Lactate saturation limits bicarbonate detection in hyperpolarized <scp><sup>13</sup>C</scp>‐pyruvate <scp>MRI</scp> of the brain

Bøgh, Nikolaj; Grist, James T.; Laustsen, Christoffer

doi:10.1002/mrm.29290

Cited by 9 publications

(10 citation statements)

References 38 publications

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“…17,18 In this study, it was shown that increased RF saturation of the 13 C-lactate pool resulted in reduced 13 C-bicarbonate signal. The is in agreement with a prior rat study that assessed the effects of 13 C-lactate saturation in multiple organs, with the strongest increase in 13 C-bicarbonate signal observed in the brain, 7 though supraphysiological 13 C-pyruvate concentrations being constrained within vasculature by the blood-brain barrier may be why the effect of 13 C-lactate saturation is more profound in the brain than in other organs.…”

Section: Discussionsupporting

confidence: 91%

Evidence of ¹³C‐lactate oxidation in the human brain from hyperpolarized ¹³C‐MRI

Uthayakumar,

Soliman,

Chen

et al. 2024

Magnetic Resonance in Med

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

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Section: Discussionsupporting

confidence: 91%

Evidence of ¹³C‐lactate oxidation in the human brain from hyperpolarized ¹³C‐MRI

Uthayakumar,

Soliman,

Chen

et al. 2024

Magnetic Resonance in Med

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“…However, this may lead to a confounding contribution from signals outside the brain. Previous studies have shown that it is possible to image bicarbonate signal, although great care will be needed when optimizing the experiment 44 . Increased pyruvate polarization levels will also help, as polarization levels more than double those achieved here have already been reported 52 …”

Section: Discussionmentioning

confidence: 68%

“…Interestingly, a recent study suggested that dDNP experiments may be directly sensitive to the effects of lactate shuttling, but this is not expected to contribute to the current study due to the low flip angles used. 44 As discussed above, unlike the case of the bicarbonate signal, where a CO 2 is released directly because of enzymatic activity and rapidly equilibrated with bicarbonate, the observed lactate signal mainly reflects labelling of the preexisting lactate pool, both signals being heavily modulated by pyruvate uptake. 26 Recent reports on mice suggest that hyperpolarized glucose might show greater response to alterations in cellular energy metabolism, due to it entering the cells via more effective glucose transporters and reporting on actual de novo synthesis of lactate.…”

Section: Discussionmentioning

confidence: 88%

“…However, as only a fraction of the lactate pool is labelled, an increase in extracellular lactate pool during 1 H MRS, over a time scale of several minutes, may not result in a similar acute change in hyperpolarized lactate labelling. Interestingly, a recent study suggested that dDNP experiments may be directly sensitive to the effects of lactate shuttling, but this is not expected to contribute to the current study due to the low flip angles used 44 . As discussed above, unlike the case of the bicarbonate signal, where a CO 2 is released directly because of enzymatic activity and rapidly equilibrated with bicarbonate, the observed lactate signal mainly reflects labelling of the pre‐existing lactate pool, both signals being heavily modulated by pyruvate uptake 26 .…”

Section: Discussionmentioning

confidence: 95%

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Simultaneous fMRI and metabolic MRS of hyperpolarized [1‐¹³C]pyruvate during nicotine stimulus in rat

Hyppönen,

Rosa,

Kettunen

2024

NMR in Biomedicine

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Functional MRI (fMRI) and MRS (fMRS) can be used to noninvasively map cerebral activation and metabolism. Recently, hyperpolarized 13C spectroscopy and metabolic imaging have provided an alternative approach to assess metabolism. In this study, we combined 1H fMRI and hyperpolarized [1‐13C]pyruvate MRS to compare cerebral blood oxygenation level‐dependent (BOLD) response and real‐time cerebral metabolism, as assessed with lactate and bicarbonate labelling, during nicotine stimulation. Simultaneous 1H fMRI (multislice gradient echo echo‐planar imaging) and 13C spectroscopic (single slice pulse‐acquire) data were collected in urethane‐anaesthetized female Sprague–Dawley rats (n = 12) at 9.4 T. Animals received an intravenous (i.v.) injection of either nicotine (stimulus; 88 μg/kg, n = 7, or 300 μg/kg, n = 5) or 0.9% saline (matching volume), followed by hyperpolarized [1‐13C]pyruvate injection 60 s later. Three hours later, a second injection was administered: the animals that had previously received saline were injected with nicotine and vice versa, both followed by another hyperpolarized [1‐13C]pyruvate i.v. injection 60 s later. The low‐dose (88 μg/kg) nicotine injection led to a 12% ± 4% (n = 7, t‐test, p ~ 0.0006 (t‐value −5.8, degrees of freedom 6), Wilcoxon p ~ 0.0078 (test statistic 0)) increase in BOLD signal. At the same time, an increase in 13C‐bicarbonate signal was seen in four out of six animals. Bicarbonate‐to‐total carbon ratios were 0.010 ± 0.004 and 0.018 ± 0.010 (n = 6, t‐test, p ~ 0.03 (t‐value −2.3, degrees of freedom 5), Wilcoxon p ~ 0.08 (test statistic 3)) for saline and nicotine experiments, respectively. No increase in the lactate signal was seen; lactate‐to‐total carbon was 0.16 ± 0.02 after both injections. The high (300 μg/kg) nicotine dose (n = 5) caused highly variable BOLD and metabolic responses, possibly due to the apparent respiratory distress. Simultaneous detection of 1H fMRI and hyperpolarized 13C‐MRS is feasible. A comparison of metabolic response between control and stimulated states showed differences in bicarbonate signal, implying that the hyperpolarization technique could offer complimentary information on brain activation.

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“…This observation is consistent with previous studies that saturated lactate prior to bicarbonate imaging. [21][22][23]…”

Section: Pathway Analysis Of Cerebral [ 13 C]bicarbonate Production F...mentioning

confidence: 99%

Functional activation of pyruvate dehydrogenase in human brain using hyperpolarized [1‐¹³C]pyruvate

Zaidi,

Ma,

Thomas

et al. 2024

Magnetic Resonance in Med

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PurposePyruvate, produced from either glucose, glycogen, or lactate, is the dominant precursor of cerebral oxidative metabolism. Pyruvate dehydrogenase (PDH) flux is a direct measure of cerebral mitochondrial function and metabolism. Detection of [13C]bicarbonate in the brain from hyperpolarized [1‐13C]pyruvate using carbon‐13 (13C) MRI provides a unique opportunity for assessing PDH flux in vivo. This study is to assess changes in cerebral PDH flux in response to visual stimuli using in vivo 13C MRS with hyperpolarized [1‐13C]pyruvate.MethodsFrom seven sedentary adults in good general health, time‐resolved [13C]bicarbonate production was measured in the brain using 90° flip angles with minimal perturbation of its precursors, [1‐13C]pyruvate and [1‐13C]lactate, to test the hypothesis that the appearance of [13C]bicarbonate signals in the brain reflects the metabolic changes associated with neuronal activation. With a separate group of healthy participants (n = 3), the likelihood of the bolus‐injected [1‐13C]pyruvate being converted to [1‐13C]lactate prior to decarboxylation was investigated by measuring [13C]bicarbonate production with and without [1‐13C]lactate saturation.ResultsIn the course of visual stimulation, the measured [13C]bicarbonate signal normalized to the total 13C signal in the visual cortex increased by 17.1% ± 15.9% (p = 0.017), whereas no significant change was detected in [1‐13C]lactate. Proton BOLD fMRI confirmed the regional activation in the visual cortex with the stimuli. Lactate saturation decreased bicarbonate‐to‐pyruvate ratio by 44.4% ± 9.3% (p < 0.01).ConclusionWe demonstrated the utility of 13C MRS with hyperpolarized [1‐13C]pyruvate for assessing the activation of cerebral PDH flux via the detection of [13C]bicarbonate production.

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Lactate saturation limits bicarbonate detection in hyperpolarized ¹³C‐pyruvate MRI of the brain

Cited by 9 publications

References 38 publications

Evidence of ¹³C‐lactate oxidation in the human brain from hyperpolarized ¹³C‐MRI

Evidence of ¹³C‐lactate oxidation in the human brain from hyperpolarized ¹³C‐MRI

Simultaneous fMRI and metabolic MRS of hyperpolarized [1‐¹³C]pyruvate during nicotine stimulus in rat

Functional activation of pyruvate dehydrogenase in human brain using hyperpolarized [1‐¹³C]pyruvate

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Lactate saturation limits bicarbonate detection in hyperpolarized 13C‐pyruvate MRI of the brain

Cited by 9 publications

References 38 publications

Evidence of 13C‐lactate oxidation in the human brain from hyperpolarized 13C‐MRI

Evidence of 13C‐lactate oxidation in the human brain from hyperpolarized 13C‐MRI

Simultaneous fMRI and metabolic MRS of hyperpolarized [1‐13C]pyruvate during nicotine stimulus in rat

Functional activation of pyruvate dehydrogenase in human brain using hyperpolarized [1‐13C]pyruvate

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Lactate saturation limits bicarbonate detection in hyperpolarized ¹³C‐pyruvate MRI of the brain

Evidence of ¹³C‐lactate oxidation in the human brain from hyperpolarized ¹³C‐MRI

Evidence of ¹³C‐lactate oxidation in the human brain from hyperpolarized ¹³C‐MRI

Simultaneous fMRI and metabolic MRS of hyperpolarized [1‐¹³C]pyruvate during nicotine stimulus in rat

Functional activation of pyruvate dehydrogenase in human brain using hyperpolarized [1‐¹³C]pyruvate