T2 measurement of J-coupled metabolites in the human brain at 3T

Proton T₂ relaxation times of metabolites in the human brain were measured using point resolved spectroscopy at 3T in vivo. Four echo times (54, 112, 246 and 374 ms) were selected from numerical and phantom analyses for effective detection of the glutamate multiplet at ~ 2.35 ppm. In vivo data were obtained from medial and left occipital cortices of five healthy volunteers. The cortices contained predominantly gray and white matter, respectively. Spectra were analyzed with LCModel software using volume‐localized calculated spectra of brain metabolites. The estimate of the signal strength vs. TE was fitted to a monoexponential function for estimation of apparent T₂ (T₂^?). T₂^? was estimated to be similar between the brain regions for creatine, choline, glutamate and myo‐inositol, but significantly different for N‐acetylaspartate singlet and multiplet. T₂^?s of glutamate and myo‐inositol were measured as 181 ± 16 and 197 ± 14 ms (mean ± SD, N = 5) for medial occipital cortices, and 180 ± 12 and 196 ± 17 ms for left occipital cortices, respectively. Copyright © 2011 John Wiley & Sons, Ltd.     

Improvement of resolution for brain coupled metabolites by optimized (1)H MRS at 7T

Resolution enhancement for glutamate (Glu), glutamine (Gln) and glutathione (GSH) in the human brain by TE‐optimized point‐resolved spectroscopy (PRESS) at 7 T is reported. Sub‐TE dependences of the multiplets of Glu, Gln, GSH, γ‐aminobutyric acid (GABA) and N‐acetylaspartate (NAA) at 2.2–2.6 ppm were investigated with density matrix simulations, incorporating three‐dimensional volume localization. The numerical simulations indicated that the C4‐proton multiplets can be completely separated with (TE₁, TE₂) = (37, 63) ms, as a result of a narrowing of the multiplets and suppression of the NAA 2.5 ppm signal. Phantom experiments reproduced the signal yield and lineshape from simulations within experimental errors. In vivo tests of optimized PRESS were conducted on the prefrontal cortex of six healthy volunteers. In spectral fitting by LCModel, Cramér–Rao lower bounds (CRLBs) of Glu, Gln and GSH were 2 ± 1, 5 ± 1 and 6 ± 2 (mean ± SD), respectively. To evaluate the performance of the optimized PRESS method under identical experimental conditions, stimulated‐echo spectra were acquired with (TE, TM) = (14, 37) and (74, 68) ms. The CRLB of Glu was similar between PRESS and short‐TE stimulated‐echo acquisition mode (STEAM), but the CRLBs of Gln and GSH were lower in PRESS than in both STEAM acquisitions. Copyright © 2010 John Wiley & Sons, Ltd.     

Evaluation of short‐TE 1H MRSI for quantification of metabolites in the prostate

Back‐to‐back ¹H MRSI scans, using an endorectal and phased‐array coil combination, were performed on 18 low‐risk patients with prostate cancer at 3 T, employing TEs of 32 and 100 ms in order to compare metabolite visualization at each TE. Outer‐volume suppression of lipid signals was performed using regional saturation (REST) slabs and the quantification of spectra at both TEs was achieved with the quantitation using quantum estimation (QUEST) routine. Metabolite nulling experiments in an additional five patients found that there were negligible macromolecule background signals in prostate spectra at TE = 32 ms. Metabolite visibility was judged using the criterion Cramér–Rao lower bound (CRLB)/amplitude < 20%, and metabolite concentrations were corrected for relaxation effects and referenced to the data acquired in corresponding water‐unsuppressed MRSI scans. For the first time, the prostate metabolites spermine and myo‐inositol were quantified individually in vivo, together with citrate, choline and creatine. All five metabolite visibilities were higher in TE = 32 ms MRSI than in TE = 100 ms MRSI. At TE = 32 ms, citrate was visible in 99.0% of lipid‐free spectra, whereas, at TE = 100 ms, no metabolite simulation of citrate matched the in vivo peaks. Spermine, choline and creatine were visualised separately in 30.4% more spectra at TE = 32 ms than at TE = 100 ms, and myo‐inositol in 72.5% more spectra. T₂ values were calculated for spermine (53 ± 16 ms), choline (62 ± 17 ms) and myo‐inositol (90 ± 48 ms). Data from the TE = 32 ms spectra showed that the concentrations of citrate and spermine secretions were positively correlated in both the peripheral zone and central gland (R² = 0.73 and R² = 0.43, respectively), and that the citrate content was significantly higher in the former at 64 ± 22 mm than in the latter at 32 ± 16 mm (p = 0.01). However, lipid contamination at TE = 32 ms was substantial; therefore, to make clinical use of the greater visualisation of prostate metabolites at TE = 32 ms rather than at TE = 100 ms, three‐dimensional MRSI at TE = 32 ms with effective lipid suppression must be implemented. ©2014 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd.     

Quantification of J‐resolved proton spectra in two‐dimensions with LCModel using GAMMA‐simulated basis sets at 4 Tesla

A two‐dimensional, J‐resolved magnetic resonance spectroscopic extraction approach was developed employing GAMMA‐simulated, LCModel basis‐sets. In this approach, a two‐dimensional J‐resolved (2D‐JPRESS) dataset was resolved into a series of one‐dimensional spectra where each spectrum was modeled and fitted with its theoretically customized LCModel template. Metabolite levels were derived from the total integral across the J‐series of spectra for each metabolite. Phantoms containing physiologic concentrations of the major brain chemicals were used for validation. Varying concentrations of glutamate and glutamine were evaluated at and around their accepted in vivo concentrations in order to compare the accuracy and precision of our method with 30 ms PRESS. We also assessed 2D‐JPRESS and 30 ms PRESS in vivo, in a single voxel within the parieto‐occipital cortex by scanning ten healthy volunteers once and a single healthy volunteer over nine repeated measures. Phantom studies demonstrated that serial fitting of 2D‐JPRESS spectra with simulated LCModel basis sets provided accurate concentration estimates for common metabolites including glutamate and glutamine. Our in vivo results using 2D‐JPRESS suggested superior reproducibility in measuring glutamine and glutamate relative to 30 ms PRESS. These novel methods have clear implications for clinical and research studies seeking to understand neurochemical dysfunction. Copyright © 2009 John Wiley & Sons, Ltd.     

The case of the missing glutamine

A theoretical study was performed to determine the accuracy and repeatability of multiple one‐dimensional pulse sequences in the quantification of glutamine concentration at 3 T. Variable repeatability (12% to > 50%) and significant absolute error (?50% to +70%) were noted for the eight pulse sequences considered. Data acquired in vivo using three of the pulse sequences used for simulation matched the predicted repeatability well; among the pulse sequences considered, point‐resolved spectroscopy (TE = 80 ms) offered minimal error and acceptable repeatability (12%) for brain glutamine measurements. Following correction for the expected bias of each pulse sequence, consistent glutamine measurements, in the 1‐mM range, were reported with the three sequences. An explanation for the mismatch between in vivo ¹H MRS and in vitro ¹³C/¹H MRS at high field was attempted. Copyright © 2011 John Wiley & Sons, Ltd.     

Long‐TE 1H MRS suggests that liver fat is more saturated than subcutaneous and visceral fat

Cross‐talk between adipose tissue and liver is disturbed in the metabolic syndrome. Moreover, the relative fatty acid composition of adipose and liver fat is poorly characterized. Long‐TE ¹H MRS can determine the unsaturation and polyunsaturation of adipose tissue. The aim of this study was to use long‐TE ¹H MRS to determine the composition of liver fat and its relation to adipose tissue composition. Sixteen subjects with increased liver fat (>5%) were recruited for the study. Using TE = 200 ms, we were able to resolve the olefinic (?CH, 5.3 ppm) and water (H₂O, 4.7 ppm) resonances in liver spectra and to obtain a repeatable estimate of liver fat unsaturation (coefficient of variation, 2.3%). With TE = 135 ms, the diallylic (?C? CH₂? C?, 2.8 ppm) resonance was detectable in subjects with a liver fat content above 15%. Long‐TE ¹H MRS was also used to determine the unsaturation in subcutaneous (n = 16) and visceral (n = 11) adipose tissue in the same subjects. Liver fat was more saturated (double bonds per fatty acid chain, 0.812 ± 0.022) than subcutaneous (double bonds per fatty acid chain, 0.862 ± 0.022, p < 0.0004) or visceral (double bonds per fatty acid chain, 0.865 ± 0.033, p < 0.0004) fat. Liver fat unsaturation correlated with subcutaneous unsaturation (R = 0.837, p < 0.0001) and visceral unsaturation (R = 0.879, p < 0.0004). The present study introduces a new noninvasive method for the assessment of the composition of liver fat. The results suggest that liver fat is more saturated than subcutaneous or visceral adipose tissue, which may be attributed to differences in de novo lipogenesis. Copyright © 2010 John Wiley & Sons, Ltd.     

Spatial location and strength of BOLD activation in high-spatial-resolution fMRI of the motor cortex: a comparison of spin echo and gradient echo fMRI at 7 T

The increased blood oxygenation level‐dependent contrast‐to‐noise ratio at ultrahigh field (7 T) has been exploited in a comparison of the spatial location and strength of activation in high‐resolution (1.5 mm isotropic) gradient echo (GE) and spin echo (SE), echo planar imaging data acquired during the execution of a simple motor task in five subjects. SE data were acquired at six echo times from 30 to 55 ms. Excellent fat suppression was achieved in the SE echo planar images using slice‐selective gradient reversal. Threshold‐free cluster enhancement was used to define regions of interest (ROIs) containing voxels showing significant stimulus‐locked signal changes from the GE and average SE data. These were used to compare the signal changes and spatial locations of activated regions in SE and GE data. T₂ and T₂* values were measured, with means of 48.3 ± 1.1 ms and 36.5 ± 3.4 ms in the SE ROI. In addition, we identified a dark band in SE images of the motor cortex corresponding to a region in which T₂ and T₂* were significantly lower than in the surrounding grey matter. The fractional SE signal change in the ROI was found to vary linearly as a function of TE, with a slope that was dependent on the particular ROI assessed: the mean ΔR₂ value was found to be 0.85 ± 0.11 s^–1 for the SE ROI and ?0.37 ± 0.05 s^–1 for the GE ROI. The fractional signal change relative to the shortest TE revealed that the largest signal change occurred at a TE of 45 ms outside of the dark band. At this TE, the ratio of the fractional signal change in GE and SE data was found to be 0.48 ± 0.05. Phase maps produced from high‐resolution GE images spanning the right motor cortex were used to identify veins. The GE ROI was found to contain 18% more voxels overlying the venous mask than the SE ROI. Copyright © 2011 John Wiley & Sons, Ltd.     

Measurement of regional variation of GABA in the human brain by optimized point‐resolved spectroscopy at 7 T in vivo

The ¹H resonances of γ‐aminobutyric acid (GABA) in the human brain in vivo are extensively overlapped with the neighboring abundant resonances of other metabolites and remain indiscernible in short‐TE MRS at 7 T. Here we report that the GABA resonance at 2.28 ppm can be fully resolved by means of echo time optimization of a point‐resolved spectroscopy (PRESS) scheme. Following numerical simulations and phantom validation, the subecho times of PRESS were optimized at (TE, TE₂) = (31, 61) ms for detection of GABA, glutamate (Glu), glutamine (Gln), and glutathione (GSH). The in vivo feasibility of the method was tested in several brain regions in nine healthy subjects. Spectra were acquired from the medial prefrontal, left frontal, medial occipital, and left occipital brain and analyzed with LCModel. Following the gray and white matter (GM and WM) segmentation of T₁‐weighted images, linear regression of metabolite estimates was performed against the fractional GM contents. The GABA concentration was estimated to be about seven times higher in GM than in WM. GABA was overall higher in frontal than in occipital brain. Glu was about twice as high in GM as in WM in both frontal and occipital brain. Gln was significantly different between frontal GM and WM while being similar between occipital GM and WM. GSH did not show significant dependence on tissue content. The signals from N‐acetylaspartylglutamate were clearly resolved, giving the concentration more than 10 times higher in WM than in GM. Our data indicate that the PRESS TE = 92 ms method provides an effective means for measuring GABA and several challenging J‐coupled spin metabolites in human brain at 7 T. Copyright © 2014 John Wiley & Sons, Ltd.     

Diffusion behavior of cerebral metabolites of congenital portal systemic shunt mice assessed noninvasively by diffusion‐weighted 1H magnetic resonance spectroscopy

Diffusion‐weighted ¹H‐MRS (DW‐MRS) allows for noninvasive investigation of the cellular compartmentalization of cerebral metabolites. DW‐MRS applied to the congenital portal systemic shunt (PSS) mouse brain may provide specific insight into alterations of cellular restrictions associated with PSS in humans. At 14.1 T, adult male PSS and their age‐matched healthy (Ctrl) mice were studied using DW‐MRS covering b‐values ranging from 0 to 45 ms/μm² to determine the diffusion behavior of abundant metabolites. The remarkable sensitivity and spectral resolution, in combination with very high diffusion weighting, allowed for precise measurement of the diffusion properties of endogenous N‐acetyl‐aspartate, total creatine, myo‐inositol, total choline with extension to glutamine and glutamate in mouse brains, in vivo. Most metabolites had comparable diffusion properties in PSS and Ctrl mice, suggesting that intracellular distribution space for these metabolites was not affected in the model. The slightly different diffusivity of the slow decaying component of taurine (0.015 ± 0.003 μm²/ms in PSS vs 0.021 ± 0.002 μm²/ms in Ctrl, P < 0.05) might support a cellular redistribution of taurine in the PSS mouse brain.     

In vivo and ex vivo evidence for ketamine-induced hyperglutamatergic activity in the cerebral cortex of the rat: Potential relevance to schizophrenia

Subanesthetic doses of ketamine, a noncompetitive N‐methyl‐D ‐aspartate (NMDA) receptor antagonist, impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in patients with schizophrenia. In the present study, in vivo ¹H‐MRS and ex vivo ¹H high‐resolution magic angle spinning (HR‐MAS) spectroscopy was used to examine the brain metabolism of rats treated with subanesthetic doses of ketamine (30 mg/kg) for 6 days. A single voxel localization sequence (PRESS, TR/TE = 4000/20 ms and NEX = 512) was used to acquire the spectra in a 30‐µl voxel positioned in the cerebral cortex (including mainly PFC) of the rats (ketamine group: n = 12; saline group: n = 12) anesthetized with isoflurane. After the in vivo ¹H‐MRS acquisition, the animals were sacrificed and the cerebral cortex tissues were extracted (ketamine group: n = 7; saline group: n = 7) for ex vivo ¹H HR‐MAS spectroscopy (CPMG sequence, 2.0‐s presaturation delay, 2.0‐s acquisition time, 128 transients and 4‐ms inter‐pulse delay) using a 500‐MHz NMR spectrometer. All proton metabolites were quantified using the LCModel. For the in vivo spectra, there was a significant increase in glutamate concentration in the cerebral cortex of the ketamine group compared with the controls (p < 0.05). For the ex vivo HR‐MAS spectra, there was a significant increase in the glutamate/total creatine ratio, and a decrease in the glutamine/total creatine and glutamine/glutamate ratios in the cerebral cortex tissue of the ketamine group compared with the controls. The results of the present study demonstrated that administration of subanesthetic doses of ketamine in the rat may exert at least part of their effect in the cerebral cortex by activation of glutamatergic neurotransmission. Copyright © 2011 John Wiley & Sons, Ltd.     

Towards a neurochemical profile of the amygdala using short‐TE 1H magnetic resonance spectroscopy at 3 T

The amygdala plays a key role in emotional learning and in the processing of emotions. As disturbed amygdala function has been linked to several psychiatric conditions, a knowledge of its biochemistry, especially neurotransmitter levels, is highly desirable. The spin echo full intensity acquired localized (SPECIAL) sequence, together with a transmit/receive coil, was used to perform very short‐TE magnetic resonance spectroscopy at 3 T to determine the neurochemical profile in a spectroscopic voxel containing the amygdala in 21 healthy adult subjects. For spectral analysis, advanced data processing was applied in combination with a macromolecule baseline measured in the anterior cingulate for spectral fitting. The concentrations of total N‐acetylaspartate, total creatine, total choline, myo‐inositol and, for the first time, glutamate were quantified with high reliability (uncertainties far below 10%). For these metabolites, the inter‐individual variability, reflected by the relative standard deviations for the cohort studied, varied between 12% (glutamate) and 22% (myo‐inositol). Glutamine and glutathione could also be determined, albeit with lower precision. Retest on four subjects showed good reproducibility. The devised method allows the determination of metabolite concentrations in the amygdala voxel, including glutamate, provides an estimation of glutamine and glutathione, and may help in the study of disturbed amygdala metabolism in pathologies such as anxiety disorder, autism and major depression.     

Neonatal hyperglycemia alters the neurochemical profile,dendritic arborization and gene expression in the developing rat hippocampus

Hyperglycemia (blood glucose concentration >150 mg/dL) is common in extremely low gestational age newborns (ELGANs; birth at <28 week gestation). Hyperglycemia increases the risk of brain injury in the neonatal period. The long‐term effects are not well understood. In adult rats, hyperglycemia alters hippocampal energy metabolism. The effects of hyperglycemia on the developing hippocampus were studied in rat pups. In Experiment 1, recurrent hyperglycemia of graded severity (moderate hyperglycemia (moderate‐HG), mean blood glucose 214.6 ± 11.6 mg/dL; severe hyperglycemia (severe‐HG), 338.9 ± 21.7 mg/dL; control, 137.7 ± 2.6 mg/dL) was induced from postnatal day (P) 3 to P12. On P30, the hippocampal neurochemical profile was determined using in vivo ¹H MR spectroscopy. Dendritic arborization in the hippocampal CA1 region was determined using microtubule‐associated protein (MAP)‐2 immunohistochemistry. In Experiment 2, continuous hyperglycemia (mean blood glucose 275.3 ± 25.8 mg/dL; control, 142.3 ± 2.6 mg/dL) was induced from P2 to P6 by injecting streptozotocin (STZ) on P2. The mRNA expression of glycogen synthase 1 (Gys1), lactate dehydrogenase (Ldh), glucose transporters 1 (Glut1) and 3 (Glut3) and monocarboxylate transporters 1 (Mct1), 2 (Mct2) and 4 (Mct4) in the hippocampus was determined on P6. In Experiment 1, MRS demonstrated lower lactate concentration and glutamate/glutamine (Glu/Gln) ratio in the severe‐HG group, compared with the control group (p < 0.05). Phosphocreatine/creatine ratio was higher in both hyperglycemia groups (p < 0.05). MAP‐2 histochemistry demonstrated longer apical segment length, indicating abnormal synaptic efficacy in both hyperglycemia groups (p < 0.05). Experiment 2 showed lower Glut1, Gys1 and Mct4 expression and higher Mct1 expression in the hyperglycemia group, relative to the control group (p < 0.05). These results suggest that hyperglycemia alters substrate transport, lactate homeostasis, dendritogenesis and Glu‐Gln cycling in the developing hippocampus. Abnormal neurochemical profile and dendritic structure due to hyperglycemia may partially explain the long‐term hippocampus‐mediated cognitive deficits in human ELGANs.     

Regional neurochemical profiles in the human brain measured by 1H MRS at 7 T using local B1 shimming

Increased sensitivity and chemical shift dispersion at ultra‐high magnetic fields enable the precise quantification of an extended range of brain metabolites from ¹H MRS. However, all previous neurochemical profiling studies using single‐voxel MRS at 7 T have been limited to data acquired from the occipital lobe with half‐volume coils. The challenges of ¹H MRS of the human brain at 7 T include short T₂ and complex B₁ distribution that imposes limitations on the maximum achievable B₁ strength. In this study, the feasibility of acquiring and quantifying short‐echo (TE = 8 ms), single‐voxel ¹H MR spectra from multiple brain regions was demonstrated by utilizing a 16‐channel transceiver array coil with 16 independent transmit channels, allowing local transmit B₁ (B₁⁺) shimming. Spectra were acquired from volumes of interest of 1–8 mL in brain regions that are of interest for various neurological disorders: frontal white matter, posterior cingulate, putamen, substantia nigra, pons and cerebellar vermis. Local B₁⁺ shimming substantially increased the transmit efficiency, especially in the peripheral and ventral brain regions. By optimizing a STEAM sequence for utilization with a 16‐channel coil, artifact‐free spectra were acquired with a small chemical shift displacement error (<5% /ppm/direction) from all regions. The high signal‐to‐noise ratio enabled the quantification of neurochemical profiles consisting of at least nine metabolites, including γ‐aminobutyric acid, glutamate and glutathione, in all brain regions. Significant differences in neurochemical profiles were observed between brain regions. For example, γ‐aminobutyric acid levels were highest in the substantia nigra, total creatine was highest in the cerebellar vermis and total choline was highest in the pons, consistent with the known biochemistry of these regions. These findings demonstrate that single‐voxel ¹H MRS at ultra‐high field can reliably detect region‐specific neurochemical patterns in the human brain, and has the potential to objectively detect alterations in neurochemical profiles associated with neurological diseases. Copyright © 2011 John Wiley & Sons, Ltd.     

Single‐voxel 1H spectroscopy in the human hippocampus at 3 T using the LASER sequence: characterization of neurochemical profile and reproducibility

The hippocampus is crucial for long‐term episodic memory and learning. It undergoes structural change in aging and is sensitive to neurodegenerative and psychiatric diseases. MRS studies have seldom been performed in the hippocampus due to technical challenges. The reproducibility of MRS in the hippocampus has not been evaluated at 3 T. The purpose of the present study was to quantify the concentration of metabolites in a small voxel placed in the hippocampus and evaluate the reproducibility of the quantification. Spectra were measured in a 2.4 mL voxel placed in the left hippocampus covering the body and most of the tail of the structure in 10 healthy subjects across three different sessions and quantified using LCModel. High‐quality spectra were obtained, which allowed a reliable quantification of 10 metabolites including glutamate and glutamine. Reproducibility of MRS was evaluated with coefficient of variation, standard errors of measurement, and intraclass correlation coefficients. All of these measures showed improvement with increased number of averages. Changes of less than 5% in concentration of N‐acetylaspartate, choline‐containing compounds, and total creatine and of less than 10% in concentration of myo‐inositol and the sum of glutamate and glutamine can be confidently detected between two measurements in a group of 20 subjects. A reliable and reproducible neurochemical profile of the human hippocampus was obtained using MRS at 3 T in a small hippocampal volume. Copyright © 2015 John Wiley & Sons, Ltd.     

Fast volumetric imaging of bound and pore water in cortical bone using three‐dimensional ultrashort‐TE (UTE) and inversion recovery UTE sequences

We report the three‐dimensional ultrashort‐TE (3D UTE) and adiabatic inversion recovery UTE (IR‐UTE) sequences employing a radial trajectory with conical view ordering for bi‐component T₂* analysis of bound water (T₂*^BW) and pore water (T₂*^PW) in cortical bone. An interleaved dual‐echo 3D UTE acquisition scheme was developed for fast bi‐component analysis of bound and pore water in cortical bone. A 3D IR‐UTE acquisition scheme employing multiple spokes per IR was developed for bound water imaging. Two‐dimensional UTE (2D UTE) and IR‐UTE sequences were employed for comparison. The sequences were applied to bovine bone samples (n = 6) and volunteers (n = 6) using a 3‐T scanner. Bi‐component fitting of 3D UTE images of bovine samples showed a mean T₂*^BW of 0.26 ± 0.04 ms and T₂*^PW of 4.16 ± 0.35 ms, with fractions of 21.5 ± 3.6% and 78.5 ± 3.6%, respectively. The 3D IR‐UTE signal showed a single‐component decay with a mean T₂*^BW of 0.29 ± 0.05 ms, suggesting selective imaging of bound water. Similar results were achieved with the 2D UTE and IR‐UTE sequences. Bi‐component fitting of 3D UTE images of the tibial midshafts of healthy volunteers showed a mean T₂*^BW of 0.32 ± 0.08 ms and T₂*^PW of 5.78 ± 1.24 ms, with fractions of 34.2 ± 7.4% and 65.8 ± 7.4%, respectively. Single‐component fitting of 3D IR‐UTE images showed a mean T₂*^BW of 0.35 ± 0.09 ms. The 3D UTE and 3D IR‐UTE techniques allow fast volumetric mapping of bound and pore water in cortical bone. Copyright © 2016 John Wiley & Sons, Ltd.     

Brain neurochemical and hemodynamic findings in the NY1DD mouse model of mild sickle cell disease

To characterize the cerebral profile associated with sickle cell disease (SCD), we used in vivo proton MRI and MRS to quantify hemodynamics and neurochemicals in the thalamus of NY1DD mice, a mild model of SCD, and compared them with wild‐type (WT) control mice. Compared with WT mice, NY1DD mice at steady state had elevated cerebral blood flow (CBF) and concentrations of N‐acetylaspartate (NAA), glutamate (Glu), alanine, total creatine and N‐acetylaspartylglutamate. Concentrations of glutathione (GSH) at steady state showed a negative correlation with BOLD signal change in response to 100% oxygen, a marker for oxidative stress, and mean diffusivity assessed using diffusion‐tensor imaging, a marker for edematous inflammation. In NY1DD mice, elevated basal CBF was correlated negatively with [NAA], but positively with concentration of glutamine ([Gln]). Immediately after experimental hypoxia (at reoxygenation after 18 hours of 8% O₂), concentrations of NAA, Glu, GSH, Gln and taurine (Tau) increased only in NY1DD mice. [NAA], [Glu], [GSH] and [Tau] all returned to baseline levels two weeks after the hypoxic episode. The altered neurochemical profile in the NY1DD mouse model of SCD at steady state and following experimental hypoxia/reoxygenation suggests a state of chronic oxidative stress leading to compensatory cerebral metabolic adjustments.     

Region‐specific changes in ascorbate concentration during rat brain development quantified by in vivo 1H NMR spectroscopy

Ascorbate (vitamin C, Asc) was quantified in vivo using short‐TE ¹H NMR spectra from a previously published study on regional and developmental changes in the neurochemical profile of the rat brain (Tkac I, Rao R, Georgieff MK, Gruetter R. Magn Reson Med. 2003; 50: 24–32). Asc concentration was quantified on postnatal days P7–P28 from three regions that are of interest in the study of neurocognitive development, i.e. the hippocampus, striatum and cerebral cortex. The previously measured ¹H NMR spectra were re‐analyzed using LCModel with the Asc spectrum included in the basis set. The Asc concentration was consistently quantified from all 110 re‐analyzed spectra with an estimated fitting error of 7% (i.e. the average Cramer–Rao lower bound). The sensitivity of Asc quantification was sufficiently high to detect regional and developmental changes in Asc concentration. The concentration of Asc was highest on P7, and decreased with age in all three brain regions (p < 0.001) in agreement with previous in vitro studies. At P10 and older postnatal ages, an inhomogeneous distribution of Asc among brain regions was detected. In addition to facilitating the quantification of this important antioxidant concentration, the inclusion of the Asc spectrum in the LCModel basis set improved the quantification accuracy of other brain metabolite concentrations in the neurochemical profile. Copyright © 2010 John Wiley & Sons, Ltd.     

Non‐invasive detection of glycine as a biomarker of malignancy in childhood brain tumours using in‐vivo 1H MRS at 1.5 Tesla confirmed by ex‐vivo high‐resolution magic‐angle spinning NMR

Management of brain tumours in children would benefit from improved non‐invasive diagnosis, characterisation and prognostic biomarkers. Metabolite profiles derived from in‐vivo MRS have been shown to provide such information. Studies indicate that using optimum a priori information on metabolite contents in the construction of linear combination (LC) models of MR spectra leads to improved metabolite profile estimation. Glycine (Gly) is usually neglected in such models due to strong overlap with myo‐inositol (mI) and a low concentration in normal brain. However, biological studies indicate that Gly is abundant in high‐grade brain tumours. This study aimed to investigate the quantitation of Gly in paediatric brain tumours using MRS analysed by LCModel?, and its potential as a non‐invasive biomarker of malignancy. Single‐voxel MRS was performed using PRESS (TR 1500 ms, TE 30 ms/135 ms) on a 1.5 T scanner. Forty‐seven cases (18 high grade (HG), 17 low grade (LG), 12 ungraded) were retrospectively selected if both short‐TE and long‐TE MRS (n = 33) or short‐TE MRS and high‐resolution magic‐angle spinning (HRMAS) of matched surgical samples (n = 15) were available. The inclusion of Gly in LCModel? analyses led to significantly reduced fit residues for both short‐TE and long‐TE MRS (p < 0.05). The Gly concentrations estimated from short‐TE MRS were significantly correlated with the long‐TE values (R = 0.91, p < 0.001). The Gly concentration estimated by LCModel? was significantly higher in HG versus LG tumours for both short‐TE (p < 1e‐6) and long‐TE (p = 0.003) MRS. This was consistent with the HRMAS results, which showed a significantly higher normalised Gly concentration in HG tumours (p < 0.05) and a significant correlation with the normalised Gly concentration measured from short‐TE in‐vivo MRS (p < 0.05). This study suggests that glycine can be reliably detected in paediatric brain tumours using in‐vivo MRS on standard clinical scanners and that it is a promising biomarker of tumour aggressiveness. Copyright © 2009 John Wiley & Sons, Ltd.     

Localized MRS reliability of in vivo glutamate at 3 T in shortened scan times: a feasibility study

Glutamate is the prime excitatory neurotransmitter in the mammalian brain and has been implicated in a wide range of psychiatric conditions. To improve the applicability and clinical reach of magnetic resonance spectroscopy (MRS), research is needed to develop shortened, yet reliable, MRS scanning procedures for standard 1.5–3‐T clinical magnetic resonance imaging (MRI) systems, particularly with young or vulnerable populations unable to tolerate longer protocols. To this end, we evaluated the test–retest reliability of a shortened J ‐resolved MRS sequence in healthy adolescents (n  = 22) aged 12–14 years. Participants underwent a series of sequential 6‐min MRS scans, with the participants remaining in situ between successive scans. Glutamate and other metabolites were acquired from the rostral anterior cingulate cortex, as glutamatergic function in this region has been implicated in a number of psychiatric illnesses. Thirteen neurochemicals were quantified as ratios to total creatine, and reliability scores were expressed as the percentage difference between the two scans for each metabolite. Test–retest assessment of glutamate was reliable, as scores were less than 10% different (7.1 ± 4.2%), and glutamate values across scans were significantly correlated (Pearson r  = 0.680, p  < 10^?4). Several other neurochemicals demonstrated satisfactory reliability, including choline (Cho) (7.4 ± 5.6%), glutathione (GSH) (8.6 ± 4.1%), myo‐inositol (mI) (6.5 ± 7.1%) and N ‐acetylaspartate (NAA) (3.5 ± 3.6%), with test–retest correlations ranging from 0.747 to 0.953. A number of metabolites, however, did not demonstrate acceptable test–retest reliability using the current J ‐resolved MRS sequence, ranging from 13.8 ± 13.7% (aspartate, Asp) to 45.9 ± 38.3% (glycine, Gly). Collectively, test–retest analyses suggest that clinically viable quantitative data can be obtained on standard MRI systems for glutamate, as well as the other metabolites, during short scan times in a traditionally challenging brain region.     

Neurochemical changes in the rat prefrontal cortex following acute phencyclidine treatment: an in vivo localized 1H MRS study

Acute phencyclidine (PCP) administration mimics some aspects of schizophrenia in rats, such as behavioral alterations, increased dopaminergic activity and prefrontal cortex dysfunction. In this study, we used single‐voxel ¹H‐MRS to investigate neurochemical changes in rat prefrontal cortex in vivo before and after an acute injection of PCP. A short‐echo time sequence (STEAM) was used to acquire spectra in a 32‐µL voxel positioned in the prefrontal cortex area of 12 rats anesthetized with isoflurane. Data were acquired for 30 min before and for 140 min after a bolus of PCP (10 mg/kg, n = 6) or saline (n = 6). Metabolites were quantified with the LCModel. Time courses for 14 metabolites were obtained with a temporal resolution of 10 min. The glutamine/glutamate ratio was significantly increased after PCP injection (p < 0.0001, pre‐ vs. post‐injection), while the total concentration of these two metabolites remained constant. Glucose was transiently increased (+70%) while lactate decreased after the injection (both p < 0.0001). Lactate, but not glucose and glutamine, returned to baseline levels after 140 min. These results show that an acute injection of PCP leads to changes in glutamate and glutamine concentrations, similar to what has been observed in schizophrenic patients, and after ketamine administration in humans. MRS studies of this pharmacological rat model may be useful for assessing the effects of potential anti‐psychotic drugs in vivo. Copyright © 2009 John Wiley & Sons, Ltd.