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Clinical Neuroradiology
Published in: Clinical Neuroradiology 1/2019

01-03-2019 | Original Article

In vivo Metabolic Profiles as Determined by 31P and short TE 1H MR-Spectroscopy

No Difference Between Patients with IDH Wildtype and IDH Mutant Gliomas

Authors: Katharina J. Wenger, Elke Hattingen, Kea Franz, Joachim Steinbach, Oliver Bähr, Ulrich Pilatus

Published in: Clinical Neuroradiology | Issue 1/2019

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Abstract

Purpose

Previous ex vivo spectroscopic data from tissue samples revealed differences in phospholipid metabolites between isocitrate dehydrogenase mutated (IDHmut) and IDH wildtype (IDHwt) gliomas. We investigated whether these changes can be found in vivo using 1H-decoupled 31P magnetic resonance spectroscopic imaging (MRSI) with 3D chemical shift imaging (CSI) at 3 T in patients with low and high-grade gliomas.

Methods

The study included 33 prospectively enrolled, mostly untreated patients who met spectral quality criteria according to the World Health Organization (WHO II n = 7, WHO III n = 17, WHO IV n = 9; 25 patients IDHmut, 8 patients IDHwt). The MRSI protocol included 1H decoupled 31P MRSI with 3D CSI (3D 31P CSI), 2D 1H CSI and a 1H single voxel spectroscopy sequence (TE 30 ms) from the tumor area. For 1H MRS, absolute metabolite concentration values were calculated (phantom replacement method). For 31P MRS, metabolite intensity ratios were calculated for the choline (C) and ethanolamine (E)-containing metabolites.

Results

In our patient cohort we did not find significant differences for the ratio of phosphocholine (PC) and phosphoethanolamine (PE), PC/PE, (p = 0.24) for IDHmut compared to IDHwt gliomas. Furthermore, we found no elevated ratios of glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE), GPC/GPE, (p = 0.68) or GPC/PE (p = 0.12) for IDHmut gliomas. Even the ratio (PC+GPC)/(PE+GPE) showed no significant differences with respect to mutation status (p = 0.16). Nonetheless, changes related to tumor grade regarding intracellular pH (pHi) and phospholipid metabolism as well as absolute metabolite concentrations of co-registered 2D 1H CSI data for tumor and control tissue showed the anticipated results.

Conclusion

Using 3D-CSI data acquisition, in vivo 31P MR spectroscopic measurement of phospholipid metabolites could not distinguish between IDHmut and IDHwt.
Appendix
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Literature
1.
Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131:803–20.CrossRefPubMed
2.
Chen R, Cohen AL, Colman H. Targeted therapeutics in patients with high-grade gliomas: past, present, and future. Curr Treat Options Oncol. 2016;17:42.CrossRefPubMed
3.
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360:765–73.CrossRefPubMedPubMedCentral
4.
Bleeker FE, Lamba S, Leenstra S, Troost D, Hulsebos T, Vandertop WP, Frattini M, Molinari F, Knowles M, Cerrato A, Rodolfo M, Scarpa A, Felicioni L, Buttitta F, Malatesta S, Marchetti A, Bardelli A. IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum Mutat. 2009;30:7–11.CrossRefPubMed
5.
Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 2008;116:597–602.CrossRefPubMed
6.
Watanabe T, Nobusawa S, Kleihues P, Ohgaki H. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol. 2009;174:1149–53.CrossRefPubMedPubMedCentral
7.
Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, Su SM. Cancer-associated IDH1 mutations produce 2‑hydroxyglutarate. Nature. 2009;462:739–44.CrossRefPubMedPubMedCentral
8.
Zhao H, Heimberger AB, Lu Z, Wu X, Hodges TR, Song R, Shen J. Metabolomics profiling in plasma samples from glioma patients correlates with tumor phenotypes. Oncotarget. 2016;7:20486–95.CrossRefPubMedPubMedCentral
9.
Capper D, Simon M, Langhans CD, Okun JG, Tonn JC, Weller M, von Deimling A, Hartmann C; German Glioma Network. 2‑Hydroxyglutarate concentration in serum from patients with gliomas does not correlate with IDH1/2 mutation status or tumor size. Int J Cancer. 2012;131:766–8.CrossRefPubMed
10.
Fathi AT, Nahed BV, Wander SA, Iafrate AJ, Borger DR, Hu R, Thabet A, Cahill DP, Perry AM, Joseph CP, Muzikansky A, Chi AS. Elevation of urinary 2‑hydroxyglutarate in IDH-mutant glioma. Oncologist. 2016;21:214–9.CrossRefPubMedPubMedCentral
11.
de la Fuente MI, Young RJ, Rubel J, Rosenblum M, Tisnado J, Briggs S, Arevalo-Perez J, Cross JR, Campos C, Straley K, Zhu D, Dong C, Thomas A, Omuro AA, Nolan CP, Pentsova E, Kaley TJ, Oh JH, Noeske R, Maher E, Choi C, Gutin PH, Holodny AI, Yen K, DeAngelis LM, Mellinghoff IK, Thakur SB. Integration of 2‑hydroxyglutarate-proton magnetic resonance spectroscopy into clinical practice for disease monitoring in isocitrate dehydrogenase-mutant glioma. Neuro Oncol. 2016;18:283–90.CrossRefPubMed
12.
Jalbert LE, Elkhaled A, Phillips JJ, Neill E, Williams A, Crane JC, Olson MP, Molinaro AM, Berger MS, Kurhanewicz J, Ronen SM, Chang SM, Nelson SJ. Metabolic profiling of IDH mutation and malignant progression in infiltrating glioma. Sci Rep. 2017;7:44792.CrossRefPubMedPubMedCentral
13.
de Graaf RA. In vivo NMR spectroscopy: principles and techniques. 2nd ed. Hoboken: Wiley; 2007.CrossRef
14.
Andronesi OC, Kim GS, Gerstner E, Batchelor T, Tzika AA, Fantin VR, Vander Heiden MG, Sorensen AG. Detection of 2‑hydroxyglutarate in IDH-mutated glioma patients by in vivo spectral-editing and 2D correlation magnetic resonance spectroscopy. Sci Transl Med. 2012;4:116ra4.CrossRefPubMedPubMedCentral
15.
Choi C, Ganji SK, DeBerardinis RJ, Hatanpaa KJ, Rakheja D, Kovacs Z, Yang XL, Mashimo T, Raisanen JM, Marin-Valencia I, Pascual JM, Madden CJ, Mickey BE, Malloy CR, Bachoo RM, Maher EA. 2‑hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med. 2012;18:624–9.CrossRefPubMedPubMedCentral
16.
Choi C, Raisanen JM, Ganji SK, Zhang S, McNeil SS, An Z, Madan A, Hatanpaa KJ, Vemireddy V, Sheppard CA, Oliver D, Hulsey KM, Tiwari V, Mashimo T, Battiste J, Barnett S, Madden CJ, Patel TR, Pan E, Malloy CR, Mickey BE, Bachoo RM, Maher EA. Prospective longitudinal analysis of 2‑hydroxyglutarate magnetic resonance spectroscopy identifies broad clinical utility for the management of patients with IDH-mutant Glioma. J Clin Oncol. 2016;34:4030–9.CrossRefPubMedPubMedCentral
17.
Esmaeili M, Hamans BC, Navis AC, van Horssen R, Bathen TF, Gribbestad IS, Leenders WP, Heerschap A. IDH1 R132H mutation generates a distinct phospholipid metabolite profile in glioma. Cancer Res. 2014;74:4898–907.CrossRefPubMed
18.
Wiestler B, Capper D, Hovestadt V, Sill M, Jones DT, Hartmann C, Felsberg J, Platten M, Feiden W, Keyvani K, Pfister SM, Wiestler OD, Meyermann R, Reifenberger G, Pietsch T, von Deimling A, Weller M, Wick W. Assessing CpG island methylator phenotype, 1p/19q codeletion, and MGMT promoter methylation from epigenome-wide data in the biomarker cohort of the NOA-04 trial. Neuro Oncol. 2014;16:1630–8.CrossRefPubMedPubMedCentral
19.
Provencher SW. Automatic quantitation of localized in vivo 1H spectra with LCModel. NMR Biomed. 2001;14:260–4.CrossRefPubMed
20.
Hattingen E, Magerkurth J, Pilatus U, Mozer A, Seifried C, Steinmetz H, Zanella F, Hilker R. Phosphorus and proton magnetic resonance spectroscopy demonstrates mitochondrial dysfunction in early and advanced Parkinson’s disease. Brain. 2009;132:3285–97.CrossRefPubMed
21.
Hattingen E, Bähr O, Rieger J, Blasel S, Steinbach J, Pilatus U. Phospholipid metabolites in recurrent glioblastoma: in vivo markers detect different tumor phenotypes before and under antiangiogenic therapy. PLoS One. 2013;8(3):e56439.CrossRefPubMedPubMedCentral
22.
Wenger KJ, Hattingen E, Franz K, Steinbach JP, Bähr O, Pilatus U. Intracellular pH measured by 31 P-MR-spectroscopy might predict site of progression in recurrent glioblastoma under antiangiogenic therapy. J Magn Reson Imaging. 2017;18:160.CrossRef
23.
Petroff OA, Prichard JW, Behar KL, Alger JR, den Hollander JA, Shulman RG. Cerebral intracellular pH by 31P nuclear magnetic resonance spectroscopy. Neurology. 1985;35:781–8.CrossRefPubMed
24.
Hattingen E, Magerkurth J, Pilatus U, Hübers A, Wahl M, Ziemann U. Combined (1)H and (31)P spectroscopy provides new insights into the pathobiochemistry of brain damage in multiple sclerosis. NMR Biomed. 2011;24:536–46.CrossRefPubMed
25.
Starčuk Z Jr, Starčuková J. Quantum-mechanical simulations for in vivo MR spectroscopy: principles and possibilities demonstrated with the program NMRscopeB. Anal Biochem. 2017;529:79-97.CrossRefPubMed
26.
Tofts P, Grossman RI. Quantitative MRI of the brain: measuring changes caused by disease. Hoboken: Wiley; 2004.
27.
Hattingen E, Pilatus U, Franz K, Zanella FE, Lanfermann H. Evaluation of optimal echo time for 1H-spectroscopic imaging of brain tumors at 3 Tesla. J Magn Reson Imaging. 2007;26:427–31.CrossRefPubMed
28.
Herminghaus S, Pilatus U, Möller-Hartmann W, Raab P, Lanfermann H, Schlote W, Zanella FE. Increased choline levels coincide with enhanced proliferative activity of human neuroepithelial brain tumors. NMR Biomed. 2002;15:385–92.CrossRefPubMed
29.
Ishimaru H, Morikawa M, Iwanaga S, Kaminogo M, Ochi M, Hayashi K. Differentiation between high-grade glioma and metastatic brain tumor using single-voxel proton MR spectroscopy. Eur Radiol. 2001;11:1784–91.CrossRefPubMed
30.
McLean MA, Sun A, Bradstreet TE, Schaeffer AK, Liu H, Iannone R, Herman G, Railkar RA, Joubert I, Gillard JH, Price SJ, Griffiths JR. Repeatability of edited lactate and other metabolites in astrocytoma at 3T. J Magn Reson Imaging. 2012;36:468–75.CrossRefPubMed
31.
Rijpkema M, Schuuring J, van der Meulen Y, van der Graaf M, Bernsen H, Boerman R, van der Kogel A, Heerschap A. Characterization of oligodendrogliomas using short echo time 1H MR spectroscopic imaging. NMR Biomed. 2003;16:12–8.CrossRefPubMed
32.
Reitman ZJ, Jin G, Karoly ED, Spasojevic I, Yang J, Kinzler KW, He Y, Bigner DD, Vogelstein B, Yan H. Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome. Proc Natl Acad Sci U S A. 2011;108:3270–5.CrossRefPubMedPubMedCentral
33.
Bisdas S, Chadzynski GL, Braun C, Schittenhelm J, Skardelly M, Hagberg GE, Ethofer T, Pohmann R, Shajan G, Engelmann J, Tabatabai G, Ziemann U, Ernemann U, Scheffler K. MR spectroscopy for in vivo assessment of the oncometabolite 2‑hydroxyglutarate and its effects on cellular metabolism in human brain gliomas at 9.4T. J Magn Reson Imaging. 2016;44:823–33.CrossRefPubMed
34.
Izquierdo-Garcia JL, Viswanath P, Eriksson P, Chaumeil MM, Pieper RO, Phillips JJ, Ronen SM. Metabolic reprogramming in mutant IDH1 glioma cells. PLoS One. 2015;10(2):e0118781.CrossRefPubMedPubMedCentral
35.
Elkhaled A, Jalbert LE, Phillips JJ, Yoshihara HAI, Parvataneni R, Srinivasan R, Bourne G, Berger MS, Chang SM, Cha S, Nelson SJ. Magnetic resonance of 2‑hydroxyglutarate in IDH1-mutated low-grade gliomas. Sci Transl Med. 2012;4:116ra5.CrossRefPubMedPubMedCentral
36.
Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, Campos C, Fabius AW, Lu C, Ward PS, Thompson CB, Kaufman A, Guryanova O, Levine R, Heguy A, Viale A, Morris LG, Huse JT, Mellinghoff IK, Chan TA. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012;483:479–83.CrossRefPubMedPubMedCentral
37.
Righi V, Roda JM, Paz J, Mucci A, Tugnoli V, Rodriguez-Tarduchy G, Barrios L, Schenetti L, Cerdán S, García-Martín ML. 1H HR-MAS and genomic analysis of human tumor biopsies discriminate between high and low grade astrocytomas. NMR Biomed. 2009;22:629–37.CrossRefPubMed
38.
Venkatesh HS, Chaumeil MM, Ward CS, Haas-Kogan DA, James CD, Ronen SM. Reduced phosphocholine and hyperpolarized lactate provide magnetic resonance biomarkers of PI3K/Akt/mTOR inhibition in glioblastoma. Neuro Oncol. 2012;14:315–25.CrossRefPubMed
39.
Bottomley PA, Griffiths JR, editors. Handbook of magnetic resonance spectroscopy in vivo: MRS theory, practice and applications. Chichester, Hoboken: Wiley & Sons; 2016.
40.
Metadata
Title
In vivo Metabolic Profiles as Determined by 31P and short TE 1H MR-Spectroscopy
No Difference Between Patients with IDH Wildtype and IDH Mutant Gliomas
Authors
Katharina J. Wenger
Elke Hattingen
Kea Franz
Joachim Steinbach
Oliver Bähr
Ulrich Pilatus
Publication date
01-03-2019
Publisher
Springer Berlin Heidelberg
Published in
Clinical Neuroradiology / Issue 1/2019
Print ISSN: 1869-1439
Electronic ISSN: 1869-1447
DOI
https://doi.org/10.1007/s00062-017-0630-8

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