Improved resolution of glutamate,glutamine and γ‐aminobutyric acid with optimized point‐resolved spectroscopy sequence timings for their simultaneous quantification at 9.4 T

Glutamine (Gln), glutamate (Glu) and γ‐aminobutyric acid (GABA) are relevant brain metabolites that can be measured with magnetic resonance spectroscopy (MRS). This work optimizes the point‐resolved spectroscopy (PRESS) sequence echo times, TE₁ and TE₂, for improved simultaneous quantification of the three metabolites at 9.4 T. Quantification was based on the proton resonances of Gln, Glu and GABA at ≈2.45, ≈2.35 and ≈2.28 ppm, respectively. Glu exhibits overlap with both Gln and GABA; in addition, the Gln peak is contaminated by signal from the strongly coupled protons of N‐acetylaspartate (NAA), which resonate at about 2.49 ppm. J‐coupling evolution of the protons was characterized numerically and verified experimentally. A {TE₁, TE₂} combination of {106 ms, 16 ms} minimized the NAA signal in the Gln spectral region, whilst retaining Gln, Glu and GABA peaks. The efficacy of the technique was verified on phantom solutions and on rat brain in vivo. LCModel was employed to analyze the in vivo spectra. The average T₂‐corrected Gln, Glu and GABA concentrations were found to be 3.39, 11.43 and 2.20 mM, respectively, assuming a total creatine concentration of 8.5 mM. LCModel Cramér–Rao lower bounds (CRLBs) for Gln, Glu and GABA were in the ranges 14–17%, 4–6% and 16–19%, respectively. The optimal TE resulted in concentrations for Gln and GABA that agreed more closely with literature concentrations compared with concentrations obtained from short‐TE spectra acquired with a {TE₁, TE₂} combination of {12 ms, 9 ms}. LCModel estimations were also evaluated with short‐TE PRESS and with the optimized long TE of {106 ms, 16 ms}, using phantom solutions of known metabolite concentrations. It was shown that concentrations estimated with LCModel can be inaccurate when combined with short‐TE PRESS, where there is peak overlap, even when low (<20%) CRLBs are reported.     

A comparison of 2‐hydroxyglutarate detection at 3 and 7 T with long‐TE semi‐LASER

Abnormally high levels of the ‘oncometabolite’ 2‐hydroxyglutarate (2‐HG) occur in many grade II and III gliomas, and correlate with mutations in the genes of isocitrate dehydrogenase (IDH) isoforms. In vivo measurement of 2‐HG in patients, using magnetic resonance spectroscopy (MRS), has largely been carried out at 3 T, yet signal overlap continues to pose a challenge for 2‐HG detection. To combat this, several groups have proposed MRS methods at ultra‐high field (≥7 T) where theoretical increases in signal‐to‐noise ratio and spectral resolution could improve 2‐HG detection. Long echo time (long‐TE) semi‐localization by adiabatic selective refocusing (semi‐LASER) (TE = 110 ms) is a promising method for improved 2‐HG detection in vivo at either 3 or 7 T owing to the use of broad‐band adiabatic localization. Using previously published semi‐LASER methods at 3 and 7 T, this study directly compares the detectability of 2‐HG in phantoms and in vivo across nine patients. Cramér–Rao lower bounds (CRLBs) of 2‐HG fitting were found to be significantly lower at 7 T (6 ± 2%) relative to 3 T (15 ± 7%) (p = 0.0019), yet were larger at 7 T in an IDH wild‐type patient. Although no increase in SNR was detected at 7 T (77 ± 26) relative to 3 T (77 ± 30), the detection of 2‐HG was greatly enhanced through an improved spectral profile and increased resolution at 7 T. 7 T had a large effect on pairwise fitting correlations between γ‐aminobutyric acid (GABA) and 2‐HG (p = 0.004), and resulted in smaller coefficients. The increased sensitivity for 2‐HG detection using long‐TE acquisition at 7 T may allow for more rapid estimation of 2‐HG (within a few spectral averages) together with other associated metabolic markers in glioma.     

Measurement of glycine in healthy and tumorous brain by triple‐refocusing MRS at 3 T in vivo

Glycine (Gly) has been implicated in several neurological disorders, including malignant brain tumors. The precise measurement of Gly is challenging largely as a result of the spectral overlap with myo‐inositol (mI). We report a new triple‐refocusing sequence for the reliable co‐detection of Gly and mI at 3 T and for the evaluation of Gly in healthy and tumorous brain. The sequence parameters were optimized with density‐matrix simulations and phantom validation. With a total TE of 134 ms, the sequence gave complete suppression of the mI signal between 3.5 and 3.6 ppm and, consequently, well‐defined Gly (3.55 ppm) and mI (3.64 ppm) peaks. In vivo ¹H magnetic resonance spectroscopy (MRS) data were acquired from the gray matter (GM)‐dominant medial occipital and white matter (WM)‐dominant left parietal regions in six healthy subjects, and analyzed with LCModel using in‐house‐calculated basis spectra. Tissue segmentation was performed to obtain the GM and WM contents within the MRS voxels. Metabolites were quantified with reference to GM‐rich medial occipital total creatine at 8 mM. The Gly and mI concentrations were estimated to be 0.63 ± 0.05 and 8.6 ± 0.6 mM for the medial occipital and 0.34 ± 0.05 and 5.3 ± 0.8 mM for the left parietal regions, respectively. From linear regression of the metabolite estimates versus fractional GM content, the concentration ratios between pure GM and pure WM were estimated to be 2.6 and 2.1 for Gly and mI, respectively. Clinical application of the optimized sequence was performed in four subjects with brain tumor. The Gly levels in tumors were higher than those of healthy brain. Gly elevation was more extensive in a post‐contrast enhancing region than in a non‐enhancing region. The data indicate that the optimized triple‐refocusing sequence may provide reliable co‐detection of Gly and mI, and alterations of Gly in brain tumors can be precisely evaluated.     

Unedited in vivo detection and quantification of γ‐aminobutyric acid in the occipital cortex using short‐TE MRS at 3 T

Short‐TE MRS has been proposed recently as a method for the in vivo detection and quantification of γ‐aminobutyric acid (GABA) in the human brain at 3 T. In this study, we investigated the accuracy and reproducibility of short‐TE MRS measurements of GABA at 3 T using both simulations and experiments. LCModel analysis was performed on a large number of simulated spectra with known metabolite input concentrations. Simulated spectra were generated using a range of spectral linewidths and signal‐to‐noise ratios to investigate the effect of varying experimental conditions, and analyses were performed using two different baseline models to investigate the effect of an inaccurate baseline model on GABA quantification. The results of these analyses indicated that, under experimental conditions corresponding to those typically observed in the occipital cortex, GABA concentration estimates are reproducible (mean reproducibility error, <20%), even when an incorrect baseline model is used. However, simulations indicate that the accuracy of GABA concentration estimates depends strongly on the experimental conditions (linewidth and signal‐to‐noise ratio). In addition to simulations, in vivo GABA measurements were performed using both spectral editing and short‐TE MRS in the occipital cortex of 14 healthy volunteers. Short‐TE MRS measurements of GABA exhibited a significant positive correlation with edited GABA measurements (R = 0.58, p < 0.05), suggesting that short‐TE measurements of GABA correspond well with measurements made using spectral editing techniques. Finally, within‐session reproducibility was assessed in the same 14 subjects using four consecutive short‐TE GABA measurements in the occipital cortex. Across all subjects, the average coefficient of variation of these four GABA measurements was 8.7 ± 4.9%. This study demonstrates that, under some experimental conditions, short‐TE MRS can be employed for the reproducible detection of GABA at 3 T, but that the technique should be used with caution, as the results are dependent on the experimental conditions. Copyright © 2013 John Wiley & Sons, Ltd.     

A quantitative comparison of metabolite signals as detected by in vivo MRS with ex vivo 1H HR‐MAS for childhood brain tumours

¹H MRS provides a powerful method for investigating tumour metabolism by allowing the measurement of metabolites in vivo. Recently, the technique of ¹H high‐resolution magic angle spinning (HR‐MAS) has been shown to produce high‐quality data, allowing the accurate measurement of many metabolites present in unprocessed biopsy tissue. The purpose of this study was to evaluate the agreement between the techniques of in vivo MRS and ex vivo HR‐MAS for investigating childhood brain tumours. Short‐TE (30 ms), single‐voxel, in vivo MRS was performed on 16 paediatric patients with brain tumours at 1.5 T. A frozen biopsy sample was available for each patient. HR‐MAS was performed on the biopsy samples, and metabolite quantities were determined from the MRS and HR‐MAS data using the LCModel? and TARQUIN algorithms, respectively. Linear regression was performed on the metabolite quantities to asses the agreement between MRS and HR‐MAS. Eight of the 12 metabolite quantities were found to correlate significantly (P < 0.05). The four worst correlating metabolites were aspartate, scyllo‐inositol, glycerophosphocholine and N‐acetylaspartate, and, except for glycerophosphocholine, this error was reflected in their higher Cramer–Rao lower bounds (CRLBs), suggesting that low signal‐to‐noise was the greatest source of error for these metabolites. Glycerophosphocholine had a lower CRLB implying that interference with phosphocholine and choline was the most significant source of error. The generally good agreement observed between the two techniques suggests that both MRS and HR‐MAS can be used to reliably estimate metabolite quantities in brain tumour tissue and that tumour heterogeneity and metabolite degradation do not have an important effect on the HR‐MAS metabolite profile for the tumours investigated. HR‐MAS can be used to improve the analysis and understanding of MRS data. Copyright © 2009 John Wiley & Sons, Ltd.     

Characterizing human adipose tissue lipids by long echo time 1H‐MRS in vivo at 1.5 Tesla: validation by gas chromatography

The aim of this study was to investigate the use of ¹H‐MRS with various echo times to characterize subcutaneous human adipose tissue (SAT) triglyceride composition and to validate the findings with fatty acid (FA) analysis of SAT biopsies by gas chromatography (GC). ¹H‐MRS spectra were acquired with a 1.5 Tesla clinical imager from the SAT of 17 healthy volunteers, with 10 undergoing SAT biopsy. Spectra were localized with PRESS and a series of echo times; 30,50,80,135,200,300 and 540 ms were acquired with TR = 3000 ms. Prior knowledge from phantom measurements was used to construct AMARES fitting models for the lipid spectra. SAT FA composition were compared with serum lipid levels and subject characteristics in 17 subjects. Long TE (135,200 ms) spectra corresponded better with the GC data than short TE (30,50 ms) spectra. TE = 135 ms was found optimal for determining diallylic content (R = 0.952, p < 0.001) and TE = 200 ms was optimal for determining olefinic content (R = 0.800, p < 0.01). The improved performance of long TE spectra is a result of an improved baseline and better peak separation, due to J‐modulation and suppression of water. The peak position of the diallylic resonance correlated with the average double bond content of polyunsatured fatty acids with R = 0.899 (p < 0.005). The apparent T₂ of the methylene resonance displayed relatively small inter‐individual variation, 88.1 ± 1.1 ms (mean ± SD). The outer methyl triplet line of ω‐3 PUFA at 1.08 ppm could be readily detected and quantitated from spectra obtained at TE = 540. The ω‐3 resonance correlated with the ω‐3 content determined by GC with R = 0.737 (p < 0.05, n = 8). Age correlated significantly with SAT diallylic content (R = 0.569, p = 0.017, n = 17), but serum lipid levels showed no apparent relation to SAT FA composition. We conclude that long TE ¹H‐MRS provides a robust non‐invasive method for characterizing adipose tissue triglycerides in vivo. Copyright © 2010 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.     

A comparative study of short‐ and long‐TE 1H MRS at 3 T for in vivo detection of 2‐hydroxyglutarate in brain tumors

2‐Hydroxyglutarate (2HG) is produced in gliomas with mutations of isocitrate dehydrogenase (IDH) 1 and 2. The ¹H resonances of the J‐coupled spins of 2HG are extensively overlapped with signals from other metabolites. Here, we report a comparative study at 3 T of the utility of the point‐resolved spectroscopy sequence with a standard short TE (35 ms) and a long TE (97 ms), which had been theoretically designed for the detection of the 2HG 2.25‐ppm resonance. The performance of the methods is evaluated using data from phantoms, seven healthy volunteers and 22 subjects with IDH‐mutated gliomas. The results indicate that TE = 97 ms provides higher detectability of 2HG than TE = 35 ms, and that this improved capability is gained when data are analyzed with basis spectra that include the effects of the volume localizing radiofrequency and gradient pulses. Copyright © 2013 John Wiley & Sons, Ltd.     

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.     

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.     

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.     

Direct in vivo measurement of glycine and the neurochemical profile in the rat medulla oblongata

The medulla oblongata (MO) contains a high density of glycinergic synapses and a particularly high concentration of glycine. The aims of this study were to measure directly in vivo the neurochemical profile, including glycine, in MO using a spin‐echo‐based ¹H MRS sequence at TE = 2.8 ms and to compare it with three other brain regions (cortex, striatum and hippocampus) in the rat. Glycine was quantified in MO at TE = 2.8 ms with a Cramér–Rao lower bound (CRLB) of approximately 5%. As a result of the relatively low level of glycine in the other three regions, the measurement of glycine was performed at TE = 20 ms, which provides a favorable J‐modulation of overlapping myo‐inositol resonance. The other 14 metabolites composing the neurochemical profile were quantified in vivo in MO with CRLBs below 25%. Absolute concentrations of metabolites in MO, such as glutamate, glutamine, γ‐aminobutyrate, taurine and glycine, were in the range of previous in vitro quantifications in tissue extracts. Compared with the other regions, MO had a three‐fold higher glycine concentration, and was characterised by reduced (p < 0.001) concentrations of glutamate (?50 ± 4%), glutamine (–54 ± 3%) and taurine (?78 ± 3%). This study suggests that the functional specialisation of distinct brain regions is reflected in the neurochemical profile. Copyright © 2010 John Wiley & Sons, Ltd.     

In vivo magnetic resonance spectroscopy detection of combined glutamate‐glutamine in healthy upper cervical cord at 3 T

The possibility of quantifying the superimposed signal of glutamate and glutamine (Glx) and its components by ¹ H magnetic resonance spectroscopy (MRS) in the spinal cord is an exciting challenge with important clinical applications in neurological conditions. The spinal cord is a particularly difficult region of interest due to its small volume, magnetic field inhomogeneities and physiological motion. In this study, we investigated for the first time the feasibility of obtaining quantitative measurements of Glx in healthy cervical spinal cord by ¹ H MRS at 3 T. The aim of this study was to compare two commercially available MRS sequences by spectral simulations and in vivo. A short echo time (TE) point resolved spectroscopy (PRESS) with TE = 30 ms and a stimulated echo acquisition mode (STEAM) with TE = 11 ms and mixing time (TM) = 17 ms were compared for reliability of Glx fit. Data allowed us to determine sample size estimates for future clinical studies for the first time. Results showed that PRESS provided a reliable fit for Glx in all cases (Cramér Rao lower bounds < 20%) whereas no reliable Glx fits were achieved using STEAM. Neither protocol provided reliable Glu quantification. The power calculations showed that a minimum sample size of 17 subjects per group was needed to detect Glx changes of > 20% using the PRESS sequence. This study proposed a clinically feasible MRS method for Glx detection in the human cervical cord in vivo including sample sizes needed for conclusive clinical studies. Copyright © 2012 John Wiley & Sons, Ltd.     

Linear discriminant analysis of brain tumour (1)H MR spectra: a comparison of classification using whole spectra versus metabolite quantification

(1)H MRS is an attractive choice for non-invasively diagnosing brain tumours. Many studies have been performed to create an objective decision support system, but there is not yet a consensus as to the best techniques of MRS acquisition or data processing to be used for optimum classification. In this study, we investigate whether LCModel analysis of short-TE (30 ms), single-voxel tumour spectra provide a better input for classification than the use of the original spectra. A total of 145 histologically diagnosed brain tumour spectra were acquired [14 astrocytoma grade II (AS2), 15 astrocytoma grade III (AS3), 42 glioblastoma (GBM), 41 metastases (MET) and 33 meningioma (MNG)], and linear discriminant analyses (LDA) were performed on the LCModel analysis of the spectra and the original spectra. The results consistently suggest improvement in classification when the LCModel concentrations are used. LDA of AS2, MNG and high-grade tumours (HG, comprising GBM and MET) correctly classified 94% using the LCModel dataset compared with 93% using the spectral dataset. The inclusion of AS3 reduced the accuracy to 82% and 78% for LCModel analysis and the original spectra, respectively, and further separating HG into GBM and MET gave 70% compared with 60%. Generally MNG spectra have profiles that are visually distinct from those of the other tumour types, but the classification accuracy was typically about 80%, with MNG with substantial lipid/macromolecule signals being classified as HG. Omission of the lipid/macromolecule concentrations in the LCModel dataset provided an improvement in classification of MNG (91% compared with 76%). In conclusion, there appears to be an advantage to performing pattern recognition on the quantitative analysis of tumour spectra rather than using the whole spectra. However, the results suggest that a two-step LDA process may help in classifying the five tumour groups to provide optimum classification of MNG with high lipid/macromolecule contributions which maybe misclassified as HG.     

In vivo T2 relaxation time measurement with echo‐time averaging

The accuracy of metabolite concentrations measured using in vivo proton (¹H) MRS is enhanced following correction for spin–spin (T₂) relaxation effects. In addition, metabolite proton T₂ relaxation times provide unique information regarding cellular environment and molecular mobility. Echo‐time (TE) averaging ¹H MRS involves the collection and averaging of multiple TE steps, which greatly simplifies resulting spectra due to the attenuation of spin‐coupled and macromolecule resonances. Given the simplified spectral appearance and inherent metabolite T₂ relaxation information, the aim of the present proof‐of‐concept study was to develop a novel data processing scheme to estimate metabolite T₂ relaxation times from TE‐averaged ¹H MRS data. Spectral simulations are used to validate the proposed TE‐averaging methods for estimating methyl proton T₂ relaxation times for N‐acetyl aspartate, total creatine, and choline‐containing compounds. The utility of the technique and its reproducibility are demonstrated using data obtained in vivo from the posterior‐occipital cortex of 10 healthy control subjects. Compared with standard methods, distinct advantages of this approach include built‐in macromolecule resonance attenuation, in vivo T₂ estimates closer to reported values when maximum TE ≈ T₂, and the potential for T₂ calculation of metabolite resonances otherwise inseparable in standard ¹H MRS spectra recorded in vivo. Copyright © 2014 John Wiley & Sons, Ltd.     

Applications of high‐resolution magic angle spinning MRS in biomedical studies II—Human diseases

High‐resolution magic angle spinning (HRMAS) MRS is a powerful method for gaining insight into the physiological and pathological processes of cellular metabolism. Given its ability to obtain high‐resolution spectra of non‐liquid biological samples, while preserving tissue architecture for subsequent histopathological analysis, the technique has become invaluable for biochemical and biomedical studies. Using HRMAS MRS, alterations in measured metabolites, metabolic ratios, and metabolomic profiles present the possibility to improve identification and prognostication of various diseases and decipher the metabolomic impact of drug therapies. In this review, we evaluate HRMAS MRS results on human tissue specimens from malignancies and non‐localized diseases reported in the literature since the inception of the technique in 1996. We present the diverse applications of the technique in understanding pathological processes of different anatomical origins, correlations with in vivo imaging, effectiveness of therapies, and progress in the HRMAS methodology.     

Added value of magnetic resonance spectroscopy for diagnosing childhood cerebellar tumours

¹H-magnetic resonance spectroscopy (MRS) provides noninvasive metabolite profiles with the potential to aid the diagnosis of brain tumours. Prospective studies of diagnostic accuracy and comparisons with conventional MRI are lacking. The aim of the current study was to evaluate, prospectively, the diagnostic accuracy of a previously established classifier for diagnosing the three major childhood cerebellar tumours, and to determine added value compared with standard reporting of conventional imaging. Single-voxel MRS (1.5 T, PRESS, TE 30 ms, TR 1500 ms, spectral resolution 1 Hz/point) was acquired prospectively on 39 consecutive cerebellar tumours with histopathological diagnoses of pilocytic astrocytoma, ependymoma or medulloblastoma. Spectra were analysed with LCModel and predefined quality control criteria were applied, leaving 33 cases in the analysis. The MRS diagnostic classifier was applied to this dataset. A retrospective analysis was subsequently undertaken by three radiologists, blind to histopathological diagnosis, to determine the change in diagnostic certainty when sequentially viewing conventional imaging, MRS and a decision support tool, based on the classifier. The overall classifier accuracy, evaluated prospectively, was 91%. Incorrectly classified cases, two anaplastic ependymomas, and a rare histological variant of medulloblastoma, were not well represented in the original training set. On retrospective review of conventional MRI, MRS and the classifier result, all radiologists showed a significant increase (Wilcoxon signed rank test, p < 0.001) in their certainty of the correct diagnosis, between viewing the conventional imaging and MRS with the decision support system. It was concluded that MRS can aid the noninvasive diagnosis of posterior fossa tumours in children, and that a decision support classifier helps in MRS interpretation.     

Simultaneous detection of valine and lactate using MEGA‐PRESS editing in pyogenic brain abscess

Valine and lactate have been recognized as important metabolic markers to diagnose brain abscess by means of MRS. However, in vivo unambiguous detection and quantification is hampered by macromolecular contamination. In this work, MEGA‐PRESS difference editing of valine and lactate is proposed. The method is validated in vitro and applied for quantitative in vivo experiments in one healthy subject and two brain abscess patients. It is demonstrated that with this technique the overlapping lipid signal can be reduced by more than an order of magnitude and thus the robustness of valine and lactate detection in vivo can be enhanced. Quantification of the two abscess MEGA‐PRESS spectra yielded valine/lactate concentration ratios of 0.10 and 0.27. These ratios agreed with the concentration ratios determined from concomitantly acquired short‐T_E PRESS data and were in line with literature values. The quantification accuracy of lactate (as measured with Cramér‐Rao lower bounds in LCModel processing) was better for MEGA‐PRESS than for short‐T_E PRESS in all acquired in vivo datasets. The Cramér‐Rao lower bounds of valine were only better for MEGA‐PRESS in one of the two abscess cases, while in the other case coediting of isoleucine confounded the quantification in the MEGA‐PRESS analysis. MEGA‐PRESS and short‐T_E PRESS should be combined for unambiguous quantification of amino acids in abscess measurements. Simultaneous valine/lactate MEGA‐PRESS editing might benefit the distinction of brain abscesses from tumors, and further categorization of bacteria with reasonable sensitivity and specificity.     

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.     

Identifying the translational complexity of magnetic resonance spectroscopy in neonates and infants

Little attention has been paid to relating MRS outputs of vendor‐supplied platforms to those from research software. This comparison is crucial to advance MRS as a clinical prognostic tool for disease or injury, recovery, and outcome. The work presented here investigates the agreement between metabolic ratios reported from vendor‐provided and LCModel fitting algorithms using MRS data obtained on Siemens 3 T TIM Trio and 3 T Skyra MRI scanners in a total of 55 premature infants and term neonates with hypoxic ischemic encephalopathy (HIE). We compared peak area ratios in single voxels placed in basal ganglia (BG) and frontal white matter (WM) using standard PRESS (TE = 30 ms and 270 ms) and STEAM (TE = 20 ms) MRS sequences at multiple times after birth from 5 to 60 days. A total of 74 scans met quality standards for inclusion, reflecting a spectrum of neonatal disease and several months of early infant development. For the long TE PRESS sequence, N‐acetylaspartate (NAA) and Choline (Cho) ratios to Creatine (Cr) correlated strongly between LCModel and vendor‐supplied software in the BG. For shorter TEs, the ratios of NAA/Cr and Cho/Cr were more closely related using STEAM at TE = 20 ms in BG and WM, which was significantly better than using PRESS at TE = 30 ms in the BG of HIE infants. At short TEs, however, it is still unclear which MRS sequence, STEAM or PRESS, is superior and thus more work is required in this regard for translating research‐generated MRS ratios to clinical diagnosis and prognostication, and unlocking the potential of MRS for in vivo metabolomics. MRS at both long and short TEs is desirable for standard metabolites such as NAA, Cho and Cr, along with important lower concentration metabolites such as myo‐inositol and glutathione.