Zahra Shams1, Uzay Emir2, Wybe J.M. van der Kemp1, Dennis W.J. Klomp1, Jannie P. Wijnen1, and Evita Wiegers1
1Radiology, University Medical Center Utrecht, Utrecht, Netherlands, 2School of Health Sciences, College of Health and Human Sciences, Purdue University, West Lafayette, IN, United States
Synopsis
This study evaluates the performance of
semi-LASER and MEGA-sLASER for 2-hydroxyglutarate (2-HG) detection at 7T. We
compared a semi-LASER with TE of 110ms with editing of 2-HG at 4.02 ppm using
MEGA-sLASER with TE of 74ms in phantoms with different concentrations of 2-HG. Both methods were able to detect
2-HG concentrations as low as 0.5mM. MEGA-sLASER provided a clean 2-HG signal. Contrary, the
fact that the fitting accuracy for 2-HG in semi-LASER is similar to MEGA-sLASER
promotes to choose for a semi-LASER implementation.
Introduction
The onco-metabolite 2-hydroxyglutarate (2-HG), a biomarker
of IDH-mutant gliomas1-3, can be detected with 1H-MRS. Assesment
of 2-HG is complicated by spectral overlap with other brain metabolites, such
as g-aminobutyric acid(GABA), glutamate(Glu)
and glutamine(Gln). Therefore, spectral editing at long echo time (TE) and
J-difference spectroscopy became of interest to achieve the reliable detection
of 2-HG2,3. Recent studies showed measurements of 2-HG at 7T with
substantial gain in SNR and spectral resolution, offering higher specificity
and sensitivity than 3T as well4. Here we compare spectral editing
at long TE and J-difference spectroscopy using TE-optimized semi-LASER5
with MEGA-sLASER for detection of 2-HG at 7T in-vitro to assess the sensitivity
of 2-HG detection and robustness against B0 inhomogeneity of each method. Methods
Phantom
preparation
We prepared four phantoms (pH=7.2; diameter=4cm)
with different concentrations of 2-HG (5, 1.5, 1 and 0.5mM) and Glycine (Gly) (10,
10, 10 , 5mM). Another phantom (pH=7.2; diameter=4cm) was prepared with 2-HG (5mM),
GABA (1mM), Glu (5mM), Gln (5mM), NAA (10mM), Creatine (Cr) (10mM) and myo-Inositol
(7mM). PBS (Phosphate-buffered saline) was used as buffer solution and the
acidity was adjusted using HCl and NaOH to pH7.
Experiments
MR experiments were performed on a 7T MR scanner (Philips,
Achieva, Best, NL) equipped with a 32-channel receive-only and 8-channel
transmit coil. Semi-LASER voxel localization was used with four FOCI pulses for
the semi-LASER and MEGA-sLASER acquisitions (Figure
1). For semi-LASER measurements, we tuned the timing between the pulses
to achieve optimized J-coupling patterns for 2-HG at a TE of 110ms5.
For MEGA-sLASER, the 2-HG Hα resonance (Figure
1C) was edited at echo time of 74ms using a 13.9ms Gaussian RF pulse tuned
to 1.78 and 7.38ppm respectively, i.e. shifted -0.12ppm from the in vivo values
of 1.9 and 7.5 ppm, because of the lower temperature of the phantom. The number
of averages (64), TR (5s), spectral bandwidth (6kHz), voxel size (8cm3
isotropic) and voxel orientation for all experiments were kept the same. We
used VAPOR water suppression and automatic volume shimming using second order
shim terms.
Additionally, we assessed the performance of the two methods
in less optimal shimming condition, as to mimic in-vivo experiments. The local B0
field in the voxel was perturbed by changing the z-component of the shim
gradients.
Preprocessing and
Analysis
Channel combination, frequency and phase alignment of the
data was performed with the FID-A toolbox6. For MEGA-sLASER, the on
and off spectra were subtracted after alignment and averaging. Spectral
simulation was done using the Vespa library of pyGAMMA7 for creating
the basis sets for LCModel analysis8. Spectra were analyzed using
LCModel. Differences in T1 and T2 relaxation times were ignored.
Results
In both techniques, 2-HG can be detected with CRLB(%) of
less than 30%. In MEGA-sLASER, the reported CRLB (%) of 2-HG for all the
phantoms is higher than semi-LASER (Figure 2A). In Figure
2B, the ratio of detected 2-HG/Gly is plotted as a function of number of
averages (NSA). Note that the error bar on the point represent the confidence
interval of the concentration according to the fit accuracy (% CRLB). At low
concentrations, MEGA-sLASER exhibits high variations in the 2-HG/Gly ratio. For
2-HG concentrations of 1mM and higher, both methods converge to the same value
from 16 NSA and higher. When the signal of 2-HG overlaps with metabolite
signals of GABA, Glu and Gln, MEGA-sLASER leads to detection of 2-HG with relative
concentration (/NAA) of 0.41 and CRLB of 6% compared to 0.36 and 13% with
sLASER as shown in Figure 3.
Table1.1 and 1.2 summarize the effect of metabolite
signal overlap on CRLB% and concentration by removing the relevant metabolites
from the basis set. It shows that removing GABA or 2-HG from the basis set has
very negligible or even no influence on detecting 2-HG using MEGA-sLASER, while
it does influence the detection of 2-HG using semi-LASER. Removing Glu and Gln
from the basis set has almost no influence on quantification of 2-HG in semi-LASER.
Figure 4 demonstrates that the CRLB
for the 2-HG, Glu, Gln fit remains rather stable in MR spectra with increasing
line width in both sequences. Discussion and conclusions
The sensitivity of the two methods for 2-HG detection was
assessed with four phantoms containing 2-HG with different concentrations,
revealing semi-LASER as more sensitive for 2-HG detection. Both methods were
able to detect 2-HG concentrations as low as 0.5mM, however 64 averages were
needed. Despite the fact that the MEGA-sLASER provides a clean 2-HG signal, the
fitting accuracy for 2-HG in spectra with broader line widths was not better
for MEGA-sLASER. Contrary, the fact that the fitting accuracy for 2-HG in semi-LASER
is similar to MEGA-sLASER promotes to choose for a semi-LASER implementation.
Also, semi-LASER is a simpler
implementation and retains signals from all other metabolites.
Note that overlapping resonances from GABA, Glu and Gln
combined with poorer shim conditions in brain tumor tissue may be more
problematic than presented here in phantoms. If so, this would mainly effect 2-HG
detection with semi-LASER, since the edited 2-HG signal at 4.0 ppm using MEGA-semi-LASER
is uniquely generated via the J-couplings of 2-HG.Acknowledgements
We like to thank Eurostars IMAGINE for financial support.References
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