The semi-LASER sequence optimized for 2-HG detection with a TE of 110 ms successfullydemonstrated distinct cystathionine peaks in glioma patients with molecularly definedoligodendroglioma (IDH-mutant and 1p/19q codeleted) at 7T. While a prospective, betterpowered study is needed to confirm our observations, we propose that our method has thepotential to allow presurgical stratification of patients with IDH-mutant glioma into those witholigodendrogliomas and astrocytomas; which is of important prognostic significance. (PDF) Detection of Cystathionine, 2-Hydroxyglutarate and Citrate in Oligodendrogliomas at 7T using Long-TE Semi-LASER. Available from: https://www.researchgate.net/publication/349575306_Detection_of_Cystathionine_2-Hydroxyglutarate_and_Citrate_in_Oligodendrogliomas_at_7T_using_Long-TE_Semi-LASER [accessed Mar 03 2021].

1. Detection of Cystathionine, 2-hydroxyglutarate and Citrate in Oligodendrogliomas (IDH-mutant
and 1p/19q codeleted) at 7T using at 3 T Using Long-TE Semi-LASER
Uzay E Emir12, Natalie Voets3, Sarah Larkin4, Nick de Pennington4, Puneet Plaha4, Richard
Stacey4, James Mccullagh4, Christopher J. Schofield4, Stuart Clare3, Peter Jezzard3, Tom
Cadoux-Hudson4, Olaf Ansorge4,
1Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, United
States,
2School of Health Sciences, Purdue University, West Lafayette, IN, United States
3Wellcome Centre for Integrative Neuroimaging, Nuffield Dept of Clinical Neurosciences,
University of Oxford, Oxford, United Kingdom,
4Oxford University Hospitals NHS Trust, Oxford, United Kingdom.
Introduction
Diffuse gliomas are the most common primary brain tumor. Biopsy represents the gold standard
for diagnosis and classification and will remain part of standard of care (1). However, biopsies are
invasive, static, and prone to sampling bias, and are therefore unsuitable for disease monitoring
and capturing tumor heterogeneity. There is a clear need for non-invasive clinical biomarkers that
are: (a) robustly diagnostic at the molecular level, (b) quantitative, (c) prognostic, (d) predictive,
and (e) dynamic. Accumulating evidence suggests that MRS at ultra-high field (UHF) can meet
these needs by providing robust molecular feature elucidation in vivo and offering a novel strategy
for diagnostic imaging in glioma patients (2).
Given the rapid pace of discoveries in glioma genomics and metabolomics, it is likely that
improvements in diagnostic imaging using UHF MRS can be made by systematically reanalyzing
previously generated data in light of new knowledge. It has been recently demonstrated that
cystathionine can be detected in vivo via MRS and it is proposed to be a potential biomarker for
1p/19q co-deleted gliomas (3). If confirmed, this approach effectively would allow us to make a
non-invasive diagnosis of oligodendroglioma (IDH-mutant and 1p/19q codeleted) versus
astrocytoma (IDH-mutant but 1p/19q wildtype) (4). This is clinically relevant as
oligodendrogliomas have a better prognosis than astrocytomas and benefit from supramaximal
neurosurgical resection. In this study, we tested this by reanalyzing existing UHF MRS spectra
using a refined basis set that included the potential oncometabolite cystathionine (2).
Methods:
A total of 20 glioma patients were recruited (age= 37±11, 13 males) for a 7T MRI scan. Written
and informed consent was obtained from all participants in the study, which was approved by the
relevant institutional ethics committee. As assessed by immunohistochemical and DNA
sequencing from surgical tissue biopsies, 15 patients (age = 41±10, 12 males) were identified as
carrying isocitrate dehydrogenase 1 (IDH1) R132H mutation (4 of them with 1p/19q co-deletion)
and 5 (age = 27±5, four females) with a rare IDH2 variant and 1p/19q co-deletion. A semi-
localization by an adiabatic selective refocusing (semi-LASER) pulse sequence was performed
within each voxel of interest (VOI) for spectra measurements (5). The spectroscopy acquisition

2. parameters were as below: volume size = 20 x 20 x 20 mm3 = 8 mL, TE = 110 ms, TR = 5-6 s,
number of transients NT = 128, spectral bandwidth = 6 kHz, and data points = 2048. LCModel
analysis with a refined basis set that included cystathionine, 2-hydroxyglutarate (2-HG), and citrate
was applied for metabolite quantification. Metabolite concentrations are reported relative to the
internal reference of total choline (tCho).
Results:
Due to the negative spectral pattern of 2-HG at a TE of 110 ms, and increased chemical shift
dispersion at 7T, the cystathionine signal was clearly discernible in addition to the 2-HG signal in
spectra of the tumor voxel in glioma patients with 1p/19q codeletion (Figure 1). The quantification
of cystathionine using a refined LCModel basis set is illustrated in Figure 2. In line with a recent
study (ref), 1p/19q co-deleted gliomas have a significantly higher level of cystathionine/tCho
(1.06±0.48 vs. 0.46±0.22, P<0.002).
Conclusion and Discussion
The semi-LASER sequence optimized for 2-HG detection with a TE of 110 ms successfully
demonstrated distinct cystathionine peaks in glioma patients with molecularly defined
oligodendroglioma (IDH-mutant and 1p/19q codeleted) at 7T. While a prospective, better powered
study is needed to confirm our observations, we propose that our method has the potential to allow
presurgical stratification of patients with IDH-mutant glioma into those with oligodendrogliomas
and astrocytomas; which is of important prognostic significance.
1. Young RM, Jamshidi A, Davis G, Sherman JH. Current trends in the surgical management and
treatment of adult glioblastoma. Annals of Translational Medicine 2015;3:9–9 doi:
10.3978/j.issn.2305-5839.2015.05.10.
2. Shen X, Voets NL, Larkin SJ, et al. A Noninvasive Comparison Study between Human
Gliomas with IDH1 and IDH2 Mutations by MR Spectroscopy. Metabolites 2019;9 doi:
10.3390/metabo9020035.
3. Branzoli F, Deelchand DK, Sanson M, Lehéricy S, Marjańska M. In vivo 1H MRS detection
of cystathionine in human brain tumors. Magnetic Resonance in Medicine 2019;82:1259–1265
doi: https://doi.org/10.1002/mrm.27810.
4. van den Bent MJ, Chang SM. Grade II and III Oligodendroglioma and Astrocytoma. Neurol
Clin 2018;36:467–484 doi: 10.1016/j.ncl.2018.04.005.
5. Emir UE, Larkin SJ, de Pennington N, et al. Noninvasive quantification of 2-hydroxyglutarate
in human gliomas with IDH1 and IDH2 mutations. Cancer research 2016;76:43–49.
Figure 1

3. Figure 2

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