The benefits of in vivo 2-hydroxyglutarate detection using semi-LASER at 7T and 3T: a comparative study
Adam Berrington1, Natalie Voets1, Sarah J Larkin2, Nick de Pennington2, James Mccullagh3, Khalid Al-Qahtani3, Richard Stacey4, Peter Jezzard1, Stuart Clare1, Christopher J Schofield3, Olaf Ansorge2, Tom Cadoux-Hudson4, Puneet Plaha4, and Uzay E Emir1

1FMRIB Centre, University of Oxford, Oxford, United Kingdom, 2Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom, 3Department of Chemistry, University of Oxford, Oxford, United Kingdom, 4Department of Neurosurgery, University of Oxford, Oxford, United Kingdom

Synopsis

We assess the ability of semi-LASER to detect 2-hydroxyglutarate (2-HG), a metabolic product of mutation in the enzyme IDH, in gliomas at 3T and 7T. Robust detection could lead to increased patient stratification yet is hindered by signal overlap and compartmental artifacts. We find semi-LASER (TE=110ms), with broadband adiabatic refocussing, is able to correctly identify IDH-mutants at 3T and 7T in a sample of six patients. Fitting errors are greatly reduced at 7T and additional metabolites (GABA, Gly) are detected in some IDH-mutated tumours. We conclude semi-LASER provides a unique clinical opportunity for 2-HG detection at both 3T and 7T.

Aim

We directly compare long TE semi-LASER acquisition schemes at 3T and 7T in glioma patients to assess the advantages of ultra-high field (UHF) for in vivo 2-hydroxyglutarate detection.

Introduction

2-hydroxyglutarate (2-HG) accumulates in the majority (~80%) of low grade gliomas as a product of somatic mutation of isocitrate dehydrogenase (IDH)1,2. Robust detection of the ‘tumour metabolite’ 2-HG, therefore, presents a unique clinical opportunity to non-invasively stratify glioma patients and target therapy3. Several 2-HG-specific MRS acquisition methods at 3T have been suggested, such as J-editing4 and PRESS5,6, yet detection poses a significant challenge because of overlaps with glutamate (Glu), glutamine (Gln) and γ-aminobutyric acid (GABA) signals. Spectral patterns are also modulated by compartmental artifacts, chemical shift and B1 inhomogeneity. Semi-LASER localisation, with low chemical shift displacement and insensitivity to B1 inhomogeneity7, has recently been proposed for 2-HG detection at 3T (TE = 110ms)8 and shows reduced signal overlap from Gln and Glu as well as resolved 2-HG peak at 1.9 ppm (Fig. 1: top), which leads to lower fitting cross-correlations. Additionally, 2-HG detection with semi-LASER has been demonstrated at UHF (≥7T) using the same echo time9 (Fig. 1: bottom). UHF benefits from increased SNR and spectral resolution, but experiences greater B1 inhomogeneity and chemical shift. Hence, compartmental J-evolution artifacts may lessen UHF gains for 2-HG. As clinical 7T systems begin to emerge, there is a need to assess the advantage they provide relative to current 3T systems. We therefore performed a direct comparison using long TE (110ms) semi-LASER, with broadband adiabatic refocussing, on six glioma patients at 3T and 7T.

Methods

Six glioma patients, with histopathologically confirmed IDH status following surgical resection (5 IDH-mutant, 1 wild-type IDH), were scanned over two sessions on 3T and 7T whole body MR systems (Siemens, Erlangen) with 32-channel receive array head-coils. Our [20x20x20]mm3 voxel was positioned, with reference to a 1mm isotropic resolution T1-MPRAGE image, in tumour regions of maximum homogeneity. Care was taken to position voxels in similar positions at both field strengths. We use 2-HG-optimised semi-LASER sequences at 3T8 and 7T9 (TE = 110ms, TR = 3 / 5-6 s, sw = 6kHz, np = 2048, NT = 71-128) with outer volume suppression (OVS) and VAPOR water suppression10. First- and second-order shimming was performed with GRESHIM11 and first-order shims were adjusted at 7T using FASTMAP12. An unsuppressed water spectrum was acquired for eddy-current correction. LCModel13 was used to fit metabolite concentrations using fully-localised basis sets of 20 metabolites, generated from density matrix simulations with real refocussing pulses in Matlab (Mathworks, Inc). Fitted concentrations are reported relative to total creatine (tCr). Only metabolite concentrations with Cramér-Rao lower bound of fitting (CRLB) ≤ 40% are reported.

Results

High quality spectra were achieved across field strengths with similar voxel positioning (Fig. 2). Using semi-LASER (110ms) at 3T and 7T resulted in clear 2-HG peaks in the spectra at 1.9 ppm (and additionally 2.25 ppm at 7T) in all IDH-mutant subjects (Fig. 3). As expected, 2-HG could not be quantified at either field strength in the wild-type IDH (i.e. non-mutated) patient (7T: 55%; 3T: 47%) (Fig. 3, right). The mean error of fitting (CRLB) for 2-HG in IDH-mutant tumours was much lower at 7T (5.8 ± 2.6%) than at 3T (14.8 ± 6.5%). We find no significant difference between the relative concentration values of 2-HG at 3T or 7T (Fig. 4). Similar concentrations of Glu, Gln, total Cho (tCho) and inositol (Ins) were found at both field strengths, with slightly reduced CRLBs at 7T (Fig. 5). The metabolites GABA and glycine (Gly) were undetected in all IDH-mutant tumours at 3T, yet detected in small quantities at 7T in three patients.

Conclusion

We confirmed that semi-LASER at 3T and 7T was robustly able to identify increased 2-HG levels arising from IDH-mutants in a sample of six patients. The increased spectral resolution at 7T, in addition to the unambiguous inverted 2-HG peak at 2.25 ppm, results in reduced overlap with Glu/Gln/GABA thus improving the fitting. The absence of GABA at 3T may be explained by peak overlap with 2-HG at 1.9 ppm, which also resulted in larger CRLBs. The additional detection of Gly at 7T may allow further metabolic profiling of tumours. We conclude that semi-LASER at TE=110ms may provide a unique clinical opportunity to simultaneously obtain a robust in vivo measurement of 2-HG as well as detect other cancer-specific metabolic markers, particularly at 7T. Further work, on a larger cohort of patients, is required to fully establish these findings.

Acknowledgements

ESPRC funding through the Life Sciences Interface Doctoral Training Centre

References

1 Parsons D W, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008;321:1807–1812.

2 Dang L, White D W, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009;462:739–44.

3 Yen K E, Bittinger M A, Su S M, Fantin V R. Cancer-associated IDH mutations: biomarker and therapeutic opportunities. Oncogene 2010;29:6409–6417.

4 Andronesi O C, Kim G S, Gerstner E, Batchelor T, et al.. 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.

5 Pope W B, Prins R M, Albert Thomas M, et al. Non-invasive detection of 2-hydroxyglutarate and other metabolites in IDH1 mutant glioma patients using magnetic resonance spectroscopy. J. Neurooncol. 2012;107:197–205.

6 Choi C, Ganji S K, DeBerardinis R J, et al. 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat. Med. 2012;18:624–9.

7 Oz G, Tkác I. Short-echo, single-shot, full-intensity proton magnetic resonance spectroscopy for neurochemical profiling at 4 T: validation in the cerebellum and brainstem. MRM. 2011;65:901–10.

8 Berrington A, Voets N, Larkin S J, et al. Improved detection of 2-hydroxyglutarate with a broadband semi-LASER sequence at 3T. In: ESMRMB. Edinburgh UK; 2015. p. S299.

9 Emir U E, Larkin S J, de Pennington N, et al. Non-invasive quantification of 2-hydroxyglutarate in human gliomas with IDH1 and IDH2 mutations. Cancer Res. In Press.

10 Tkác I, Gruetter R. Methodology of 1H NMR spectroscopy of the human brain at very high magnetic fields. Appl. Magn. Reson. 2005;29:139–157.

11 Shah S, Kellman P, Greiser A, Weale P J, Zuehlsdorff S, Jerecic R. Rapid Fieldmap Estimation for Cardiac Shimming. In: Proc. Int. Soc. Magn. Reson. Med. Honolulu, USA; 2009. p565

12 Gruetter R. Automatic, localized in vivo adjustment of all first and second order shim coils. MRM. 1993;29:804–811.

13 Provencher S W. Estimation of metabolite concentrations from localized in vivo proton NMR spectra. MRM. 1993;30:672–9.

Figures

Comparison of optimised semi-LASER (TE=110ms) acquisition schemes on a phantom containing glycine (Gly) and 2-HG at 3T and 7T (NT = 256). Spin resonances of 2-HG labelled H2-H4.

Voxel positioning and basis fitting with LCModel for a single IDH-mutant tumour. Individual fits of overlapping metabolites 2-HG, Glu, Gln, GABA and also lactate (Lac) shown. CRLBs lower at 7T for 2-HG and Lac. Gln CRLB is higher at 7T but still present, whereas Glu not detected at 3T.

2-HG fits of all patients (except P02: Fig. 2). The fit of P04 is restricted to 1.5 ppm because of large macromolecular contamination within this voxel. No 2-HG is detected in the wild-type IDH patient across both field strengths as expected. Excellent spectral quality at 3T and 7T achieved with semi-LASER.

Average metabolite concentrations across all IDH-mutants (N=5) relative to total creatine for 3T and 7T shown with standard deviation. Concentrations of 2-HG similar at 7T and 3T. GABA and Gly only detected at 7T.

Table comparing IDH-mutant fitting CRLBs at 3T and 7T where N = number of patients. Reliable detection ≤ 40 % and mean CRLB given when N > 2. All metabolites except Gln have reduced CRLBs at 7T.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
1123