [13C]bicarbonate were most strongly associated with cerebral blood flow (CBF), glucose consumption (CMRglc), and oxygen metabolism (CMRO2). Neither [1-13C]lactate nor [13C]bicarbonate was correlated with non-oxidative glucose consumption, also known as aerobic glycolysis. These results are consistent with the view that in the healthy brain, the production of [1-13C]lactate reflects overall energy metabolism rather than being specific to glycolysis.

Background:Brain metastases (BM) are increasingly treated with stereotactic radiosurgery (SRS); however, up to 30% of BM recur locally. This work investigated whether hyperpolarized (HP) [1-13C]-pyruvate MRI can be used to predict SRS treatment response in patients with BM. Methods:Eighteen patients with 44 BM were imaged with HP [1-13C]-pyruvate MRI prior to SRS. Treatment response was determined using the Response Assessment in Neuro-Oncology BM (RANO-BM) working group guidelines at 6-month follow-up. Fourteen parameters, including lesion [1-13C]-lactate to [13C]-bicarbonate, [1-13C]-lactate to [1-13C]-pyruvate and [13C]-bicarbonate to [1-13C]-pyruvate signal ratios, in addition to prognostic and dosimetric parameters, were analyzed using univariable and multivariable analysis. Results:Univariable analysis identified lesion [1-13C]-lactate to [13C]-bicarbonate ratio (P = .0003), lesion [13C]-bicarbonate to [1-13C]-pyruvate ratio (P = .0118), lesion volume (P = .0264), and the number of involved organs with metastases including the brain (P = .0448) as significant predictors of treatment response. The lesion [1-13C]-lactate to [13C]-bicarbonate ratio was predictive of response with the best overall performance, achieving an AUCROC = 0.88, AUCPRC = 0.83, sensitivity = 67% (CI: 40%-87%), specificity = 97% (CI: 90%-100%), and positive predictive value (PPV) = 91% (CI: 73%-100%). Conclusions:HP lesion [1-13C]-lactate to [13C]-bicarbonate ratio can predict SRS response with a high PPV.

Hyperpolarized- 13 C magnetic resonance imaging (HP- 13 C MRI) was used to image changes in 13 C-lactate signal during a visual stimulus condition in comparison to an eyes-closed control condition. Whole-brain 13 C-pyruvate, 13 C-lactate and 13 C-bicarbonate production was imaged in healthy volunteers (N=6, ages 24-33) for the two conditions using two separate hyperpolarized 13 C-pyruvate injections. BOLD-fMRI scans were used to delineate regions of functional activation. 13 C-metabolite signal was normalized by 13 C-metabolite signal from the brainstem and the percentage change in 13 C-metabolite signal conditions was calculated. A one-way Wilcoxon signed-rank test showed a significant increase in 13 C-lactate in regions of activation when compared to the remainder of the brain ( p = 0.02, V = 21). No significant increase was observed in 13 C-pyruvate ( p = 0.11, V = 17) or 13 C-bicarbonate ( p = 0.95, V = 3) signal. The results show an increase in 13 C-lactate production in the activated region that is measurable with HP- 13 C MRI.

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MRI with hyperpolarized (HP) 13C agents, also known as HP 13C MRI, can measure processes such as localized metabolism that is altered in numerous cancers, liver, heart, kidney diseases, and more. It has been translated into human studies during the past 10 years, with recent rapid growth in studies largely based on increasing availability of hyperpolarized agent preparation methods suitable for use in humans. This paper aims to capture the current successful practices for HP MRI human studies with [1-13C]pyruvate - by far the most commonly used agent, which sits at a key metabolic junction in glycolysis. The paper is divided into four major topic areas: (1) HP 13C-pyruvate preparation, (2) MRI system setup and calibrations, (3) data acquisition and image reconstruction, and (4) data analysis and quantification. In each area, we identified the key components for a successful study, summarized both published studies and current practices, and discuss evidence gaps, strengths, and limitations. This paper is the output of the HP 13C MRI Consensus Group as well as the ISMRM Hyperpolarized Media MR and Hyperpolarized Methods Equipment study groups. It further aims to provide a comprehensive reference for future consensus building as the field continues to advance human studies with this metabolic imaging modality.

PURPOSE:To investigate the safety and value of hyperpolarized (HP) MRI of [1-13C]pyruvate in healthy volunteers using deuterium oxide (D2O) as a solvent. METHODS:Healthy volunteers (n = 5), were injected with HP [1-13C]pyruvate dissolved in D2O and imaged with a metabolite-specific 3D dual-echo dynamic EPI sequence at 3T at one site (Site 1). Volunteers were monitored following the procedure to assess safety. Image characteristics, including SNR, were compared to data acquired in a separate cohort using water as a solvent (n = 5) at another site (Site 2). The apparent spin-lattice relaxation time (T1) of [1-13C]pyruvate was determined both in vitro and in vivo from a mono-exponential fit to the image intensity at each time point of our dynamic data. RESULTS:All volunteers completed the study safely and reported no adverse effects. The use of D2O increased the T1 of [1-13C]pyruvate from 66.5 ± 1.6 s to 92.1 ± 5.1 s in vitro, which resulted in an increase in signal by a factor of 1.46 ± 0.03 at the time of injection (90 s after dissolution). The use of D2O also increased the apparent relaxation time of [1-13C]pyruvate by a factor of 1.4 ± 0.2 in vivo. After adjusting for inter-site SNR differences, the use of D2O was shown to increase image SNR by a factor of 2.6 ± 0.2 in humans. CONCLUSIONS:HP [1-13C]pyruvate in D2O is safe for human imaging and provides an increase in T1 and SNR that may improve image quality.

PURPOSE:To test the hypothesis that lactate oxidation contributes to the   13 $$ {}^{13} $$ C-bicarbonate signal observed in the awake human brain using hyperpolarized   13 $$ {}^{13} $$ C MRI. METHODS:Healthy human volunteers (N = 6) were scanned twice using hyperpolarized   13 $$ {}^{13} $$ C-MRI, with increased radiofrequency saturation of   13 $$ {}^{13} $$ C-lactate on one set of scans.   13 $$ {}^{13} $$ C-lactate,   13 $$ {}^{13} $$ C-bicarbonate, and   13 $$ {}^{13} $$ C-pyruvate signals for 132 brain regions across each set of scans were compared using a clustered Wilcoxon signed-rank test. RESULTS:Increased   13 $$ {}^{13} $$ C-lactate radiofrequency saturation resulted in a significantly lower   13 $$ {}^{13} $$ C-bicarbonate signal (p = 0.04). These changes were observed across the majority of brain regions. CONCLUSION:Radiofrequency saturation of   13 $$ {}^{13} $$ C-lactate leads to a decrease in   13 $$ {}^{13} $$ C-bicarbonate signal, demonstrating that the   13 $$ {}^{13} $$ C-lactate generated from the injected   13 $$ {}^{13} $$ C-pyruvate is being converted back to   13 $$ {}^{13} $$ C-pyruvate and oxidized throughout the human brain.

Purpose: To test the hypothesis that lactate oxidation contributes to the (13)13 C-bicarbonate signal observed in the awake human brain using hyperpolarized (13)13 C MRI.Methods: Healthy human volunteers (N = 6) were scanned twice using hyperpolarized (13)13 C-MRI, with increased radiofrequency saturation of (13)13 C-lactate on one set of scans. (13)13 C-lactate, (13)13 C-bicarbonate, and (13)13 C-pyruvate signals for 132 brain regions across each set of scans were compared using a clustered Wilcoxon signed-rank test.Results: Increased (13)13 C-lactate radiofrequency saturation resulted in a significantly lower (13)13 C-bicarbonate signal (p = 0.04). These changes were observed across the majority of brain regions.Conclusion: Radiofrequency saturation of (13)13 C-lactate leads to a decrease in (13)13 C-bicarbonate signal, demonstrating that the (13)13 C-lactate generated from the injected (13)13 C-pyruvate is being converted back to (13)13 C-pyruvate and oxidized throughout the human brain.

PurposeTo develop a novel particle-based in silico MR model and demonstrate applications of this model to signal mechanisms which are affected by the spatial organization of particles, including metabolic reaction kinetics, microstructural effects on diffusion, and radiofrequency (RF) refocusing effects in gradient-echo sequences.MethodsThe model was developed by integrating a forward solution of the Bloch equations with a Brownian dynamics simulator. Simulation configurations were then designed to model MR signal dynamics of interest, with a primary focus on hyperpolarized 13C MRI methods. Phantom scans and spectrophotometric assays were conducted to validate model results in vitro.ResultsThe model accurately reproduced the reaction kinetics of enzyme-mediated conversion of pyruvate to lactate. When varying proportions of restrictive structure were added to the reaction volume, nonlinear changes in the reaction rate measured in vitro were replicated in silico. Modeling of RF refocusing effects characterized the degree of diffusion-weighted contribution from preserved residual magnetization in nonspoiled gradient-echo sequences.ConclusionsThese results show accurate reproduction of a range of MR signal mechanisms, establishing the model's capability to investigate the multifactorial signal dynamics such as those underlying hyperpolarized 13C MRI data.

Purpose To test the hypothesis that lactate shuttling contributes to the 13 C-lactate and 13 C-bicarbonate signal observed in the awake human brain using hyperpolarized 13 C MRI. Methods Healthy human volunteers (n = 6) were scanned twice using hyperpolarized 13 C-MRI, with reduced radiofrequency saturation of 13 C-lactate on one set of scans. 13 C-lactate, 13 C-bicarbonate, and 13 C-pyruvate signals for 132 brain regions across each set of scans were compared using a clustered Wilcoxon sum rank test. Results Reduced 13 C-lactate radiofrequency saturation resulted in a significantly greater 13 C-bicarbonate signal ( p = 0.04). These changes were observed across the majority of brain regions. Conclusion Radiofrequency saturation of 13 C-lactate leads to a decrease in 13 C-bicarbonate signal, demonstrating that the 13 C-lactate generated from the injected 13 C-pyruvate is being converted back to 13 C-pyruvate and oxidized throughout the human brain.

It is well known that glucose is the primary source of energy in the brain, but mounting evidence suggests that at least some of this glucose is first converted to lactate and shuttled between cellular compartments before being oxidized in the TCA cycle. In this study, the hypothesis that this ”lactate shuttle” contributes to the 13 C-lactate and 13 C-bicarbonate signal observed in the awake human brain is tested using hyperpolarized 13 C MRI (HP 13 C-MRI).

In this study, hyperpolarized C-13 MRI (HP-C-13 MRI) was used to investigate changes in the uptake and metabolism of pyruvate with age. Hyperpolarized C-13-pyruvate was administered to healthy aging individuals (N = 35, ages 21-77) and whole-brain spatial distributions of C-13-lactate and C-13-bicarbonate production were measured. Linear mixed-effects regressions were performed to compute the regional percentage change per decade, showing a significant reduction in both normalized C-13-lactate and normalized C-13-bicarbonate production with age: -7%+/- 2%$$ -7\%\pm 2\% $$ per decade for C-13-lactate and -9%+/- 4%$$ -9\%\pm 4\% $$ per decade for C-13-bicarbonate. Certain regions, such as the right medial precentral gyrus, showed greater rates of change while the left caudate nucleus had a flat C-13-lactate versus age and a slightly increasing C-13-bicarbonate versus age. The results show that both the production of lactate (visible as C-13-lactate signal) as well as the consumption of monocarboxylates to make acetyl-CoA (visible as C-13-bicarbonate signal) decrease with age and that the rate of change varies by brain region.

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.

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.

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 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 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 , and the AUC from an ROC analysis was 0.77 p < 0.05 . The distribution of ^13 C-lactate z -scores was different for intracranial metastases from different primary cancer types (F = 2.46, p = 0.1 ). Conclusions Hyperpolarized ^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.

Hyperpolarized (HP) MRI provides the means to monitor lactate metabolism noninvasively in tumours. Since ‐lactate signal levels obtained from HP imaging depend on multiple factors, such as the rate of 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 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 data and the ex vivo measures. The lactate‐to‐pyruvate ratio from HP MRI was strongly correlated with [1‐ ]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 ( = 0.78 and 0.93, respectively, p 0.01). Lactate pool size and the lactate‐to‐pyruvate ratio were not significantly correlated.

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.

Evidence supports the hypothesis that the changes in the way the heart uses fuel may be causative in the pathogenesis of heart failure (HF) and treatments that target these metabolic changes are a promising direction for improving outcomes. We have recently demonstrated an augmented form of magnetic resonance imaging (MRI) that gives metabolic information about the human heart, providing a potential new tool to guide the management of patients at risk of developing HF. The 13C images, which show biochemical reactions within cardiomyocytes, are made after the injection of an intravenous contrast agent that is prepared using a recently developed method known as dynamic nuclear polarization (DNP). The addition of 13C imaging only lengthens a routine MRI examination by approximately 10 minutes, giving metabolic information that would complement the wealth of other parameters that can currently be measured using cardiovascular MRI, including structure, perfusion, and pump parameters. L Heart Metab. 2018;77:37-39