Korean J Radiol.  2016 Oct;17(5):620-632. 10.3348/kjr.2016.17.5.620.

In-Vivo Proton Magnetic Resonance Spectroscopy of 2-Hydroxyglutarate in Isocitrate Dehydrogenase-Mutated Gliomas: A Technical Review for Neuroradiologists

• Kim H
• Kim S
• Lee HH
• Heo H

• KMID: 2458053
• DOI: http://doi.org/10.3348/kjr.2016.17.5.620

Abstract

The diagnostic and prognostic potential of an onco-metabolite, 2-hydroxyglutarate (2HG) as a proton magnetic resonance spectroscopy (1H-MRS) detectable biomarker of the isocitrate dehydrogenase (IDH)-mutated (IDH-MT) gliomas has drawn attention of neuroradiologists recently. However, due to severe spectral overlap with background signals, quantification of 2HG can be very challenging. In this technical review for neuroradiologists, first, the biochemistry of 2HG and its significance in the diagnosis of IDH-MT gliomas are summarized. Secondly, various 1H-MRS methods used in the previous studies are outlined. Finally, wereview previous in vivo studies, and discuss the current status of 1H-MRS in the diagnosis of IDH-MT gliomas.

Keyword

Proton; Magnetic resonance spectroscopy; MRS; Isocitrate dehydrogenase; 2-hydroxyglutarate; Glioma; Mutation

MeSH Terms

Biomarkers, Tumor/*metabolism
Brain Neoplasms/*diagnosis/genetics/metabolism
Glioma/*diagnosis/genetics/metabolism
Glutarates/*metabolism
Humans
Isocitrate Dehydrogenase/*genetics
Mutation
Prognosis
Proton Magnetic Resonance Spectroscopy/*methods
Biomarkers, Tumor
Glutarates
Isocitrate Dehydrogenase

Figure

• 

  Fig. 1 Simplified metabolic pathways associated with isocitrate dehydrogenase (IDH) and 2-hydroxyglutarate (2HG). Mutations of IDH1 and IDH2 result in overproduction of 2HG. 1H-MRS-visible metabolites including 2HG are marked in bold. Acetyl-CoA = acetyl coenzyme A, Gln = glutamine, Glu = glutamate, GSH = glutathione, GSSG = glutathione disulfide, H2O = water, H2O2 = hydrogen peroxide, IDH-MT = mutant isocitrate dehydrogenase, NAD = nicotinamide adenine dinucleotide, NADH = nicotinamide adenine dinucleotide hydrate, NADP = nicotinamide adenine dinucleotide phosphate, NADPH = nicotinamide adenine dinucleotide phosphate hydrate, α-KG = alpha-ketoglutarate

• 

  Fig. 2 Simulated spectra of 2HG and its background metabolites at 3T. Concentration ratio of 5:9.25:4.5:1.5:1.5 (mM) was assumed for 2HG:Glu:Gln:GABA:NAAG. Linewidth of all spectra were broadened to mimic in-vivo spectra. GABA = gamma-aminobutylic acid, Gln = glutamine, Glu = glutamate, NAAG = N-acetylaspartylglutamate, 2HG = 2-hydroxyglutarate

• 

  Fig. 3 Representative in-vivo spectra of normal human brain at 3T acquired at short TE (A) and long TE (B). Spectral baseline is also illustrated in A, which is typically assumed to be negligible in B. In B, spectrum consists mainly of Cr (~3.0 and ~3.9 ppm), Cho (~3.2 ppm), and NAA (~2.0 ppm) signals. Spectral locations of 2HG are also shown. Asp = aspartate, Cho = choline, Cr = creatine, GABA = gamma-aminobutylic acid, Gln = glutamine, Glu = glutamate, Gly = glycine, Lac = lactate, mI = myo-inositol, NAA = N-acetylaspartate, NAAG = N-acetylaspartylglutamate, Tau = taurine, TE = echo time, 2HG = 2-hydroxyglutarate

• 

  Fig. 4 Illustration of basic principle of difference editing method for 2HG editing in phantom at 3T. Spectra acquired with and without editing pulses that are tuned at ~1.9 ppm are shown in red and blue, respectively. By subtracting latter from former, edited 2HG signal is obtained at ~4.0 ppm in difference spectrum (shown in inset), which appears as doublet. Note that peak-to-peak distance of edited 2HG doublet is ~10 Hz at 3T. 2HG = 2-hydroxyglutarate

• 

  Fig. 5 Representative brain spectra of glioma patients by using short TE and long TE methods at 3T. Spectra from IDH-MT glioma patient (A, B) are compared with those from IDH-WT glioma patient (C, D). For all spectra, correct diagnostic results were obtained by LCModel (i.e., 2HG-positive for A and B, and 2HG-negative for C and D). Compared to spectra from normal human brain (Fig. 3), Cho/NAA ratios were substantially increased in these glioma patients. Cho = choline, Cr = creatine, GABA = gamma-aminobutylic acid, Gln = glutamine, Glu = glutamate, IDH-MT = isocitrate dehydrogenase-mutated, IDH-WT = isocitrate dehydrogenase wild-type, Lac = lactate, mI = myo-inositol, NAA = N-acetylaspartate, NAAG = N-acetylaspartylglutamate, TE = echo time, 2HG = 2-hydroxyglutarate

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