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![Figure 1. Metabolic Fate of Hyperpolarized [1-13 C]Pyruvate in the Brain](publication/347781276/figure/fig1/AS:974339071561728@1609311945181/Metabolic-Fate-of-Hyperpolarized-1-13-CPyruvate-in-the-Brain_Q320.jpg)
Traumatic brain injury (TBI) involves complex secondary injury processes following the primary injury. The secondary injury is often associated with rapid metabolic shifts and impaired brain function immediately after the initial tissue damage. Magnetic resonance spectroscopic imaging (MRSI) coupled with hyperpolarization of ¹³C-labeled substrates...
Citations
... MRI [32]. In patients with mild traumatic brain injury, focal changes at the injured site revealed decreased bicarbonate levels and increased lactate production without apparent anatomical alterations [33]. Uthayakumar et al. [35] employed HP 13 C-MRI to measure the whole-brain metabolism in individuals of various ages. ...
... Cunningham et al. [36] performed the first human heart HP 13 C-MRI utilizing the electrocardiogram (EKG)-gated fast metabolic imaging technique (SPSP) in healthy volunteers. They observed the downstream metabolism of pyruvate with lactate in both chambers and the myocardium, and [26] 8 Infiltrative glioma Post radio-chemotherapy follow-up Autry et al., 2021 [27] 10 Pediatric brain tumor Tumor vs. normal brain, safety profile Lee et al., 2021 [28] 11 Intracranial metastasis Prediction of radiotherapy response Chen et al., 2021 [29] 3 Glioblastoma Tumor vs. normal brain Zaccagna et al., 2022 [30] 8 Glioblastoma Tumor vs. normal brain Grist et al., 2019 [31] 4 Normal brain Technical feasibility in human brain Lee et al., 2020 [32] 14 Normal brain Metabolite topography in human brain Hackett et al., 2020 [33] 2 Brain trauma Traumatic brain injury Ma et al., 2022 [34] 4 Normal brain Technical feasibility in human brain Uthayakumar et al., 2023 [35] 35 Brain aging Metabolic changes in brain aging Heart and skeletal muscle Cunningham et al., 2016 [36] 4 Heart 1st human healthy heart study Rider et al., 2020 [37] 10 Heart Healthy heart vs. diabetic heart Park et al., 2020 [38] 9 kjronline.org bicarbonate only in the myocardium. ...
Hyperpolarized (HP) carbon-13 (¹³C) MRI represents an innovative approach for noninvasive, real-time assessment of dynamic metabolic flux, with potential integration into routine clinical MRI. The use of [1-¹³C]pyruvate as a probe and its conversion to [1-¹³C]lactate constitute an extensively explored metabolic pathway. This review comprehensively outlines the establishment of HP ¹³C-MRI, covering multidisciplinary team collaboration, hardware prerequisites, probe preparation, hyperpolarization techniques, imaging acquisition, and data analysis. This article discusses the clinical applications of HP ¹³C-MRI across various anatomical domains, including the brain, heart, skeletal muscle, breast, liver, kidney, pancreas, and prostate. Each section highlights the specific applications and findings pertinent to these regions, emphasizing the potential versatility of HP ¹³C-MRI in diverse clinical contexts. This review serves as a comprehensive update, bridging technical aspects with clinical applications and offering insights into the ongoing advancements in HP ¹³C-MRI.
... Clinical studies suggest impaired mitochondrial pyruvate metabolism in TBI, leading to decreased aerobic respiration at the location of injury. 54,55 Elevated lactate-to-pyruvate ratio (LPR) in cerebral microdialysis is associated with unfavorable outcomes in TBI patients. 56 Another human study with 223 TBI patients reported that pyruvate is a significant independent negative predictor of mortality. ...
... The utilization of 1-13 C-pyruvate has shed light on post-TBI mechanisms 54,55,122,136,137 (Figure 2), revealing how 13 C-bicarbonate production, an OXPHOS activity marker, 136 aligns with 13 C-pyruvate mitochondrial consumption. Impaired mitochondrial function is marked by reduced bicarbonate and increased 13 C-lactate levels due to a shift toward anaerobic respiration via LDH. ...
... Studies in both animals and humans post-TBI have consistently found significant mitochondrial dysfunction from the acute phase to at least a week post-injury, necessitating a switch from oxidative to anaerobic respiration to meet cerebral energy needs. 54,55,122,136,137 One study using hyperpolarized 1-13 C-pyruvate demonstrated these changes are detectable in repetitive TBI brains extending beyond 3 months post-injury. 137 Others have utilized it to explore aspects of pyruvate metabolism in the injured brain in closer detail. ...
Cerebral metabolic dysfunction is a critical pathological hallmark observed in the aftermath of traumatic brain injury (TBI), as extensively documented in clinical investigations and experimental models. An in‐depth understanding of the bioenergetic disturbances that occur following TBI promises to reveal novel therapeutic targets, paving the way for the timely development of interventions to improve patient outcomes. The ¹³C isotope tracing technique represents a robust methodological advance, harnessing biochemical quantification to delineate the metabolic trajectories of isotopically labeled substrates. This nuanced approach enables real‐time mapping of metabolic fluxes, providing a window into the cellular energetic state and elucidating the perturbations in key metabolic circuits. By applying this sophisticated tool, researchers can dissect the complexities of bioenergetic networks within the central nervous system, offering insights into the metabolic derangements specific to TBI pathology. Embraced by both animal studies and clinical research, ¹³C isotope tracing has bolstered our understanding of TBI‐induced metabolic dysregulation. This review synthesizes current applications of isotope tracing and its transformative potential in evaluating and addressing the metabolic sequelae of TBI.
... 3D metabolite-specific imaging of the whole brain, with phase encoding of the slice direction (34,57), has been shown to provide similar SNR efficiency (87) compared with multislice imaging. A number of studies have employed MRS/I (5,6,29,(31)(32)(33)50,55) resulting in a spectrum from each voxel, which has the advantage of not requiring a priori information about which peaks to encode. This was important in early brain studies when it was not known which peaks would be detectable. ...
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.
... Hyperpolarized (HP) 13 C pyruvate MRI is an emerging tool for non-invasive imaging of metabolism in cancer and disease research, including brain tumors and traumatic brain injury. [1][2][3][4] In the brain, HP [1-13 C]pyruvate is injected intravenously and rapidly converted to either lactate or bicarbonate, which provides a measure of metabolic preference for either glycolysis or oxidative phosphorylation, respectively. Both lactate and bicarbonate are produced in normal brain metabolism, and an increase in lactate and decrease in bicarbonate has been observed in brain tumor lesions. ...
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.
... 17 A recent preliminary patient study demonstrated the translatability and sensitivity of this method to cerebral metabolic changes after mild TBI. 18 In particular, decreased [ 13 C]bicarbonate production was found in the brain nearest the site of trauma, suggesting that [ 13 C]bicarbonate is a viable biomarker for monitoring the mitochondrial dysfunction during the secondary injury process. In the present study, we focused on longitudinally assessment of [ 13 C]bicarbonate production from hyperpolarized [1-13 C]pyruvate in rodents following a CCI to characterize the chronology of cerebral mitochondrial metabolism during secondary injury associated with acute TBI. ...
Purpose
[¹³C]Bicarbonate formation from hyperpolarized [1‐¹³C]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 [¹³C]bicarbonate production from hyperpolarized [1‐¹³C]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 ¹H/¹³C‐integrated MR protocol that includes a bolus injection of hyperpolarized [1‐¹³C]pyruvate at 0 (2 h), 1, 2, 5, and 10 days 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 24 h 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 [¹³C]bicarbonate production from hyperpolarized [1‐¹³C]pyruvate, suggesting that [¹³C]bicarbonate is a sensitive in‐vivo biomarker of the secondary injury processes.
... In this context, it should be underlined that, despite the clinical decision on a child's sufficient stability for the more time-consuming imaging method WBMR, the interdisciplinary team of trauma surgeons and radiologists limited the extent of the examination protocols as much as possible, with a focus on the imaging duration. While other MRI techniques, like metabolic and dynamic imaging, have the potential to revolutionize insights into the molecular level of trauma, their applicability in acute diagnostics and treatment, especially in children, are far beyond current comprehension [27]. MRI protocols also excluded administration of Gadolinium, which could have been used for imaging of the great vessels because non-contrast techniques, like steady-state free precession imaging, have shown similar results compared to contrast-enhanced imaging [28]. ...
... There is no evidence for using WBMR in the case of polytraumatized children with unstable circulation, in our opinion. Furthermore, as there are obvious advantages of implementing WBMR into primary diagnostic guidelines in polytraumatized children, innovative WBMR technologies could optimize protocols concerning shorter examination time, while remaining high image-resolution and future supplementary use of molecular markers could improve structural imaging in the assessment of internal damage [14,27,37]. However, research concerning this topic currently appears sparse and warrants priority. ...
Although serious accidents remain the leading cause of pediatric mortality, protocols to orient diagnostic procedures towards a certain type of initial imaging are widely needed. Since 2007, we have performed whole-body magnetic resonance imaging (WBMR) and whole-body computed tomography (WBCT) for diagnoses of severely injured children. We retrospectively reviewed 134 WBMR and 158 WBCT in patients younger than 16 years that were performed at two trauma centers between 2007 and 2018. A higher Injury Severity Score (ISS) was found in WBCT vs. WBMR (10.6 vs. 5.8; p = 0.001), but without any significant difference in mortality. The WBMR was significantly preferred at younger ages (9.6 vs. 12.8 years; p < 0.001). The time between patient’s arrival until diagnosis was 2.5 times longer for WBCT (92.1 vs. 37.1 min; p < 0.001). More patients in the CT group received analgesic sedation and/or intubation at 37.3% vs. 21.6% in the MRI group. Of these patients, 86.4% (CT) and 27.6% (MRI) were already preclinically sedated (p < 0.001). Correspondingly, 72.4% of the patients were first sedated in-hospital for MRIs. In conclusion, WBMR is an alternative and radiation-free imaging method for high-energy-traumatized children. Although the selected diagnostics seemed appropriate, limitations regarding longer duration or additional analgesic sedation are present, and further studies are needed.
... Proton magnetic resonance spectroscopy ( 1 H MRS) also detected focal or systemic elevated lactate and related PDH caused by primary or secondary injured inflammation [14,15]. HP-13 C MRSI could be used as a direct, rapid, and noninvasive method to explore the effects of TBI on energetic metabolism in the brain [16,17]. In rats with moderate TBI induced by control cortical impingement on one cerebral hemisphere, measured by injection of HP-[1-13 C]-pyruvate, the injured side of the brain was found to produce a 13 C-bicarbonate signal 24 ± 6% lower than the injured side, while the HP-bicarbonate-to-HP-lactate ratio was 33 ± 8% lower than that of the injured side [16]. ...
... Clinically, HP-[1-13 C]-pyruvate MRSI is used to image patients with acute mild TBI several days after head trauma, but with no obvious anatomic changes. One patient showed high levels of lactic acid production at the injured site, and both patients showed a notable reduction in bicarbonate production [17] (Fig. 2). This study indicates using HP-pyruvate feasibly to image the metabolic changes in TBI patients and proves the transformability and sensitivity of this technology to the changes in cerebral metabolism after mild TBI. ...
With the development of heteronuclear fluorine, sodium, phosphorus, and other probes and imaging technologies as well as the optimization of magnetic resonance imaging (MRI) equipment and sequences, multi-nuclear magnetic resonance (multi-NMR) has enabled localize molecular activities in vivo that are central to a variety of diseases, including cardiovascular disease, neurodegenerative pathologies, metabolic diseases, kidney, and tumor, to shift from the traditional morphological imaging to the molecular imaging, precision diagnosis, and treatment mode. However, due to the low natural abundance and low gyromagnetic ratios, the clinical application of multi-NMR has been hampered. Several techniques have been developed to amplify the NMR sensitivity such as the dynamic nuclear polarization, spin-exchange optical pumping, and brute-force polarization. Meanwhile, a wide range of nuclei can be hyperpolarized, such as ² H, ³ He, ¹³ C, ¹⁵ N, ³¹ P, and ¹²⁹ Xe. The signal can be increased and allows real-time observation of biological perfusion, metabolite transport, and metabolic reactions in vivo, overcoming the disadvantages of conventional magnetic resonance of low sensitivity. HP-NMR imaging of different nuclear substrates provides a unique opportunity and invention to map the metabolic changes in various organs without invasive procedures. This review aims to focus on the recent applications of multi-NMR technology not only in a range of preliminary animal experiments but also in various disease spectrum in human. Furthermore, we will discuss the future challenges and opportunities of this multi-NMR from a clinical perspective, in the hope of truly bridging the gap between cutting-edge molecular biology and clinical applications.
... 4 The subsequent development of commercial research polarizers enabled new technical developments and initial human studies over the past 5 years in a variety of applications including prostate cancer, brain tumors, renal cancer, cardiac disease, pancreatic cancer, traumatic brain injury and breast cancer. [5][6][7][8][9][10][11][12][13][14] Since 2018, numerous studies have focused on investigating cerebral energy metabolism in the normal human brain and neuro-pathologies, demonstrating novel insights into brain bioenergetics by measuring HP pyruvate conversions to lactate and bicarbonate. 6,10,11,[15][16][17] Conversion from pyruvate to lactate and to bicarbonate provides a measure of metabolic preference for either oxidative phosphorylation, which generates bicarbonate, or glycolytic metabolism, which generates lactate. ...
... [5][6][7][8][9][10][11][12][13][14] Since 2018, numerous studies have focused on investigating cerebral energy metabolism in the normal human brain and neuro-pathologies, demonstrating novel insights into brain bioenergetics by measuring HP pyruvate conversions to lactate and bicarbonate. 6,10,11,[15][16][17] Conversion from pyruvate to lactate and to bicarbonate provides a measure of metabolic preference for either oxidative phosphorylation, which generates bicarbonate, or glycolytic metabolism, which generates lactate. The normal brain produces both lactate and bicarbonate, and increased lactate and decreased bicarbonate production were observed in brain tumor lesions. ...
Purpose
To investigate multi‐resolution hyperpolarized (HP) ¹³C pyruvate MRI for measuring kinetic conversion rates in the human brain.
Methods
HP [1‐¹³C]pyruvate MRI was acquired in 6 subjects with a multi‐resolution EPI sequence at 7.5 × 7.5 mm² resolution for pyruvate and 15 × 15 mm² resolution for lactate and bicarbonate. With the same lactate data, 2 quantitative maps of pyruvate‐to‐lactate conversion (kPL) maps were generated: 1 using 7.5 × 7.5 mm² resolution pyruvate data and the other using synthetic 15 × 15 mm² resolution pyruvate data to simulate a standard constant resolution acquisition. To examine local kPL values, 4 voxels were manually selected in each study representing brain tissue near arteries, brain tissue near veins, white matter, and gray matter.
Results
High resolution 7.5 × 7.5 mm² pyruvate images increased the spatial delineation of brain structures and decreased partial volume effects compared to coarser resolution 15 × 15 mm² pyruvate images. Voxels near arteries, veins and in white matter exhibited higher calculated kPL for multi‐resolution images.
Conclusion
Acquiring HP ¹³C pyruvate metabolic data with a multi‐resolution approach minimized partial volume effects from vascular pyruvate signals while maintaining the SNR of downstream metabolites. Higher resolution pyruvate images for kinetic fitting resulted in increased kinetic rate values, particularly around the superior sagittal sinus and cerebral arteries, by reducing extracellular pyruvate signal contributions from adjacent blood vessels. This HP ¹³C study showed that acquiring pyruvate with finer resolution improved the quantification of kinetic rates throughout the human brain.
... For brain studies, HP [1-13 C]pyruvate has been applied in healthy controls [55,60]; patients with glioma [42,43,46], brain metastasis [42,63], and TBI [64]; and pediatric patients with CNS tumors [65]. In the following section, we will discuss these most recent clinical applications. ...
... Metabolic heterogeneity in brain metastasis was confirmed in a recent study, and progression was associated with the highest lactate z-scores, converted from the mean and standard deviation of 13 C lactate signals for each region [63] (Fig. 4). (3) HP [1-13 C]pyruvate MR metabolic imaging has been applied to two patients with mild acute TBI [64]. One patient had increased [1-13 C]lactate over the total 13 C-labeled metabolite signals (TC) at the injury site, and both patients had decreased 13 C-bicarbonate over TC in the injured hemisphere. ...
The ability of hyperpolarized carbon-13 MR metabolic imaging to acquire dynamic metabolic information in real time is crucial to gain mechanistic insights into metabolic pathways, which are complementary to anatomic and other functional imaging methods. This review presents the advantages of this emerging functional imaging technology, describes considerations in clinical translations, and summarizes current human brain applications. Despite rapid development in methodologies, significant technological and physiological related challenges continue to impede broader clinical translation.
... Recent advances in clinical translation of HP pyruvate imaging (15) has enabled metabolic imaging of the human brain in healthy subjects (16,17) and patients with brain tumors (17)(18)(19)(20) or TBI (21). Most previous human brain studies focused on imaging altered lactate production in intracranial malignancies (18,19). ...
Purpose
This study is to investigate time‐resolved ¹³C MR spectroscopy (MRS) as an alternative to imaging for assessing pyruvate metabolism using hyperpolarized (HP) [1‐¹³C]pyruvate in the human brain.
Methods
Time‐resolved ¹³C spectra were acquired from four axial brain slices of healthy human participants (n = 4) after a bolus injection of HP [1‐¹³C]pyruvate. ¹³C MRS with low flip‐angle excitations and a multichannel ¹³C/¹H dual‐frequency radiofrequency (RF) coil were exploited for reliable and unperturbed assessment of HP pyruvate metabolism. Slice‐wise areas under the curve (AUCs) of ¹³C‐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 ¹³C reconstruction. Reproducibility of HP pyruvate exams was presented by performing two consecutive injections with a 45‐minutes interval.
Results
[1‐¹³C]Lactate relative to the total ¹³C signal (tC) was 0.21–0.24 in all slices. [¹³C]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 [1‐¹³C]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 [1‐¹³C]pyruvate.
