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 therapy
3. Several 2-HG-specific
MRS acquisition methods at 3T have
been suggested, such as J-editing
4 and PRESS
5,6, 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 B
1 inhomogeneity. Semi-LASER
localisation, with low chemical shift displacement and insensitivity to B
1
inhomogeneity
7, 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 time
9 (Fig. 1: bottom). UHF benefits from increased
SNR and spectral resolution, but experiences greater B
1
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]mm
3 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 3T
8 and 7T
9 (TE = 110ms, TR
= 3 / 5-6 s, sw = 6kHz, np = 2048, NT = 71-128) with outer volume suppression
(OVS) and VAPOR water suppression
10. First- and
second-order shimming was performed with GRESHIM
11 and first-order
shims were adjusted at 7T using
FASTMAP
12. An unsuppressed water spectrum was acquired
for eddy-current correction. LCModel
13 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 CentreReferences
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.