Yaewon Kim

Alpha-ketoglutarate (aKG) is a central intermediate of cerebral energy metabolism and a precursor for glutamate synthesis in the brain. Alterations in aKG metabolism occur in pathological contexts, including isocitrate dehydrogenase (IDH) mutant astrocytomas and oligodendrogliomas, in which mutant IDH converts aKG to the oncometabolite 2-hydroxyglutarate. Given its central role in brain metabolism, non-invasive interrogation of aKG-dependent metabolic flux is needed. Hyperpolarized (HP) ¹³C MR enables real-time visualization of metabolic conversion by transiently enhancing signal intensity by several orders of magnitude. Leveraging this approach, we report the first-in-human feasibility and safety study of HP [1-¹³C]aKG MR spectroscopy in the healthy brain (n = 3). A standard operating procedure (SOP) was developed for sterile [1-¹³C]aKG dose production, achieving reproducible polarization levels averaging 30.5 ± 2.2%. Following intravenous administration, time-resolved ¹³C spectra in healthy volunteers demonstrated the detection of HP aKG resonance and a measurable downstream glutamate signal, consistent across repeat acquisitions, with a delayed temporal profile relative to aKG observed in a representative dataset. Although performed in healthy volunteers, these results establish feasibility for HP [1-¹³C]aKG metabolic imaging to open a new window into normal and pathological brain cellular metabolism.

This study developed a new approach to produce sterile, hyperpolarized [¹³C,¹⁵N₂]urea as a novel molecular imaging probe and applied it for first-ever healthy brain volunteer studies. Hyperpolarized [¹³C,¹⁵N₂]urea, as a small, metabolically inert molecule, offers significant advantages for perfusion imaging due to its endogenous nature and excellent safety profile. The developed methods achieved a hyperpolarized [¹³C,¹⁵N₂]urea solution (132 ± 6 mM) with 27.4 ± 5.6% polarization and a T₁ = 50.4 ± 0.2 s. In healthy brain volunteer studies, high-resolution ¹³C imaging captured blood flow with a spatial resolution of 7.76 × 7.76 × 15 (or 10) mm³ over ~1 min following hyperpolarized [¹³C,¹⁵N₂]urea injection, visualizing detailed vascular structures. Time-to-peak and centroid analyses showed consistent arterial and venous signal patterns across subjects. Findings suggest hyperpolarized [¹³C,¹⁵N₂]urea may have applications beyond brain imaging, including the non-invasive perfusion assessment in various organs, cancer microenvironment, and renal function, paving the way for clinical translation.

Hyperpolarized carbon-13 (HP-¹³C) MRI enables the real-time measurement of dynamic metabolism by utilizing molecular probes whose magnetization has been transiently enhanced via dynamic nuclear polarization of ¹³C labels. Based on pre-clinical and clinical investigations demonstrating Warburg-related metabolic dysfunction and tricarboxylic acid (TCA)-cycle alterations in gliomas, HP¹³C techniques appear very promising for overcoming conventional challenges to evaluating tumor burden and extent, early therapeutic response and progression among patients non-invasively. This article surveys the multi-faceted translational development of HP-¹³C MRI in the context of glioma imaging, while emphasizing innovation concerning the pharmacy production of HP probes - [1-¹³C]/[2-¹³C]-pyruvate and [1-¹³C,5-¹²C]-alpha-ketoglutarate - that serve as non-radioactive metabolic contrast agents. Borrowing from practical experience, we present specific probe indications for isocitrate dehydrogenase (IDH)-wildtype glioblastomas and IDH-mutant gliomas together with example data to show the targeted, pathway-dependent function of these agents and their utility. Additional information pertaining to HP-¹³C hardware, acquisition and post-processing techniques provides an overview of the imaging methodology as it is currently performed at a leading institution. Considering the developing markers for progressive disease in glioblastomas and rapidly advancing capability, this unique imaging technology appears poised for translational impact following further evaluation.ABBREVIATIONS: 2-HG = D-2-hydroxyglutarate; α-KG = alpha-ketoglutarate; CSI = chemical shift imaging; d-DNP = dissolution-dynamic nuclear polarization; EPI = echo-planar imaging; EPSI = echo-planar spectroscopic imaging; IDHm = isocitrate dehydrogenasemutant; IR-SPGR = inversion recovery-prepared fast spoiled gradient-recalled (imaging); LrGGs = lower-grade gliomas; NMR = nuclear magnetic resonance; OGC = oxoglutarate carrier; PHIP = parahydrogen-induced polarization; SNR = signal-to-noise ratio; TCA cycle = tricarboxylic acid cycle; WHO = World Health Organization.

Purpose: Accurate quantification of metabolism in hyperpolarized (HP) ¹³ C MRI is essential for clinical applications. However, kinetic model parameters are often confounded by uncertainties in radiofrequency flip angles and other model parameters. Methods: A data‐driven kinetic fitting approach for HP ¹³ C‐pyruvate MRI was proposed that compensates for uncertainties in the B ₁ ⁺ field. We hypothesized that introducing a scaling factor to the flip angle to minimize fit residuals would allow more accurate determination of the pyruvate‐to‐lactate conversion rate ( k _PL ). Numerical simulations were performed under different conditions (flip angle, k _PL , and T ₁ relaxation), with further testing using HP ¹³ C‐pyruvate MRI of rat liver and kidneys. Results: Simulations showed that the proposed method reduced k _PL error from 60% to 1% when the prescribed and actual flip angles differed by 60%. The method also showed robustness to T ₁ uncertainties, achieving median k _PL errors within ±3% even when the assumed T ₁ was incorrect by up to a factor of 2. In rat studies, better‐quality fitting for lactate signals (a 1.4‐fold decrease in root mean square error [RMSE] for lactate fit) and tighter k _PL distributions (an average of 3.1‐fold decrease in k _PL standard deviation) were achieved using the proposed method compared with when no correction was applied. Conclusion: The proposed data‐driven kinetic fitting approach provided a method to accurately quantify HP ¹³ C‐pyruvate metabolism in the presence of B ₁ ⁺ inhomogeneity. This model may also be used to correct for other error sources, such as T ₁ relaxation and flow, and may prove to be clinically valuable in improving tumor staging or assessing treatment response.

This study aimed to implement a multimodal ¹H/HP-¹³C imaging protocol to augment the serial monitoring of patients with glioma, while simultaneously pursuing methods for improving the robustness of HP-¹³C metabolic data. A total of 100 ¹H/HP [1-¹³C]-pyruvate MR examinations (104 HP-¹³C datasets) were acquired from 42 patients according to the comprehensive multimodal glioma imaging protocol. Serial data coverage, accuracy of frequency reference, and acquisition delay were evaluated using a mixed-effects model to account for multiple exams per patient. Serial atlas-based HP-¹³C MRI demonstrated consistency in volumetric coverage measured by inter-exam dice coefficients (0.977 ± 0.008, mean ± SD; four patients/11 exams). The atlas-derived prescription provided significantly improved data quality compared to manually prescribed acquisitions (n = 26/78; p = 0.04). The water-based method for referencing [1-¹³C]-pyruvate center frequency significantly reduced off-resonance excitation relative to the coil-embedded [¹³C]-urea phantom (4.1 ± 3.7 Hz vs. 9.9 ± 10.7 Hz; p = 0.0007). Significantly improved capture of tracer inflow was achieved with the 2-s versus 5-s HP-¹³C MRI acquisition delay (p = 0.007). This study demonstrated the implementation of a comprehensive multimodal ¹H/HP-¹³C MR protocol emphasizing the monitoring of steady-state/dynamic metabolism in patients with glioma.

Purpose: Improving the quality and maintaining the fidelity of large coverage abdominal hyperpolarized (HP) C-13 MRI studies with a patch based global-local higher-order singular value decomposition (GL-HOVSD) spatiotemporal denoising approach.Methods: Denoising performance was first evaluated using the simulated [1-C-13]pyruvate dynamics at different noise levels to determine optimal k(global) and k(local) parameters. The GL-HOSVD spatiotemporal denoising method with the optimized parameters was then applied to two HP [1-C-13]pyruvate EPI abdominal human cohorts (n = 7 healthy volunteers and n = 8 pancreatic cancer patients).Results: The parameterization of k(global) = 0.2 and k(local) = 0.9 denoises abdominal HP data while retaining image fidelity when evaluated by RMSE. The k(PX) (conversion rate of pyruvate-to-metabolite, X = lactate or alanine) difference was shown to be 5) for downstream metabolites. In both human cohorts, there was a greater than nine-fold gain in peak [1-C-13]pyruvate, [1-C-13]lactate, and [1-C-13]alanine apparent SNRAUC. The improvement in metabolite SNR enabled a more robust quantification of k(PL) and k(PA). After denoising, we observed a 2.1 +/- 0.4 and 4.8 +/- 2.5-fold increase in the number of voxels reliably fit across abdominal FOVs for k(PL) and k(PA) quantification maps.Conclusion: Spatiotemporal denoising greatly improves visualization of low SNR metabolites particularly [1-C-13]alanine and quantification of [1-C-13]pyruvate metabolism in large FOV HP C-13 MRI studies of the human abdomen.

Purpose: Nonalcoholic fatty liver disease is an important cause of chronic liver disease. There are limited methods for monitoring metabolic changes during progression to steatohepatitis. Hyperpolarized (13) C MRSI (HP (13) C MRSI) was used to measure metabolic changes in a rodent model of fatty liver disease.Methods: Fifteen Wistar rats were placed on a methionine- and choline-deficient (MCD) diet for 1-18 weeks. HP (13) C MRSI, T-2 -weighted imaging, and fat-fraction measurements were obtained at 3 T. Serum aspartate aminotransaminase, alanine aminotransaminase, and triglycerides were measured. Animals were sacrificed for histology and measurement of tissue lactate dehydrogenase (LDH) activity.Results: Animals lost significant weight (13.6% +/- 2.34%), an expected characteristic of the MCD diet. Steatosis, inflammation, and mild fibrosis were observed. Liver fat fraction was 31.7% +/- 4.5% after 4 weeks and 22.2% +/- 4.3% after 9 weeks. Lactate-to-pyruvate and alanine-to-pyruvate ratios decreased significantly over the study course; were negatively correlated with aspartate aminotransaminase and alanine aminotransaminase (r = -[0.39-0.61]); and were positively correlated with triglycerides (r = 0.59-0.60). Despite observed decreases in hyperpolarized lactate signal, LDH activity increased by a factor of 3 in MCD diet-fed animals. Observed decreases in lactate and alanine hyperpolarized signals on the MCD diet stand in contrast to other studies of liver injury, where lactate and alanine increased. Observed hyperpolarized metabolite changes were not explained by alterations in LDH activity, suggesting that changes may reflect co-factor depletion known to occur as a result of oxidative stress in the MCD diet.Conclusion: HP (13) C MRSI can noninvasively measure metabolic changes in the MCD model of chronic liver disease.

Purpose: To investigate high‐resolution hyperpolarized (HP) ¹³C pyruvate MRI for measuring cerebral perfusion in the human brain.Methods: HP [1‐¹³C]pyruvate MRI was acquired in five healthy volunteers with a multi‐resolution EPI sequence with 7.5 × 7.5 mm² resolution for pyruvate. Perfusion parameters were calculated from pyruvate MRI using block‐circulant singular value decomposition and compared to relative cerebral blood flow calculated from arterial spin labeling (ASL). To examine regional perfusion patterns, correlations between pyruvate and ASL perfusion were performed for whole brain, gray matter, and white matter voxels.Results: High resolution 7.5 × 7.5 mm² pyruvate images were used to obtain relative cerebral blood flow (rCBF) values that were significantly positively correlated with ASL rCBF values (r = 0.48, 0.20, 0.28 for whole brain, gray matter, and white matter voxels respectively). Whole brain voxels exhibited the highest correlation between pyruvate and ASL perfusion, and there were distinct regional patterns of relatively high ASL and low pyruvate normalized rCBF found across subjects.Conclusion: Acquiring HP ¹³C pyruvate metabolic images at higher resolution allows for finer spatial delineation of brain structures and can be used to obtain cerebral perfusion parameters. Pyruvate perfusion parameters were positively correlated to proton ASL perfusion values, indicating a relationship between the two perfusion measures. This HP ¹³C study demonstrated that hyperpolarized pyruvate MRI can assess cerebral metabolism and perfusion within the same study.