<sup>1</sup>H and <sup>13</sup>C NMR study of 2‐hydroxyglutaric acid and its lactone

Bal, Dominika; Gryff‐Keller, Adam

doi:10.1002/mrc.1053

Cited by 43 publications

(57 citation statements)

References 14 publications

(7 reference statements)

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“…A series of phantoms with a range of 2HG concentrations expected to be present in IDH-mutant tumors were also investigated to test the sensitivity limit of MRS. Assignments of 2HG (17) and other metabolites, such as myo-inositol (Myo), choline (Cho), N -acetylaspartic acid (NAA), glutamate (Glu), glutamine (Gln), and γ-amino-butyric acid GABA were made (Fig. 1) according to published literature values (18).…”

Section: Resultsmentioning

confidence: 99%

Detection of 2-Hydroxyglutarate in IDH -Mutated Glioma Patients by In Vivo Spectral-Editing and 2D Correlation Magnetic Resonance Spectroscopy

et al. 2012

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Mutations of arginine 132 (R132) in the enzyme isocitrate dehydrogenase-1 (IDH1) are present in up to 86% of grade II and III gliomas and secondary glioblastoma. R132 mutations in IDH1 result in excess production of the metabolite 2-hydroxyglutarate (2HG), which could be used as a biomarker for this subset of gliomas. Here, we use optimized spectral-editing and two-dimensional (2D) correlation magnetic resonance spectroscopy (MRS) methods to unambiguously detect 2HG non-invasively in glioma patients with IDH1 mutations. By comparison, fitting of conventional 1D MR spectra can provide false-positive readouts owing to spectral overlap of 2HG and chemically similar brain metabolites, such as glutamate and glutamine. 2HG has been found also by 2D high-resolution magic angle spinning MRS performed ex vivo on a separate set of glioma biopsy samples. 2HG detection by in vivo or ex vivo MRS enabled detailed molecular characterization of a clinically important subset of human gliomas. This has implications for diagnosis as well as monitoring of treatments targeting IDH mutations.

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Section: Resultsmentioning

confidence: 99%

Detection of 2-Hydroxyglutarate in IDH -Mutated Glioma Patients by In Vivo Spectral-Editing and 2D Correlation Magnetic Resonance Spectroscopy

et al. 2012

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“…Pairwise comparisons were performed without correction for multiple testing chronic lesion, NAWM, and cortical GM metabolite levels. All model spectra for the basis data set were generated on the basis of reported chemical shifts and coupling constants (18,22,23) by using Vespa 0.6.0 (24). The model spectrum of succinate was also included in the basis data set to allow for possible treatment with corticosteroids.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Patterns in Chronic Multiple Sclerosis Lesions and Normal-appearing White Matter: Intraindividual Comparison by Using 2D MR Spectroscopic Imaging

Fleischer¹,

Kolb²,

Groppa³

et al. 2016

Radiology

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equally to this work.q RSNA, 2016 Purpose:To perform a direct metabolic comparison of chronic lesions and diffusely injured normal-appearing white matter (NAWM) in multiple sclerosis (MS). Materials and Methods:In this institutional review board-approved study, with the written informed consent of all patients, two-dimensional magnetic resonance spectroscopic imaging data in 46 patients with relapsing-remitting MS (median disease duration, 0.8 year) were analyzed by using the spectral quantification tool LCModel. Metabolic patterns were evaluated for non-gadolinium-enhancing chronic lesions and the corresponding contralateral NAWM. The sensitivity of the method was assessed by reproducing the known metabolic differences between cortical gray matter (GM) and NAWM. In addition to individual spectra, averaged spectra were calculated by accumulating free induction decays over all subjects to yield an increased signal-to-noise ratio (SNR), and in turn, to allow improved curve fitting as demonstrated by lower error bounds for low-concentration metabolites. Metabolite concentrations were statistically tested for intraindividual differences (paired t tests) to avoid effects resulting from variations in disease severity or treatment. Results:Differences between the metabolite concentrations in the NAWM and the cortical GM were highly significant (P , .001), demonstrating the reliability of the spectral analysis used here. The spectral patterns of the individual and averaged spectra of chronic lesions and NAWM were qualitatively very similar at visual inspection. Furthermore, in the quantitative comparison, the estimated metabolite concentrations showed only slight differences (P . .07). Owing to increased SNRs in the averaged spectra compared with individual spectra (eg, for chronic lesions, 63 vs 28.4 6 4.1), it was possible to reliably (Cramér-Rao lower bound [CRLB], ,20%) estimate scyllo-inositol levels with a CRLB of 14%. Conclusion:These findings revealed that NAWM exhibits the same metabolic changes as chronic white matter lesions, even very early in the disease course, further supporting the view that such lesions may not be as relevant as widely assumed.q RSNA, 2016

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“…As a consequence of rapid exchange with α-ketoglutarate, the 13 C NMR spectrum of glutamate and glutamine provides direct information about the labeling patterns in the citric acid cycle [8-10]. The 13 C NMR chemical shifts, 1 H chemical shifts, and 1 H- 1 H coupling constants of 2HG are known [11,4], but the 13 C- 13 C coupling constants of 2HG have not been reported. The purpose of this study was to determine all homo- and heteronuclear J couplings of 2HG, improve spectral resolution of 2HG and the overlapping metabolites, and explore methods to improve sensitivity of 2HG detection.…”

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confidence: 99%

Conditions for 13C NMR detection of 2-hydroxyglutarate in tissue extracts from isocitrate dehydrogenase-mutated gliomas

Pichumani

Mashimo

Baek

et al. 2015

Analytical Biochemistry

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13C NMR spectroscopy of extracts from patient tumor samples provides rich information about metabolism. However, in IDH-mutant gliomas 13C labeling is obscured in glutamate and glutamine by the oncometabolite, 2-hydroxyglutaric acid (2HG), prompting development of a simple method to resolve the metabolites. J-coupled multiplets in 2HG were similar to glutamate and glutamine and could be clearly resolved at pH 6. A cryogenically-cooled 13C probe but not J-resolved heteronuclear single quantum coherence spectroscopy significantly improved detection of 2HG. These methods enable the monitoring of 13C-13C spin-spin couplings in 2HG expressing IDH mutant gliomas.

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¹H and ¹³C NMR study of 2‐hydroxyglutaric acid and its lactone

Cited by 43 publications

References 14 publications

Detection of 2-Hydroxyglutarate in IDH -Mutated Glioma Patients by In Vivo Spectral-Editing and 2D Correlation Magnetic Resonance Spectroscopy

Detection of 2-Hydroxyglutarate in IDH -Mutated Glioma Patients by In Vivo Spectral-Editing and 2D Correlation Magnetic Resonance Spectroscopy

Metabolic Patterns in Chronic Multiple Sclerosis Lesions and Normal-appearing White Matter: Intraindividual Comparison by Using 2D MR Spectroscopic Imaging

Conditions for 13C NMR detection of 2-hydroxyglutarate in tissue extracts from isocitrate dehydrogenase-mutated gliomas

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1H and 13C NMR study of 2‐hydroxyglutaric acid and its lactone

Cited by 43 publications

References 14 publications

Detection of 2-Hydroxyglutarate in IDH -Mutated Glioma Patients by In Vivo Spectral-Editing and 2D Correlation Magnetic Resonance Spectroscopy

Detection of 2-Hydroxyglutarate in IDH -Mutated Glioma Patients by In Vivo Spectral-Editing and 2D Correlation Magnetic Resonance Spectroscopy

Metabolic Patterns in Chronic Multiple Sclerosis Lesions and Normal-appearing White Matter: Intraindividual Comparison by Using 2D MR Spectroscopic Imaging

Conditions for 13C NMR detection of 2-hydroxyglutarate in tissue extracts from isocitrate dehydrogenase-mutated gliomas

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¹H and ¹³C NMR study of 2‐hydroxyglutaric acid and its lactone