Homa Javadzadeh1,2 and Jean Théberge1,2,3
1Department of Medical Biophysics, University of Western Ontario, London, ON, Canada, 2Imaging Division, Lawson Health Research Institute, London, ON, Canada, 3Diagnostic Imaging Department, St. Joseph's Health Care, London, ON, Canada
Synopsis
D-serine supplements
alleviate some of the most debilitating features of schizophrenia believed to
be associated with glutamatergic abnormalities. Assessment of
endogenous serine is impossible using standard proton Magnetic Resonance
Spectroscopy (1H-MRS). This work employs a novel 1H-MRS
sequence called DANTE-PRESS (D-PRESS) and presents test-retest
reliability study for serine levels acquired at 3T in phantoms and
initial data in two human subjects. We conclude that
reproducibility and precision of serine measurements on a 3.0T scanner
is sufficient to assess endogenous levels in vivo and is a
valuable tool to examine abnormalities in schizophrenia and monitor
supplementation.Purpose
Precise and reliable measurements of endogenous
serine in the human brain using advanced
1H-MRS is crucial for examining any abnormalities
of its concentration in patients living with schizophrenia (1, 2). The
detection of endogenous serine has been unattainable utilizing standard proton
Magnetic Resonance Spectroscopy (
1H-MRS) because of its relatively low concentration and its intensive spectral overlap with the neighbouring metabolites (3). Previous
measurements of serine were obtained using advanced
1H-MRS techniques at 4.0T and 7.0T (3, 4). We introduce a
novel pulse sequence called DANTE-PRESS (D-PRESS) using a narrowly
frequency-selective refocusing DANTE pulse to select serine signals while
suppressing interfering neighbouring resonances on a 3T clinical scanner
(Siemens Biograph mMR). In this study, repeated
in vivo measurements
were obtained in two subjects and the test-retest reliability of the assessment
of
in vitro measurements was demonstrated using “
in vivo” [~0.732] mM and “double
in vivo” [~1.464] mM serine concentrations at baseline and a week
later.
Methods
The D-PRESS sequence was implemented through inserting
a spectrally-selective single-DANTE pulse to a symmetrical PRESS sequence, at
time TE1 after the first 180 degree refocusing pulse: 90-
TE1/2-180-TE1/2-DANTE-TE2/2-180-TE2-Acq (Figure 1). The 0th and 1st sideband
of the DANTE pulse were used to achieve very selective frequency passbands
centered on the 3.83 ppm resonance of serine and the 2.01-ppm resonance of NAA
(N-Acetylaspartic) (5). The DANTE pulse (duration of 118.54 ms) was
amplitude-modulated with a Gaussian envelope truncated at 5% producing a
frequency-domain inversion profile with Gaussian passbands repeating every
223Hz and it consisted of a series of 0.086 ms short, high power square RF
pulses, interleaved with delays of 4.48 ms. This profile was centered on a
frequency determined at run-time by assigning the NAA resonance from a DANTE
OFF acquisition the chemical shift valued of 2.01 ppm and adjusting the
carrier frequency to the serine resonance at 3.83ppm (TR=2.0s,TE=286ms, and
NA=64). The serine data was obtained from a DANTE ON acquisition with TR=2.0s,
TE=286ms, BW=1.5 kHz and NA=240. Water unsuppressed signal was used as
concentration reference for metabolite quantification.
In
vitro experiments: A final quantification template for in vitro data analysis was developed from the spectral
quantification templates obtained in two spherical phantoms (inner diameter
[i.d.] 10 cm) containing either high concentrations of the metabolites of
interest and NAA (8mM) as a chemical shift reference. Metabolites of interest
were: serine (30 mM), creatine (25mM), glutamate (30mM) and glutamine (30mM),
all to be included in the in vivo template (6). Ten consecutive spectra
were obtained within-session and from between-session (phantom scanned a week
later). The data was obtained with DANTE pulse with narrow passbands (15Hz =
0.11ppm at 3T), TR=2.0, TE=286ms, NA=240, number of data points in DANTE
waveform=2560, FDP (Frequency Domain Period) of 223 Hz.
In
vivo experiments: Two healthy volunteers (2 male; age of 27 ± 4) were
recruited and scanned using the same parameters as for the phantom work. For
these subjects, two consecutive spectra were obtained within sessions at
baseline. 1H -MRS data were obtained from a single voxel (20x20x20mm3)
positioned in the anterior cingulate (Figure 2). High resolution 3D MP-RAGE
images were used for voxel placement. Metabolite concentrations were quantified
using Fitman (7).
Results
An example spectral fit is displayed in figure 3,
illustrating the data, fitting line, fit components and the fit residuals.
Figure 4 displays
in vitro demonstration of ten repeated
measurements that were obtained from “
in vivo” and also acquired from “double
in vivo” serine concentrations at two intervals each obtained one a
week apart. The resulting ICC were both high (
in vivo ICC =0.91, double
in vivo
ICC =0.93) indicating excellent repeatability of
in vitro measurements within and between
scans. The two repeated measurements from the first and second
in vivo experiments were quantified and the
in vivo concentrations were: 1.17 mM, 1.99 mM and 1.11 mM and
2.17, respectively. The reproducibility of MRS measurements greatly depend on
the quality of adjustments and more advanced MRS post-processing capabilities;
as illustrated in MRS literature (8), thus this sequence is currently being further
modified for obtaining final
in vivo test-retest data.
Discussion and conclusion
This study demonstrated the first examination to
investigate the reliability of method to reliably detect endogenous serine
using a metabolite-selective single-voxel
1H-MRS technique on a clinical scanner of 3T. In the proposed
work we demonstrated the accuracy and precision (reliability/reproducibility)
of the measurements of serine obtained in phantoms. The proposed method will be
able to assess metabolic changes in neuropsychological conditions such as
schizophrenia and support the investigation of safer and more effective
treatment for the affected patients.
Acknowledgements
The salary support of this study was funded by a
grant from NSERC.
The chemicals that were used in this study and the serine
project were funded by Lawson internal research fund.References
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Choi et al., Mag Reson Med 62(4):1042-46, 2009. 4.
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81:646-52, 1989. 6. Kumashiro et al., Brain
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