Dataset Information

Dynamic ¹³ C MR spectroscopy as an alternative to imaging for assessing cerebral metabolism using hyperpolarized pyruvate in humans.

ABSTRACT:

Purpose

This study is to investigate time-resolved ¹³ C MR spectroscopy (MRS) as an alternative to imaging for assessing pyruvate metabolism using hyperpolarized (HP) [1-¹³ C]pyruvate in the human brain.

Methods

Time-resolved ¹³ C spectra were acquired from four axial brain slices of healthy human participants (n = 4) after a bolus injection of HP [1-¹³ C]pyruvate. ¹³ C MRS with low flip-angle excitations and a multichannel ¹³ C/¹ H dual-frequency radiofrequency (RF) coil were exploited for reliable and unperturbed assessment of HP pyruvate metabolism. Slice-wise areas under the curve (AUCs) of ¹³ C-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 ¹³ C reconstruction. Reproducibility of HP pyruvate exams was presented by performing two consecutive injections with a 45-minutes interval.

Results

[1-¹³ C]Lactate relative to the total ¹³ C signal (tC) was 0.21-0.24 in all slices. [¹³ C] 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 [1-¹³ C]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 [1-¹³ C]pyruvate.

SUBMITTER: Ma J

PROVIDER: S-EPMC8776582 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

Dynamic <sup>13</sup> C MR spectroscopy as an alternative to imaging for assessing cerebral metabolism using hyperpolarized pyruvate in humans.

Ma Junjie J Pinho Marco C MC Harrison Crystal E CE Chen Jun J Sun Chenhao C Hackett Edward P EP Liticker Jeff J Ratnakar James J Reed Galen D GD Chen Albert P AP Sherry A Dean AD Malloy Craig R CR Wright Steven M SM Madden Christopher J CJ Park Jae Mo JM

Magnetic resonance in medicine 20211022 3

<h4>Purpose</h4>This study is to investigate time-resolved <sup>13</sup> C MR spectroscopy (MRS) as an alternative to imaging for assessing pyruvate metabolism using hyperpolarized (HP) [1-<sup>13</sup> C]pyruvate in the human brain.<h4>Methods</h4>Time-resolved <sup>13</sup> C spectra were acquired from four axial brain slices of healthy human participants (n = 4) after a bolus injection of HP [1-<sup>13</sup> C]pyruvate. <sup>13</sup> C MRS with low flip-angle excitations and a multichannel <s ...[more]

PMID: 34687086

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Project description:IntroductionThe normal heart has remarkable metabolic flexibility that permits rapid switching between mitochondrial glucose oxidation and fatty acid (FA) oxidation to generate ATP. Loss of metabolic flexibility has been implicated in the genesis of contractile dysfunction seen in cardiomyopathy. Metabolic flexibility has been imaged in experimental models, using hyperpolarized (HP) [2-13C]pyruvate MRI, which enables interrogation of metabolites that reflect tricarboxylic acid (TCA) cycle flux in cardiac myocytes. This study aimed to develop methods, demonstrate feasibility for [2-13C]pyruvate MRI in the human heart for the first time, and assess cardiac metabolic flexibility.MethodsGood Manufacturing Practice [2-13C]pyruvic acid was polarized in a 5T polarizer for 2.5-3 hours. Following dissolution, QC parameters of HP pyruvate met all safety and sterility criteria for pharmacy release, prior to administration to study subjects. Three healthy subjects each received two HP injections and MR scans, first under fasting conditions, followed by oral glucose load. A 5cm axial slab-selective spectroscopy approach was prescribed over the left ventricle and acquired at 3s intervals on a 3T clinical MRI scanner.ResultsThe study protocol which included HP substrate injection, MR scanning and oral glucose load, was performed safely without adverse events. Key downstream metabolites of [2-13C]pyruvate metabolism in cardiac myocytes include the glycolytic derivative [2-13C]lactate, TCA-associated metabolite [5-13C]glutamate, and [1-13C]acetylcarnitine, catalyzed by carnitine acetyltransferase (CAT). After glucose load, 13C-labeling of lactate, glutamate, and acetylcarnitine from 13C-pyruvate increased by 39.3%, 29.5%, and 114%, respectively in the three subjects, that could result from increases in lactate dehydrogenase (LDH), pyruvate dehydrogenase (PDH), and CAT enzyme activity as well as TCA cycle flux (glucose oxidation).ConclusionsHP [2-13C]pyruvate imaging is safe and permits non-invasive assessment of TCA cycle intermediates and the acetyl buffer, acetylcarnitine, which is not possible using HP [1-13C]pyruvate. Cardiac metabolite measurement in the fasting/fed states provides information on cardiac metabolic flexibility and the acetylcarnitine pool.

Project description:The detection and treatment monitoring of inflammatory states remain challenging in part due to the multifactorial mechanisms of immune activation and spectrum of clinical manifestations. Currently, diagnostic strategies tend to be subjective and limited quantitative tools exist to monitor optimal treatment strategies. Pro-inflammatory M1 polarized macrophages exhibit a distinct metabolic glycolytic phenotype compared to the continuum of M2 polarization states. In the present study, the distinct metabolic phenotypes of resting and activated macrophages were successfully characterized and quantified using hyperpolarized carbon-13 (13C) labeled pyruvate and its metabolic products, i.e. lactate, as a biomarker of resting, disease and treated states. Methods: Mouse macrophage J774A.1 cells were used as a model system in an NMR compatible bioreactor to facilitate dynamic hyperpolarized 13C measurements. The glycolytic metabolism of the cells in the quiescent or resting state were compared with macrophages stimulated by lipopolysaccharide, a classical M1 activator using hyperpolarized 13C labeled pyruvate. Additionally, the activated macrophages were also treated with a non-steroidal anti-inflammatory drug to assess the changes in hyperpolarized lactate signal. The hyperpolarized lactate signals were then correlated using biochemical and molecular assays. Results: We first validated our model system of inflammatory cells by the hallmarks of M1 polarization using steady state metabolic profiling with high resolution NMR in conjunction with nitric oxide Greiss assay, enzyme activity, and mRNA expression. Subsequently, we clearly showed that the cutting edge technology of hyperpolarized 13C NMR can be used to detect elevated lactate levels in M1 polarized macrophages in comparison to control and non-steroidal anti-inflammatory drug treated M2 states. Conclusion: Hyperpolarized 13C lactate has the potential to serve as a biomarker to non-invasively detect and quantify pro-inflammatory state of immune regulatory cells and its response to therapy.

Dataset Information

Dynamic ¹³ C MR spectroscopy as an alternative to imaging for assessing cerebral metabolism using hyperpolarized pyruvate in humans.

Purpose

Methods

Results

Conclusions

Publications

Dynamic <sup>13</sup> C MR spectroscopy as an alternative to imaging for assessing cerebral metabolism using hyperpolarized pyruvate in humans.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Dynamic 13 C MR spectroscopy as an alternative to imaging for assessing cerebral metabolism using hyperpolarized pyruvate in humans.

Purpose

Methods

Results

Conclusions

Publications

Dynamic <sup>13</sup> C MR spectroscopy as an alternative to imaging for assessing cerebral metabolism using hyperpolarized pyruvate in humans.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dynamic ¹³ C MR spectroscopy as an alternative to imaging for assessing cerebral metabolism using hyperpolarized pyruvate in humans.