Kidneys play a central role in numerous disorders but current imaging methods have limited utility to probe renal metabolism. Hyperpolarized (HP) 13 C magnetic resonance imaging is uniquely suited to provide metabolite-specific information about key biochemical pathways and it offers the further advantage that renal imaging is practical in humans. This study evaluated the feasibility of hyperpolarization examinations in a widely used model for analysis of renal physiology, the isolated kidney, which enables isolation of renal metabolism from the effects of other organs and validation of HP results by independent measurements. Isolated rat kidneys were supplied with either HP [1-13 C]pyruvate only or HP [1-13 C]pyruvate plus octanoate. Metabolic activity in both groups was confirmed by stable renal oxygen consumption. HP [1-13 C]pyruvate was readily metabolized to [13 C]bicarbonate, [1-13 C]lactate, and [1-13 C]alanine, detectable seconds after HP [1-13 C]pyruvate was injected. Octanoate suppressed but did not eliminate the production of HP [13 C]bicarbonate from [1-13 C]pyruvate. Steady-state flux analyses using non-HP 13 C substrates validated the utilization of HP [1-13 C]pyruvate, as observed by HP 13 C NMR. In the presence of octanoate, lactate is generated from a tricarboxylic acid cycle intermediate, oxaloacetate. The isolated rat kidney may serve as an excellent model for investigating and establishing new HP 13 C metabolic probes for future kidney imaging applications. © 2022 John Wiley & Sons Ltd.

PURPOSE: [13 C]Bicarbonate formation from hyperpolarized [1-13 C]pyruvate via pyruvate dehydrogenase, a key regulatory enzyme, represents the cerebral oxidation of pyruvate and the integrity of mitochondrial function. The present study is to characterize the chronology of cerebral mitochondrial metabolism during secondary injury associated with acute traumatic brain injury (TBI) by longitudinally monitoring [13 C]bicarbonate production from hyperpolarized [1-13 C]pyruvate in rodents.; METHODS: Male Wistar rats were randomly assigned to undergo a controlled-cortical impact (CCI, n=31) or sham surgery (n=22). Seventeen of the CCI and 9 of the sham rats longitudinally underwent a 1 H/13 C-integrated MR protocol that includes a bolus injection of hyperpolarized [1-13 C]pyruvate at 0 (2h), 1, 2, 5, and 10days post-surgery. Separate CCI and sham rats were used for histological validation and enzyme assays.; RESULTS: In addition to elevated lactate, we observed significantly reduced bicarbonate production in the injured site. Unlike the immediate appearance of hyperintensity on T2 -weighted MRI, the contrast of bicarbonate signals between the injured region and the contralateral brain peaked at 24h post-injury, then fully recovered to the normal level at day 10. A subset of TBI rats demonstrated markedly increased bicarbonate in normal-appearing contralateral brain regions post-injury.; CONCLUSION: This study demonstrates that aberrant mitochondrial metabolism occurring in acute TBI can be monitored by detecting [13 C]bicarbonate production from hyperpolarized [1-13 C]pyruvate, suggesting that [13 C]bicarbonate is a sensitive in-vivo biomarker of the secondary injury processes. © 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.

The extracellular class of gadolinium-based contrast agents (GBCAs) is an essential tool for clinical diagnosis and disease management. In order to better understand the issues associated with GBCA administration and gadolinium retention and deposition in the human brain, the chemical properties of GBCAs such as relative thermodynamic and kinetic stabilities and their likelihood of forming gadolinium deposits in vivo will be reviewed. The chemical form of gadolinium causing the hyperintensity is an open question. On the basis of estimates of total gadolinium concentration present, it is highly unlikely that the intact chelate is causing the T-1 hyperintensities observed in the human brain. Although it is possible that there is a water-soluble form of gadolinium that has high relaxitvity present, our experience indicates that the insoluble gadolinium-based agents/salts could have high relaxivities on the surface of the solid due to higher water access. This review assesses the safety of GBCAs from a chemical point of view based on their thermodynamic and kinetic properties, discusses how these properties influence in vivo behavior, and highlights some clinical implications regarding the development of future imaging agents.

Cellular redox is intricately linked to energy production and normal cell function. Although the redox states of mitochondria and cytosol are connected by shuttle mechanisms, the redox state of mitochondria may differ from redox in the cytosol in response to stress. However, detecting these differences in functioning tissues is difficult. Here, we employed C-13 magnetic resonance spectroscopy (MRS) and co- polarized [1-C-13] pyruvate and [1,3- C-13(2)] acetoacetate ([1,3-C-13(2)]AcAc) to monitor production of hyperpolarized (HP) lactate and beta-hydroxybutyrate as indicators of cytosolic and mitochondrial redox, respectively. Isolated rat hearts were examined under normoxic conditions, during low-flow ischemia, and after pretreatment with either aminooxyacetate (AOA) or rotenone. All interventions were associated with an increase in [P-i]/[ATP] measured by P-31 NMR. In well-oxygenated untreated hearts, rapid conversion of HP [1-C-13]pyruvate to [1-C-13]lactate and [1,3-C-13(2)]AcAc to [1,3-C-13(2)]beta-hydroxybutyrate ([1,3-C-13(2)]beta-HB) was readily detected. A significant increase in HP [1,3-C-13(2)]beta-HB but not [1-C-13]lactate was observed in rotenone-treated and ischemic hearts, consistent with an increase in mitochondrial NADH but not cytosolic NADH. AOA treatments did not alter the productions of HP [1-C-13]lactate or [1,3-C-13(2)]beta-HB. This study demonstrates that biomarkers of mitochondrial and cytosolic redox may be detected simultaneously in functioning tissues using co-polarized [1-C-13]pyruvate and [1,3-C-13(2)]AcAc and C-13 MRS and that changes in mitochondrial redox may precede changes in cytosolic redox.

Purpose Previous cardiac imaging studies using hyperpolarized (HP) [1-C-13]pyruvate were acquired at end-diastole (ED). Little is known about the interaction between cardiac cycle and metabolite content in the myocardium. In this study, we compared images of HP pyruvate and products at end-systole (ES) and ED. Methods A dual-phase C-13 MRI sequence was implemented to acquire two sequential HP images within a single cardiac cycle at ES and ED during successive R-R intervals in an interleaved manner. Each healthy volunteer (N = 3) received two injections of HP [1-C-13]pyruvate for the dual-phase imaging on the short-axis and the vertical long-axis planes. Spatial distribution of HP C-13 metabolites at each cardiac phase was correlated to multiphase H-1 MRI to confirm the mechanical changes. Ratios of myocardial HP metabolites were compared between ES and ED. Segmental analysis was performed on the midcavity short-axis plane. Results In addition to mechanical changes, metabolic profiles of the heart detected by HP [1-C-13]pyruvate differed between ES and ED. The myocardial signal of [C-13]bicarbonate relative to [1-C-13]lactate was significantly smaller at ED than the ratio at ES (p < .05), particularly in mid-anterior and mid-inferoseptal segments. The distinct metabolic profiles in the myocardium likely reflect the technical aspects of the imaging approach such as the coronary flow in addition to the cyclical changes in metabolism. Conclusion The study demonstrates that metabolic profiles of the heart, measured by HP [1-C-13]pyruvate, are affected by the cardiac cycle in which that the data are acquired.

Purpose This study is to investigate time-resolved C-13 MR spectroscopy (MRS) as an alternative to imaging for assessing pyruvate metabolism using hyperpolarized (HP) [1-C-13]pyruvate in the human brain. Methods Time-resolved C-13 spectra were acquired from four axial brain slices of healthy human participants (n = 4) after a bolus injection of HP [1-C-13]pyruvate. C-13 MRS with low flip-angle excitations and a multichannel C-13/H-1 dual-frequency radiofrequency (RF) coil were exploited for reliable and unperturbed assessment of HP pyruvate metabolism. Slice-wise areas under the curve (AUCs) of C-13-metabolites were measured and kinetic analysis was performed to estimate the production rates of lactate and HCO3-. Linear regression analysis between brain volumes and HP signals was performed. Region-focused pyruvate metabolism was estimated using coil-wise C-13 reconstruction. Reproducibility of HP pyruvate exams was presented by performing two consecutive injections with a 45-minutes interval. Results [1-C-13]Lactate relative to the total C-13 signal (tC) was 0.21-0.24 in all slices. [C-13]HCO3-/tC was 0.065-0.091. Apparent conversion rate constants from pyruvate to lactate and HCO3- were calculated as 0.014-0.018 s(-1) and 0.0043-0.0056 s(-1), respectively. Pyruvate/tC and lactate/tC were in moderate linear relationships with fractional gray matter volume within each slice. White matter presented poor linear regression fit with HP signals, and moderate correlations of the fractional cerebrospinal fluid volume with pyruvate/tC and lactate/tC were measured. Measured HP signals were comparable between two consecutive exams with HP [1-C-13]pyruvate. Conclusions Dynamic MRS in combination with multichannel RF coils is an affordable and reliable alternative to imaging methods in investigating cerebral metabolism using HP [1-C-13]pyruvate.

Background: Pyruvate dehydrogenase (PDH) and lactate dehydrogenase are essential for adenosine triphosphate production in skeletal muscle. At the onset of exercise, oxidation of glucose and glycogen is quickly enabled by dephosphorylation of PDH. However, direct measurement of PDH flux in exercising human muscle is daunting, and the net effect of covalent modification and other control mechanisms on PDH flux has not been assessed.Purpose: To demonstrate the feasibility of assessing PDH activation and changes in pyruvate metabolism in human skeletal muscle after the onset of exercise using carbon 13 (C-13) MRI with hyperpolarized (HP) [1-C-13]-pyruvate.Materials and Methods: For this prospective study, sedentary adults in good general health (mean age, 42 years +/- 18 [standard deviation]; six men) were recruited from August 2019 to September 2020. Subgroups of the participants were injected with HP [1-C-13]-pyruvate at resting, during plantar flexion exercise, or 5 minutes after exercise during recovery. In parallel, hydrogen 1 arterial spin labeling MRI was performed to estimate muscle tissue perfusion. An unpaired t test was used for comparing C-13 data among the states.Results: At rest, HP [1-C-13]-lactate and [1-C-13]-alanine were detected in calf muscle, but [C-13]-bicarbonate was negligible. During moderate flexion-extension exercise, total HP C-13 signals (tC) increased 2.8-fold because of increased muscle perfusion (P = .005), and HP [1-C-13]-lactate-to-tC ratio increased 1.7-fold (P = .04). HP [C-13]-bicarbonate-to-tC ratio increased 8.4-fold (P = .002) and returned to the resting level 5 minutes after exercise, whereas the lactate-to-tC ratio continued to increase to 2.3-fold as compared with resting (P = .008).Conclusion: Lactate and bicarbonate production from hyperpolarized (HP) [1-carbon 13 {C-13}]-pyruvate in skeletal muscle rapidly reflected the onset and the termination of exercise. These results demonstrate the feasibility of imaging skeletal muscle metabolism using HP [1-C-13]-pyruvate MRI and the sensitivity of in vivo pyruvate metabolism to exercise states. (C) RSNA, 2021