Longitudinal assessment of mitochondrial dysfunction in acute traumatic brain injury using hyperpolarized [1‐¹³C]pyruvate

Abstract

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.MethodsMale 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.ResultsIn 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.ConclusionThis 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.

Enhanced Solubility and Polarization of 13C-Fumarate with Meglumine Allows for In Vivo Detection of Gluconeogenic Metabolism in Kidneys

“…The 13 C spectra acquired from the 1-T spectrometer were processed using Mnova (Mestrelab Research, A Coruña, Spain) for integrating HP [1,4- 13 C 2 ]­fumarate signal. The k-space data of 13 C CSI and dynamic 13 C FID acquired from the 3-T scanner were reconstructed using MATLAB (Mathworks Inc., Natick, MA, USA), as described previously, , with 4-fold zero-padding in both spatial and frequency domains. Metabolite maps of [1,4- 13 C 2 ]­fumarate, [1,4- 13 C 2 ]­malate, and [ 13 C]­bicarbonate were generated by integrating the corresponding peaks in the absorption mode after zeroth-order phase correction in each voxel.…”

Tracing the path of disruption: 13C isotope applications in traumatic brain injury‐induced metabolic dysfunction

“…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 .…”

“…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.…”

“…55 Further, the use of such technology in tandem with machine learning workflows was recently shown to be capable of predicting long-term behavior changes after TBI in animals that otherwise lack detectable changes in conventional imaging at the same timepoint, 137 which suggests isotope tracing may be a powerful approach to better study the link between TBI and the elevated risk of developing long-term neurobehavioral sequelae including mental health disorders 138 and dementia, 139 among others. However, it is critical to note that the application of hyperpolarized 1-13 C-pyruvate in TBI models has shown a rapid lactate increase at the injury site, 136 potentially worsening the focal injury and posing limitations for its use in TBI patient studies, and this must be carefully considered when designing experiments or clinical procedures.…”