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Background and ObjectivesD-2-hydroxyglutarate (2HG) characterizesIDH-mutant gliomas and can be detected and quantified with edited MRS (MEGA-PRESS). In this study, we investigated the clinical, radiologic, and molecular parameters affecting 2HG levels.MethodsMEGA-PRESS data were acquired in 71 patients with glioma (24 untreated, 47 treated) on a 3 T system. Eighteen patients were followed during cytotoxic (n = 12) or targeted (n = 6) therapy. 2HG was measured in tumor samples using gas chromatography coupled to mass spectrometry (GCMS).ResultsMEGA-PRESS detected 2HG with a sensitivity of 95% in untreated patients and 62% in treated patients. Sensitivity depended on tumor volume (>27 cm3;p= 0.02), voxel coverage (>75%;p= 0.002), and expansive presentation (defined by equal size of T1and FLAIR abnormalities,p= 0.04). 2HG levels were positively correlated withIDH-mutant allelic fraction (p= 0.03) and total choline levels (p< 0.001) and were higher inIDH2-mutant compared withIDH1R132H-mutant and non–R132HIDH1-mutant patients (p= 0.002). In patients receiving IDH inhibitors, 2HG levels decreased within a few days, demonstrating the on-target effect of the drug, but 2HG level decrease did not predict tumor response. Patients receiving cytotoxic treatments showed a slower decrease in 2HG levels, consistent with tumor response and occurring before any tumor volume change on conventional MRI. At progression, 1p/19q codeleted gliomas, but not the non-codeleted, showed detectable in vivo 2HG levels, pointing out to different modes of progression characterizing these 2 entities.DiscussionMEGA-PRESS edited MRS allows in vivo monitoring of 2-hydroxyglutarate, confirming efficacy ofIDHinhibition and suggests different patterns of tumor progression in astrocytomas compared with oligodendrogliomas.

Purpose: Measurements of objective response rates are critical to evaluate new glioma therapies. The hallmark metabolic alteration in gliomas with mutant isocitrate dehydrogenase (IDH) is the overproduction of oncometabolite 2-hydroxyglutarate (2HG), which plays a key role in malignant transformation. 2HG represents an ideal biomarker to probe treatment response in IDH-mutant glioma patients, and we hypothesized a decrease in 2HG levels would be measureable by in vivo magnetic resonance spectroscopy (MRS) as a result of antitumor therapy.Experimental Design: We report a prospective longitudinal imaging study performed in 25 IDH-mutant glioma patients receiving adjuvant radiation and chemotherapy. A newly developed 3D MRS imaging was used to noninvasively image 2HG. Paired Student t test was used to compare pre- and posttreatment tumor 2HG values. Test–retest measurements were performed to determine the threshold for 2HG functional spectroscopic maps (fSM). Univariate and multivariate regression were performed to correlate 2HG changes with Karnofsky performance score (KPS).Results: We found that mean 2HG (2HG/Cre) levels decreased significantly (median = 48.1%; 95% confidence interval = 27.3%–56.5%; P = 0.007) in the posttreatment scan. The volume of decreased 2HG correlates (R2 = 0.88, P = 0.002) with clinical status evaluated by KPS.Conclusions: We demonstrate that dynamic measurements of 2HG are feasible by 3D fSM, and the decrease of 2HG levels can monitor treatment response in patients with IDH-mutant gliomas. Our results indicate that quantitative in vivo 2HG imaging may be used for precision medicine and early response assessment in clinical trials of therapies targeting IDH-mutant gliomas. Clin Cancer Res; 22(7); 1632–41. ©2015 AACR.

This file contains 3 Tables and 9 Figures with additional results and details of analysis related to the main results presented in the manuscript. The complete list of figures and tables is provided below. Table 1S. Baseline metabolite levels relative to creatine. Table 2S. Demographic, genomic, molecular, histological, radiological and clinical data. Table 3S. Fractional changes for all imaging biomarkers. Table 4S. General Linear Model with change of KPS as dependent variable and grade, age and fractional volume of decreased 2HG/Cre as covariates. Figure 1S. 3D MRSI pulse sequence for 2HG imaging, detailed diagram. Figure 2S. Quantum mechanics simulations of 2HG spectral editing for MEGA-LASER, MEGA-PRESS and PRESS-97 sequences. Figure 3S. Simulations of 2HG editing for MEGA-LASER and PRESS-97 sequences in the presence of B1 field inhomogeneity. Figure 4S. Mitigation of subtraction artifacts caused by motion and scanner instability in J-difference MR spectroscopy using real-time prospective motion correction, shim update and reacquisition. Figure 5S. Metabolic maps before image interpolation. Figure 6S. Examples of OFF and difference (DIFF) MEGA-LASER spectra from 3D MRSI voxels located in the tumor and contralateral normal appearing white matter, pre- and post-treatment respectively. Figure 7S. Distributions of Δ2HG/Cre in the test-retest and post-pre longitudinal data sets. Figure 8S. Comparison of functional spectroscopic maps (fSM) and functional diffusion maps (fDM). Figure 9S. Relation between residual tumor measured by FLAIR hyperintensity volume and the SNR and CRLB of 2HG. Notes. Details related to data analysis in Figures 7S and 9S.

To evaluate the ability of the PRESS sequence (TTwenty-three subjects with a glioma were retrospectively included based on the availability of both MEGA-PRESS and PRESS acquisitions at 3T, and the presence of the cystathionine signal in the edited MR spectrum. In eight subjects, the PRESS acquisition was performed also in normal tissue. Metabolite quantification was performed using LCModel and simulated basis sets. The LCModel analysis for the PRESS data was performed with and without cystathionine.All subjects with glioma had detectable cystathionine levels1 mM with Cramér-Rao lower bounds (CRLB)15%. The mean cystathionine concentrations were 3.49 ± 1.17 mM for MEGA-PRESS and 2.20 ± 0.80 mM for PRESS data. Cystathionine concentrations showed a significant correlation between the two MRS methods (r = 0.58, p = .004), and it was not detectable in normal tissue. Using PRESS, 19 metabolites were quantified with CRLB50% for more than half of the subjects. The metabolites that were significantly (p .0028) and mostly affected by the omission of cystathionine were aspartate, betaine, citrate, γ-aminobutyric acid (GABA), and serine.Cystathionine was detectable by PRESS in all the selected gliomas, while it was not detectable in normal tissue. The omission from the spectral analysis of cystathionine led to severe biases in the quantification of other neurochemicals that may play key roles in cancer metabolism.

Bi-stable stimuli evoke two distinct perceptual interpretations that alternate and compete for dominance. Bi-stable perception is thought to be driven at least in part by mutual suppression between distinct neural populations that represent each percept. Abnormal visual perception is observed among people with psychotic psychopathology (PwPP), and there is evidence to suggest that these visual deficits may depend on impaired neural suppression in visual cortex. However, it is not yet clear whether bi-stable visual perception is abnormal among PwPP. Here, we examined bi-stable perception in a visual structure-from-motion task using a rotating cylinder illusion in a group of 65 PwPP, 44 first-degree biological relatives, and 43 healthy controls. Data from a ′real switch′ task, in which physical depth cues signaled real switches in rotation direction were used to exclude individuals who did not show adequate task performance. In addition, we measured concentrations of neurochemicals, including glutamate, glutamine, and γ-amino butyric acid (GABA), involved in excitatory and inhibitory neurotransmission. These neurochemicals were measured non-invasively in visual cortex using 7 tesla MR spectroscopy. We found that PwPP and their relatives showed faster bi-stable switch rates than healthy controls. Faster switch rates also correlated with significantly higher psychiatric symptom levels across all participants. However, we did not observe any significant relationships across individuals between neurochemical concentrations and SFM switch rates. Our results are consistent with a reduction in suppressive neural processes during structure-from-motion perception in PwPP, and suggest that genetic liability for psychosis is associated with disrupted bi-stable perception.

Germline mutations in genes encoding succinate dehydrogenase (SDH) are frequently involved in pheochromocytoma/paraganglioma (PPGL) development and were implicated in patients with the ‘3PAs’ syndrome (associating pituitary adenoma (PA) and PPGL) or isolated PA. However, the causality link between SDHx mutation and PA remains difficult to establish, and in vivo tools for detecting hallmarks of SDH deficiency are scarce. Proton magnetic resonance spectroscopy (1H-MRS) can detect succinate in vivo as a biomarker of SDHx mutations in PGL. The objective of this study was to demonstrate the causality link between PA and SDH deficiency in vivo using 1H-MRS as a novel noninvasive tool for succinate detection in PA. Three SDHx-mutated patients suffering from a PPGL and a macroprolactinoma and one patient with an apparently sporadic non-functioning pituitary macroadenoma underwent MRI examination at 3 T. An optimized 1H-MRS semi-LASER sequence (TR = 2500 ms, TE = 144 ms) was employed for the detection of succinate in vivo. Succinate and choline-containing compounds were identified in the MR spectra as single resonances at 2.44 and 3.2 ppm, respectively. Choline compounds were detected in all the tumors (three PGL and four PAs), while a succinate peak was only observed in the three macroprolactinomas and the three PGL of SDHx-mutated patients, demonstrating SDH deficiency in these tumors. In conclusion, the detection of succinate by 1H-MRS as a hallmark of SDH deficiency in vivo is feasible in PA, laying the groundwork for a better understanding of the biological link between SDHx mutations and the development of these tumors.

Background The time course of cellular damage after acute ischemic stroke (IS) is currently not well known, and specific noninvasive markers of microstructural alterations linked to inflammation are lacking, which hinders the monitoring of anti-inflammatory treatment. Purpose To evaluate the temporal pattern of neuronal and glial microstructural changes after stroke using in vivo single-voxel diffusion-weighted MR spectroscopy. Materials and Methods In this prospective longitudinal study, participants with IS and healthy volunteers (HVs) underwent MRI at 3.0 T. In participants with IS, apparent diffusion coefficients (ADCs) and concentrations of total

The increased spectral dispersion achieved at ultra-high field permits quantification of γ-aminobutyric acid (GABA) concentrations at ultra-short-TE without editing. This work investigated the influence of spectral quality and different LCModel fitting approaches on quantification of GABA. Additionally, the sensitivity with which cross-sectional and longitudinal variations in GABA concentrations can be observed was characterized.In - vivo spectra were acquired in the posterior cingulate cortex of 10 volunteers at 7 T using a STEAM sequence. Synthetically altered spectra with different levels of GABA signals were used to investigate the reliability of GABA quantification with different LCModel fitting approaches and different realizations of SNR. The synthetically altered spectra were also used to characterize the sensitivity of GABA quantification.The best LCModel fitting approach used stiff spline baseline, no soft constraints, and measured macromolecules in the basis set. With lower SNR, coefficients of variation increased dramatically. Longitudinal and cross-sectional variations in GABA of 10% could be detected with 79 and 48 participants per group, respectively. However, the small cohort may bias the calculation of the coefficients of variation and of the sample size that would be needed to detect variations in GABA.Reliable quantification of normal and abnormal GABA concentrations was achieved for high quality 7 T spectra using LCModel fitting.

Visual perception is abnormal in psychotic disorders such as schizophrenia. In addition to hallucinations, laboratory tests show differences in fundamental visual processes including contrast sensitivity, center-surround interactions, and perceptual organization. A number of hypotheses have been proposed to explain visual dysfunction in psychotic disorders, including an imbalance between excitation and inhibition. However, the precise neural basis of abnormal visual perception in people with psychotic psychopathology (PwPP) remains unknown. Here, we describe the behavioral and 7 tesla MRI methods we used to interrogate visual neurophysiology in PwPP as part of the Psychosis Human Connectome Project (HCP). In addition to PwPP (n = 66) and healthy controls (n = 43), we also recruited first-degree biological relatives (n = 44) in order to examine the role of genetic liability for psychosis in visual perception. Our visual tasks were designed to assess fundamental visual processes in PwPP, whereas MR spectroscopy enabled us to examine neurochemistry, including excitatory and inhibitory markers. We show that it is feasible to collect high-quality data across multiple psychophysical, functional MRI, and MR spectroscopy experiments with a sizable number of participants at a single research site. These data, in addition to those from our previously described 3 tesla experiments, will be made publicly available in order to facilitate further investigations by other research groups. By combining visual neuroscience techniques and HCP brain imaging methods, our experiments offer new opportunities to investigate the neural basis of abnormal visual perception in PwPP.

PURPOSE: The aim of the study is to optimize the performance of localized (1)H MRS sequences at 3 T, using the entire spin system of N-Acetyl Aspartate (NAA) as an example of the large chemical shift spread of all the metabolites routinely detected in vivo, including the amide region. We specifically focus on the design of the suitable broadband excitation RF pulses to minimize chemical shift artifacts. METHODS: The performance of the excitation and refocusing pulse shapes is evaluated with respect to NAA localization. Two new excitation RF pulses are developed to achieve optimized performance in the brain using single-voxel (1)H MRS at 3 T. Numerical simulations and in vivo experiments are carried out to demonstrate the performance of the RF pulses. RESULTS: New excitation RF pulses with the same B(1) requirements but larger excitation bandwidth (up to a factor of 2) are shown to significantly reduce localization artifacts. The large frequency spread of the entire NAA spin system necessitates the use of broadband excitation and refocusing pulses for MRS at 3 T. CONCLUSION: To minimize chemical shift artifacts of metabolic compounds with spins in the amide area (> 5 ppm) at 3 T it is important to use broadband excitation and refocusing pulses.

D-2-hydroxyglutarate (2HG) characterizesMEGA-PRESS data were acquired in 71 patients with glioma (24 untreated, 47 treated) on a 3 T system. Eighteen patients were followed during cytotoxic (n = 12) or targeted (n = 6) therapy. 2HG was measured in tumor samples using gas chromatography coupled to mass spectrometry (GCMS).MEGA-PRESS detected 2HG with a sensitivity of 95% in untreated patients and 62% in treated patients. Sensitivity depended on tumor volume (27 cmMEGA-PRESS edited MRS allows in vivo monitoring of 2-hydroxyglutarate, confirming efficacy of

In vivo MRS is a non-invasive measurement technique used not only in humans, but also in animal models using high-field magnets. MRS enables the measurement of metabolite concentrations as well as metabolic rates and their modifications in healthy animals and disease models. Such data open the way to a deeper understanding of the underlying biochemistry, related disturbances and mechanisms taking place during or prior to symptoms and tissue changes. In this work, we focus on the main preclinical (1)H, (31)P and (13)C MRS approaches to study brain metabolism in rodent models, with the aim of providing general experts’ consensus recommendations (animal models, anesthesia, data acquisition protocols). An overview of the main practical differences in preclinical compared with clinical MRS studies is presented, as well as the additional biochemical information that can be obtained in animal models in terms of metabolite concentrations and metabolic flux measurements. The properties of high-field preclinical MRS and the technical limitations are also described.

PURPOSE: The goal of this study was to propose a novel localized proton magnetic resonance spectroscopy (MRS) sequence that reduces signal loss due to J-modulation in the rat brain in vivo. METHODS: Sprague-Dawley rats were studied at 9.4 T. A semi-LASER sequence with evenly distributed echo-time (T(E)) was used, and a 90° J-refocusing pulse was inserted at T(E)/2. Proton spectra were acquired at two T(E)s (30 and 68 ms), with and without the J-refocused pulse. Data were processed in MATLAB and quantified with LCModel. RESULTS: The J-refocused spectrum acquired at T(E) = 30 ms did not show any signal losses due to J-modulation and had comparable spectral pattern to the one acquired with semi-LASER using the minimum achievable T(E). Higher signal amplitudes for glutamine, γ-aminobutyric acid and glutathione led to more reliable quantification precision for these metabolites. The refocused signal intensities at T(E) = 68 ms were also unaffected by J-modulation but were smaller than the signals at T(E) = 30 ms mainly due to transverse T(2) relaxation of metabolites. CONCLUSION: The proposed localized MRS sequence will be beneficial in both animal and human MRS studies when using ultra-short T(E) is not possible while also providing more reliable quantification precision for J-coupled metabolites.

Purpose To report the technical aspects of noninvasive detection of cystathionine in human brain glioma with edited MRS, and to investigate possible further acquisition improvements for robust quantification of this metabolite. Methods In vivo 1 H MR spectra were acquired at 3 T in 15 participants with an isocitrate dehydrogenase-mutated glioma using a MEGA-PRESS (MEscher GArwood point resolved spectroscopy) sequence previously employed for 2-hydroxyglutarate detection (TR = 2 s, TE = 68 ms). The editing pulse was applied at 1.9 ppm for the edit-on condition and at 7.5 ppm for the edit-off condition. To evaluate the editing efficiency, spectra were acquired in 1 participant by placing the editing pulse for the edit-on condition at 1.9, 2.03, and 2.16 ppm. Cystathionine concentration was quantified using LCModel and a simulated basis set. To confirm chemical shifts and J-coupling values of cystathionine, the 1 H NMR cystathionine spectrum was measured using a high-resolution 500 MHz spectrometer. Results In 12 gliomas, cystathionine was observed in the in vivo edited MR spectra at 2.72 and 3.85 ppm and quantified. The signal intensity of the cystathionine resonance at 2.72 ppm increased 1.7 and 2.13 times when the editing pulse was moved to 2.03 and 2.16 ppm, respectively. Cystathionine was not detectable in normal brain tissue. Conclusion Cystathionine can be detected in vivo by edited MRS using the same protocol as for 2-hydroxyglutarate detection. This finding may enable a more accurate, noninvasive investigation of cellular metabolism in glioma.

Proton Magnetic Resonance Spectroscopy ((1)H MRS) provides non-invasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Whilst most modern clinical MR scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges towards obtaining reliable good-quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the popular point resolved spectroscopy (PRESS) localization sequence was found to be unacceptably high at 3T, and the use of the semi-adiabatic localization by adiabatic selective refocusing (semi-LASER) sequence is a recommended solution. The incorporation of simulated metabolite basis-sets into analysis routines is recommended for reliably capturing the full spectral detail available from short echo time acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B(0)) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. We anticipate the implementation of these recommendations will strengthen current clinical applications and advance progress towards developing and validating new MRS biomarkers for clinical use.

Background Codeletion of chromosome arms 1p and 19q (1p/19q codeletion) highly benefits diagnosis and prognosis in gliomas. In this study, we investigated the effect of 1p/19q codeletion on cancer cell metabolism and evaluated possible metabolic targets for tailored therapies. Methods We combined in vivo 1H (proton) magnetic resonance spectroscopy (MRS) measurements in human gliomas with the analysis of a series of standard amino acids by liquid chromatography-mass spectroscopy (LC-MS) in human glioma biopsies. Sixty-five subjects with low-grade glioma were included in the study: 31 underwent the MRI/MRS examination, 47 brain tumor tissue samples were analyzed with LC-MS, and 33 samples were analyzed for gene expression with quantitative PCR. Additionally, we performed metabolic tracer experiments in cell models with 1p deletion. Results We report the first in vivo detection of cystathionine by MRS in 1p/19q codeleted gliomas. Selective accumulation of cystathionine was observed in codeleted gliomas in vivo, in brain tissue samples, as well as in cells harboring heterozygous deletions for serine- and cystathionine-pathway genes located on 1p: phosphoglycerate dehydrogenase (PHGDH) and cystathionine gamma-lyase (CTH). Quantitative PCR analyses showed 40-50% lower expression of both PHGDH and CTH in 1p/19q codeleted gliomas compared with their non-codeleted counterparts. Conclusions Our results provide strong evidence of a selective vulnerability of codeleted gliomas to serine and glutathione depletion and point to cystathionine as a possible noninvasive marker of treatment response.

Proton MR spectra of the brain, especially those measured at short and intermediate echo times, contain signals from mobile macromolecules (MM). A description of the main MM is provided in this consensus paper. These broad peaks of MM underlie the narrower peaks of metabolites and often complicate their quantification but they also may have potential importance as biomarkers in specific diseases. Thus, separation of broad MM signals from low molecular weight metabolites enables accurate determination of metabolite concentrations and is of primary interest in many studies. Other studies attempt to understand the origin of the MM spectrum, to decompose it into individual spectral regions or peaks and to use the components of the MM spectrum as markers of various physiological or pathological conditions in biomedical research or clinical practice. The aim of this consensus paper is to provide an overview and some recommendations on how to handle the MM signals in different types of studies together with a list of open issues in the field, which are all summarized at the end of the paper.

Diffusion-weighted magnetic resonance spectroscopy (DW-MRS) investigates noninvasively microstructural properties of tissue by probing metabolite diffusion in vivo. Despite the growing interest in DW-MRS for clinical applications, little has been published on the reproducibility of this technique. In this study, we explored the optimization of a single-voxel DW-semi-LASER sequence for clinical applications at 3 T, and evaluated the reproducibility of the method under different experimental conditions. DW-MRS measurements were carried out in ten healthy participants and repeated across three sessions. Metabolite apparent diffusion coefficients (ADCs) were calculated from mono-exponential fits (ADC(exp)) up to b-value = 3300 s/mm(2), and from the diffusional kurtosis approach (ADC(K)) up to b-value = 7300 s/mm(2). The inter-subject variabilities of ADCs of N-acetylaspartate + N-acetylaspartylglutamate (tNAA), creatine + phosphocreatine (tCr), choline containing compounds (tCho), and myo-inositol (mIns) were calculated in the posterior cingulate cortex (PCC) and in the corona radiata (CR). We explored the effect of physiological motion on the DW-MRS signal and the importance of cardiac gating and peak-thresholding to account for signal amplitude fluctuations. Additionally, we investigated the dependence of the intra-subject variability on the acquisition scheme using a bootstrapping resampling method. Coefficients of variation were lower in PCC than CR, likely due to the different sensitivity to motion artifacts of the two regions. Finally, we computed coefficients of repeatability for ADC(exp) and performed power calculations needed for designing clinical studies. Power calculation for ADC(exp) of tNAA showed that in the PCC 7 subjects per group are sufficient to detect a difference of 5% between two groups with an acquisition time of 4 minutes, suggesting that ADC(exp) of tNAA is a suitable marker for disease-related intracellular alteration even in small case-control studies. In the CR, further work is needed to evaluate voxel size and location that minimize motion artifacts and variability of the ADC measurements.

Spectral editing in in vivo 1 H-MRS provides an effective means to measure low-concentration metabolite signals that cannot be reliably measured by conventional MRS techniques due to signal overlap, for example, γ-aminobutyric acid, glutathione and D-2-hydroxyglutarate. Spectral editing strategies utilize known J-coupling relationships within the metabolite of interest to discriminate their resonances from overlying signals. This consensus recommendation paper provides a brief overview of commonly used homonuclear editing techniques and considerations for data acquisition, processing and quantification. Also, we have listed the experts' recommendations for minimum requirements to achieve adequate spectral editing and reliable quantification. These include selecting the right editing sequence, dealing with frequency drift, handling unwanted coedited resonances, spectral fitting of edited spectra, setting up multicenter clinical trials and recommending sequence parameters to be reported in publications.

Spectral editing in in vivo (1)H-MRS provides an effective means to measure low-concentration metabolite signals that cannot be reliably measured by conventional MRS techniques due to signal overlap, e.g., γ-aminobutyric acid (GABA), glutathione (GSH) and D-2-hydroxyglutarate (2HG). Spectral editing strategies utilize known J-coupling relationships within the metabolite of interest to discriminate their resonances from overlying signals. This consensus recommendation paper provides a brief overview of commonly used homo-nuclear editing techniques and considerations for data acquisition, processing, and quantification. Also, we have listed the experts’ recommendations for minimum requirements to achieve adequate spectral editing and reliable quantification. These include selecting the right editing sequence, dealing with frequency drift, handling unwanted co-edited resonances, spectral fitting of edited spectra, setting up multi-center clinical trials, and recommending sequence parameters to be reported in publications.

Proton MR spectra of the brain, especially those measured at short and intermediate echo times, contain signals from mobile macromolecules (MM). A description of the main MM is provided in this consensus paper. These broad peaks of MM underlie the narrower peaks of metabolites and often complicate their quantification but they also may have potential importance as biomarkers in specific diseases. Thus, separation of broad MM signals from low-molecular-weight metabolites enables accurate determination of metabolite concentrations and is of primary interest in many studies. Other studies attempt to understand the origin of the MM spectrum, to decompose it into individual spectral regions or peaks and to use the components of the MM spectrum as markers of various physiological or pathological conditions in biomedical research or clinical practice. The aim of this consensus paper is to provide an overview and some recommendations on how to handle the MM signals in different types of studies together with a list of open issues in the field which are all summarized at the end of the manuscript.

Normal brain aging is associated with changes occurring at all levels. This study investigates age-related differences in the brain intracellular microenvironment by comparing the apparent diffusion coefficients (ADC) and apparent transverse relaxation time constants (T2) of 5 neurochemicals (i.e., total N-acetyl-aspartate, total creatine, total choline, glutamate, and myo-inositol) between young and older adults. Thirty-two young healthy adults (18–22 years) and 26 older healthy adults (70–83 years) were recruited. Three brain regions were studied at 3 T: prefrontal, posterior cingulate and occipital cortices. ADC and T2 were measured using stimulated echo acquisition mode and localization by adiabatic selective refocusing sequences, respectively. This study shows that the diffusivities of several neurochemicals are higher in older than in younger adults. In contrast, shorter apparent T2 values for several metabolites were measured in older adults. Age-related difference in ADC and apparent T2 of metabolites seem to be region-specific. Furthermore, this study shows that it is feasible to observe age-related differences in the cellular microenvironment of neurochemicals in the normal aging brain.

In vivo magnetic resonance spectroscopy (MRS) can provide clinically valuable metabolic information from brain tumors that can be used for prognosis and monitoring response to treatment. Unfortunately, this technique has not been widely adopted in clinical practice or even clinical trials due to the difficulty in acquiring and analyzing the data. In this work we propose a computational approach to solve one of the most critical technical challenges: the problem of quickly and accurately positioning an MRS volume of interest (a cuboid voxel) inside a tumor using MR images for guidance. The proposed automated method comprises a convolutional neural network to segment the lesion, followed by a discrete optimization to position an MRS voxel optimally within the lesion. In a retrospective comparison, the novel automated method is shown to provide improved lesion coverage compared to manual voxel placement.

International audience; Purpose of review Magnetic resonance spectroscopy (MRS) may play a key role for the management of patients with glioma. We highlighted the utility of MRS in the noninvasive diagnosis of gliomas with mutations in isocitrate dehydrogenase (IDH) genes, by providing an overview of the neurochemical alterations observed in different glioma subtypes, as well as during treatment and progression, both in vivo and ex vivo.Recent findings D-2-hydroxyglutarate (2HG) decrease during anticancer treatments was recently shown to be associated with altered levels of other metabolites, including lactate, glutamate and glutathione, suggesting that tumour treatment leads to a metabolic reprogramming beyond 2HG depletion. In combination with 2HG quantification, cystathionine and glycine seem to be the most promising candidates for higher specific identification of glioma subtypes and follow-up of disease progression and response to treatment.Summary The implementation of advanced MRS methods in the routine clinical practice will allow the quantification of metabolites that are not detectable with conventional methods and may enable immediate, accurate diagnosis of gliomas, which is crucial for planning optimal therapeutic strategies and follow-up examinations. The role of different metabolites as predictors of patient outcome still needs to be elucidated.

Background Hepatic encephalopathy (HE) may occur after transjugular intrahepatic portosystemic shunt (TIPSS) placement. Multimodal magnetic resonance imaging (MRI), combining anatomical sequences, diffusion tensor imaging (DTI) and 1 H magnetic resonance spectroscopy, is modified in cirrhotic patients. Aims To describe multimodal MRI images before TIPSS, to assess if TIPSS induces changes in multimodal MRI, and to find predictors of HE after TIPSS in patients with cirrhosis. Methods Consecutive cirrhotic patients with an indication for TIPSS were prospectively screened. Diagnosis of minimal HE was performed using psychometric HE test score. Multimodal MRI was performed before and 3 months after TIPSS placement. Results Twenty-five consecutive patients were analysed (median age = 59, male gender 76%, median Child-Pugh score = 8 [5-8], MELD score = 12 [9-17], indication for TIPSS placement: ascites/secondary prophylaxis of variceal bleeding/other 20/3/2), no HE/minimal HE/overt HE: 21/4/0. 8/25 patients developed HE after TIPSS. Before TIPSS placement, metabolite concentrations were different in patients with or without minimal HE (lower myo-inositol, mI, higher glutamate/glutamine), but there were no differences in DTI data. TIPSS placement induced changes in metabolite concentrations even in asymptomatic patients, but not in DTI metrics. Baseline fractional anisotropy was significantly lower in patients who developed HE after TIPSS in five regions of interest. Conclusions TIPSS placement induced significant changes in cerebral metabolites, even in asymptomatic patients. Patients who developed HE after TIPSS displayed lower fractional anisotropy before TIPSS. Brain MRI with DTI acquisition may help selecting patients at risk of HE.

Once a magnetic resonance spectroscopy (MRS) dataset has been acquired, several important steps must be taken to obtain the desired metabolite concentration measures. First, the data must be preprocessed to prepare them for analysis. Next, the intensity of the metabolite signal(s) of interest must be estimated. Finally, the measured metabolite signal intensities must be converted into scaled concentration units employing a quantitative reference signal to allow meaningful interpretation. In this paper, we will review these three main steps in the post-acquisition workflow of a single-voxel MRS experiment (preprocessing, analysis and quantification) and provide recommendations for best practices at each step.

PURPOSE To measure the apparent diffusion coefficients (ADC) of five main metabolites in the human brain at 3T with PRESS and STEAM, avoiding measurement biases because of cross-terms. Cross-terms arise from interactions between slice-selection and spoiler gradients in the localized spectroscopy sequence and the diffusion gradients. METHODS Diffusion-weighted spectra were acquired from the prefrontal cortex in five healthy subjects using STEAM (echo time [TE]/mixing time [TM]/pulse repetition time [TR] = 21.22/105/3000 ms, b-values = 0 and 3172 s/mm2 ) and PRESS (TE/TR = 54.2/3000 ms, b-values = 0 and 2204 s/mm2 ). Diffusion weighting was applied using bipolar gradients in three orthogonal directions. Post-processed spectra were analyzed with LCModel, and the trace/3 ADC values were calculated. RESULTS Comparable trace/3 ADC values (0.14-0.18 µm2 /ms) were obtained for five main metabolites with both methods. These metabolites were quantified with Cramer-Rao lower bounds below 15%. CONCLUSION The ADC values of the five main metabolites were successfully measured in the human brain at 3T with eliminated directional dependence. Both STEAM and PRESS can be used to probe the diffusivity of metabolites in normal brain and various pathologies on the clinical scanner with slightly higher precision achieved with STEAM for glutamate and myo-inositol. Magn Reson Med 79:2896-2901, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Purpose The goal of this study was to measure and compare the apparent transverse relaxation time constants (T2 ) of five intracellular metabolites using localization by adiabatic selective refocusing (LASER) and point-resolved spectroscopy (PRESS) sequences in the human brain at 3 T. Methods Five healthy subjects were studied at 3 T. 1 H spectra from the prefrontal cortex were acquired at six different echo times using LASER and PRESS sequences. Postprocessed data were analyzed with LCModel, and the resulting amplitudes were fitted using a mono-exponential decay function to determine the T2 of metabolites. Results Twenty-one percent higher apparent T2 values for the singlet resonances of N-acetyl aspartate, total creatine, and total choline were measured with LASER as compared with PRESS, whereas comparable apparent T2 values were measured for strongly coupled metabolites, glutamate, and myo-inositol, with both sequences. Conclusions Reliable T2 measurements were obtained with both sequences for the five major intracellular metabolites. The LASER sequence appears to be more efficient in suppressing the diffusion component for singlets (having nonexchangeable protons) compared to J-coupled metabolites. Magn Reson Med 79:1260-1265, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

The concentrations of fourteen neurochemicals associated with metabolism, neurotransmission, antioxidant capacity, and cellular structure were measured noninvasively from two distinct brain regions using 1H magnetic resonance spectroscopy. Seventeen young adults (age 19 – 22 years) and sixteen cognitively normal older adults (age 70 – 88 years) were scanned. To increase sensitivity and specificity, 1H magnetic resonance spectra were obtained at the ultra-high field of 7 T and at ultra-short echo time. The concentrations of neurochemicals were determined using water as an internal reference and accounting for gray matter, white matter, and cerebrospinal fluid content of the volume of interest. In the posterior cingulate cortex (PCC), the concentrations of neurochemicals associated with energy (i.e., creatine plus phosphocreatine), membrane turnover (i.e., choline containing compounds), and gliosis (i.e., myo-inositol) were higher in the older adults while the concentrations of N-acetylaspartylglutamate (NAAG) and phosphorylethanolamine (PE) were lower. In the occipital cortex (OCC), the concentration of N-acetylaspartate (NAA), a marker of neuronal viability, concentrations of the neurotransmitters Glu and NAAG, antioxidant ascorbate (Asc), and PE were lower in the older adults while the concentration of choline containing compounds was higher. Altogether, these findings shed light on how the human brain ages differently depending on region.

A major hurdle in the development of effective treatments for amyotrophic lateral sclerosis (ALS) has been the lack of robust biomarkers for use as clinical trial endpoints. Neurochemical profiles obtained in vivo by high field proton magnetic resonance spectroscopy (1H-MRS) can potentially provide biomarkers of cerebral pathology in ALS. However, previous 1H-MRS studies in ALS have produced conflicting findings regarding alterations in the levels of neurochemical markers such as glutamate (Glu) and myo-inositol (mIns). Furthermore, very few studies have investigated the neurochemical abnormalities associated with ALS early in its course. In this study, we measured neurochemical profiles using single-voxel 1H-MRS at 7 T (T) and glutathione (GSH) levels using edited MRS at 3 T in 19 subjects with ALS who had relatively high functional status [ALS Functional Rating Scale-Revised (ALSFRS-R) mean ± SD = 39.8 ± 5.6] and 17 healthy controls. We observed significantly lower total N-acetylaspartate over mIns (tNAA/mIns) ratio in the motor cortex and pons of subjects with ALS versus healthy controls. No group differences were detected in GSH at 3 and 7 T. In subjects with ALS, the levels of tNAA, mIns, and Glu in the motor cortex were dependent on the extent of disease represented by El Escorial diagnostic subcategories. Specifically, combined probable/definite ALS had lower tNAA than possible ALS and controls (both p = 0.03), higher mIns than controls (p

A series of fluorinated macrocyclic complexes, M-DOTAm-F12, where M is LaIII, EuIII, GdIII, TbIII, DyIII, HoIII, ErIII, TmIII, YbIII, and FeII, was synthesized, and their potential as fluorine magnetic resonance imaging (MRI) contrast agents was evaluated. The high water solubility of these complexes and the presence of a single fluorine NMR signal, two necessary parameters for in vivo MRI, are substantial advantages over currently used organic polyfluorocarbons and other reported paramagnetic 19F probes. Importantly, the sensitivity of the paramagnetic probes on a per fluorine basis is at least 1 order of magnitude higher than that of diamagnetic organic probes. This increased sensitivity is due to a substantial—up to 100-fold—decrease in the longitudinal relaxation time (T1) of the fluorine nuclei. The shorter T1 allows for a greater number of scans to be obtained in an equivalent time frame. The sensitivity of the fluorine probes is proportional to the T2/T1 ratio. In water, the optimal metal complexes...

Introduction La mutation IDH offre une information diagnostique et pronostique cruciale dans les gliomes. Le 2-hydroxyglutarate (2HG) est un metabolite specifique des gliomes IDH-mutes qui est decelable par une sequence de spectroscopie editee (MEGA-PRESS). Nous avons examine (1) les parametres radiologiques et genetiques affectant l’accumulation de 2HG, (2) la variation de 2HG sous traitements et (3) la valeur pronostique de 2HG. Methode Soixante-dix gliomes (24 non-traites, 46 IDH-mutes traites) ont ete etudies sur un systeme 3 T (Verio, Siemens) avec des sequences 3DT1 EG, 3DT1 FLAIR, DTI (12 directions) et MEGA-PRESS (TR : 2s, TE : 68 ms, taille du voxel : 9,8 ml ± 2,8, dure : 8 min). Neuf gliomes IDH mutes ont ete aussi suivi pour un ans pendant radio-chimiotherapie. Nous avons analyse des parametres radiologiques (volume tumoral, volumes des portions kystiques, pourcentage de tumeur dans le voxel, profil spectroscopique, valeurs de MD, FA) ainsi que genetiques (mutation IDH1R132H, IDH2 et IDH1 mineurs). Le 2HG a ete aussi mesure dans des echantillons tumoraux, dans le plasma et dans les urines en utilisant la chromatographie en phase gazeuse couplee a la spectrometrie de masse (GCMS). Resultats MEGA-PRESS a detecte le 2HG avec une sensibilite de 95 % chez les patients non traites, de 69 % chez les patients traites et avec une specificite de 100 % dans les deux groupes. Les valeurs de 2HG ont montre une correlation positive avec la choline (r = 0,58 p = 0,0001) et negative avec le myo-inositol (r = −0,29 p = 0,03) ( Fig. 1 C–D). Le 2HG a ete plus facilement mesure en absence de lesions kystiques (p = 0,04), lorsque le volume tumoral etait > 26,9 cm3 (p = 0,02) ou le pourcentage de tumeur dans le voxel etait > 72 % (p = 0,04). Les mesures estimees par MEGA-PRESS ont correle avec les valeurs obtenues par CGSM sur des echantillons tumoraux (r = 0,68, p = 0,0009) et dans les urines (r = 0,80 p = 0,003). La concentration de 2HG est reduite chez les patients traites par rapport a ceux qui n’ont pas recu des traitements (1,1 versus 2,3 mm, p = 0,02), elle est plus elevee chez les gliomes IDH2 mutes par rapport a les plus frequentes gliomes IDH1 R132H mutes (4,7 vs 2,4 mm, p = 0,02) et plus faible chez les patients presentant des mutations IDH1 autres que R132H (1,12 vs 2,4 mm, p = 0,004). Enfin, les gliomes IDH mutes qui ont montre une concentration de 2HG plus elevees ont eu une plus longue survie ( Fig. 1 F). Conclusion La densite des cellules IDH-mutees, le volume tumoral, les traitements et les caracteristiques genetiques de la tumeur determinent la detection de 2HG. Cet oncometabolite peut etre surveille de facon fiable sous radio-chimiotherapie et a un valeur pronostique positive per se, independant de la mutation IDH.

γ-aminobutyric acid (GABA) was the first molecule that was edited with MEGA-PRESS. GABA edited spectroscopy is challenged by limited selectivity of editing pulses. Coediting of resonances from macromolecules (MM) is the greatest single limitation of GABA edited spectroscopy. In this contribution, relative signal contributions from GABA, MM and homocarnosine to the total MEGA-PRESS edited signal at ~3 ppm, i.e., GABA+, are simulated at 3 tesla using several acquisition schemes. The base scheme is modeled after those currently supplied by vendors: it uses typical pulse shapes and lengths, it minimizes the first echo time (TE), and the delay between the editing pulses is kept at TE/2. Edited spectra are simulated for imperfect acquisition parameters such as incorrect frequency, larger chemical shift displacement, incorrect transmit B(1)-field calibration for localization and editing pulses, and longer TE. An alternative timing scheme and longer editing pulses are also considered. Additional simulations are performed for symmetric editing around the MM frequency to suppress the MM signal. The relative influences of these acquisition parameters on the constituents of GABA+ are examined from the perspective of modern experimental designs for investigating brain GABA concentration differences in healthy and diseased humans. Other factors that influence signal contributions, such as T(1) and T(2) relaxation times are also considered.

Quantification of neurochemical concentrations from 1 H MR spectra is challenged by incomplete knowledge of contributing signals. Some experimental conditions hinder the acquisition of artifact-free spectra and impede the acquisition of condition-specific macromolecule (MM) spectra. This work studies differences caused by fitting solutions routinely employed to manage resonances from MM and lipids. High quality spectra (free of residual water and lipid artifacts and for which condition-specific MM spectra are available) are used to understand the influences of spline baseline flexibility and noncondition-specific MM on neurochemical quantification. Fitting with moderate spline flexibility or using noncondition-specific MM led to quantification that differed from when an appropriate, fully specified model was used. This occurred for all neurochemicals to an extent that varied in magnitude among and within approaches. The spline baseline was more tortuous when less constrained and when used in combination with noncondition-specific MM. Increasing baseline flexibility did not reproduce concentrations quantified under appropriate conditions when spectra were fitted using a MM spectrum measured from a mismatched cohort. Using the noncondition-specific MM spectrum led to quantification differences that were comparable in size with using a fitting model that had moderate freedom, and these influences were additive. Although goodness of fit was better with greater fitting flexibility, quantification differed from when fitting with a fully specified model that is appropriate for low noise data. Notable GABA and PE concentration differences occurred with lower estimates of measurement error when fitting with greater spline flexibility or noncondition-specific MM. These data support the need for improved metrics of goodness of fit. Attempting to correct for artifacts or absence of a condition-specific MM spectrum via increased spline flexibility and usage of noncondition-specific MM spectra cannot replace artifact-free data quantified with a condition-specific MM spectrum.

BACKGROUND: Psychotic disorders, including schizophrenia and bipolar disorder with psychotic features, can be conceptualized in a dimensional rather than categorical way. Such disorders might share similarities in illness pathophysiology. Disruptions in certain neurotransmitter systems (aberrant dopamine; hypo-functioning glutamatergic NMDA receptors) are thought to be involved in the development of psychosis. Whether such neurotransmitters fluctuate in tandem with psychotic symptom severity remains unclear. We sought to examine dimensional symptom severity of psychosis in relation to neurochemical concentrations using magnetic resonance spectroscopy, which allows for the quantification of neurochemicals. METHODS: As part of the ongoing Psychosis Human Connectome Project, we acquired MR spectroscopy data at 7 Tesla, which has better spectral resolution in general than data acquired at lower field-strengths. Using a STEAM sequence, we measured both excitatory (glutamate) and inhibitory metabolites (Gamma-Aminobutyric Acid; GABA) in the prefrontal cortex among individuals with psychosis (n=18) and healthy control participants (n=12). In order to explore potential genetic liability, we also studied first-degree biological relatives of individuals with a psychotic disorder (n=8). RESULTS: Among individuals with psychosis, we found a significant inverse correlation between glutamate and disorientation as measured by the Brief Psychiatric Rating Scale (BPRS; r = -.61, p = .004). Among the full sample with good-quality imaging data (N=30), we found a significant positive correlation between GABA and cognitive-perceptual disturbances as measured by the Schizotypal Personality Questionnaire (SPQ; r = .40, p = .030). DISCUSSION: More severe psychotic-like symptoms corresponded with lower concentrations of the excitatory neurotransmitter glutamate and higher concentrations of inhibitory GABA. These findings suggest that an imbalance in excitatory and inhibitory neurotransmitters may underlie psychotic-like symptoms that are present in a range of clinical and non-clinical populations. As we continue to collect data, we will increase our sample size which will enable us to examine whether concentrations of these metabolites differ across individuals affected by psychotic illness, those carrying genetic liability for such disorders, and non-psychiatric control participants.

BACKGROUND: Abnormal perceptual experiences are common in people with psychosis and have been linked to greater disease severity and poorer outcomes. While the neural basis of psychosis remains unknown, it has been suggested that an imbalance between excitation and inhibition may lead to neural dysfunction in people with psychotic disorders. It is also unclear to what extent abnormal perceptual functioning occurs across the spectrum of psychotic disorders, or is specific to particular diagnoses (e.g., schizophrenia). METHODS: To examine the link between neural dysfunction and abnormal perception, we performed a series of experiments to measure: 1) visual contrast discrimination behavior, 2) 7 tesla fMRI responses in visual cortex during contrast discrimination, and 3) neurochemical concentrations in visual cortex using 7 tesla MR spectroscopy. Data were acquired from people with psychosis, their unaffected first-degree biological relatives, and healthy control subjects as part of the ongoing Psychosis Human Connectome Project. In our behavioral task performed outside the scanner, subjects were asked to discriminate between two visual grating stimuli, and report which was higher in contrast. Discrimination thresholds, the minimum difference in contrast that could be perceived with 80% accuracy, were measured using a psychophysical adaptive staircase method. Data from 1 subject with psychosis were excluded for poor catch trial performance (< 80% accuracy). RESULTS: Thresholds were significantly higher for subjects with psychosis vs. healthy controls, indicating a reduced sensitivity to visual contrast. Threshold data were fit with a standard model that describes the nonlinear contrast-response function (input vs. output). Preliminary results suggest that the difference in contrast discrimination performance between subjects with psychosis (n = 27) and controls (n = 18) could be described by the model in terms of a multiplicative reduction in visual response magnitude. Preliminary analyses of spectroscopy data revealed no significant differences between subjects with psychosis (n = 22) and controls (n = 25) in the concentrations of glutamate or GABA (scaled to total creatine) in occipital cortex. However, across both groups, higher occipital glutamate concentrations were associated with greater response magnitude values (obtained from modeling the contrast discrimination task data). DISCUSSION: Our results may suggest a role for glutamate levels in occipital cortex in determining individual differences in contrast discrimination performance, as well as in impaired contrast perception among individuals with psychosis.

This study's objective was to increase understanding of biological mechanisms underlying clinical Alzheimer's disease (AD) by noninvasively measuring an expanded neurochemical profile and exploring how well this advanced technology distinguishes AD from cognitively normal controls. We measured concentrations of 14 neurochemicals using ultra-high field (7 T) ultra-short echo time (8 ms) magnetic resonance spectroscopy (MRS) in 16 participants with mild to moderate clinical AD and 33 age- and gender-matched control participants. MRS was localized to the posterior cingulate cortex (PCC), a region known to be impacted by AD, and the occipital cortex (OCC), a control region. Participants with AD were recruited from dementia specialty clinics. Concentration of the antioxidant ascorbate was higher (p < 0.0007) in both brain regions. Concentrations of the glial marker myo-inositol and the choline-containing compounds involved in membrane turnover were higher (p≤0.0004) in PCC of participants with AD. Ascorbate and myo-inositol concentrations were strongly associated, especially in the PCC. Random forests, using the 14 neurochemicals in the two regions, distinguished participants with AD from controls: same-sample sensitivity and specificity were 88% and 97%, respectively, though out-of-sample-values would be lower. Ultra-high field ultra-short echo time MRS identified the co-occurrence of elevated ascorbate and myo-inositol in the PCC as markers that distinguish participants with mild to moderate AD from controls. While elevated myo-inositol may be a surrogate marker of neuroinflammation, the unexpected elevation of the antioxidant ascorbate may reflect infiltration of ascorbate-rich leukocytes.

Purpose: Measurements of objective response rates are critical to evaluate new glioma therapies. The hallmark metabolic alteration in gliomas with mutant isocitrate dehydrogenase (IDH) is the overproduction of oncometabolite 2-hydroxyglutarate (2HG), which plays a key role in malignant transformation. 2HG represents an ideal biomarker to probe treatment response in IDH-mutant glioma patients, and we hypothesized a decrease in 2HG levels would be measureable by in vivo magnetic resonance spectroscopy (MRS) as a result of antitumor therapy. Experimental Design: We report a prospective longitudinal imaging study performed in 25 IDH-mutant glioma patients receiving adjuvant radiation and chemotherapy. A newly developed 3D MRS imaging was used to noninvasively image 2HG. Paired Student t test was used to compare pre- and posttreatment tumor 2HG values. Test–retest measurements were performed to determine the threshold for 2HG functional spectroscopic maps (fSM). Univariate and multivariate regression were performed to correlate 2HG changes with Karnofsky performance score (KPS). Results: We found that mean 2HG (2HG/Cre) levels decreased significantly (median = 48.1%; 95% confidence interval = 27.3%–56.5%; P = 0.007) in the posttreatment scan. The volume of decreased 2HG correlates (R2 = 0.88, P = 0.002) with clinical status evaluated by KPS. Conclusions: We demonstrate that dynamic measurements of 2HG are feasible by 3D fSM, and the decrease of 2HG levels can monitor treatment response in patients with IDH-mutant gliomas. Our results indicate that quantitative in vivo 2HG imaging may be used for precision medicine and early response assessment in clinical trials of therapies targeting IDH-mutant gliomas. Clin Cancer Res; 22(7); 1632–41. ©2015 AACR.

Although the MR editing techniques that have traditionally been used for the measurement of glutathione (GSH) concentrations in vivo address the problem of spectral overlap, they suffer detriments associated with inherently long TEs. The purpose of this study was to characterize the sensitivity and specificity for the quantification of GSH concentrations without editing at short TE. The approach was to measure synthetically generated changes in GSH concentrations from in vivo stimulated echo acquisition mode (STEAM) spectra after in vitro GSH spectra had been added to or subtracted from them. Spectra from five test subjects were synthetically altered to mimic changes in the GSH signal. To account for different background noise between measurements, retest spectra (from the same individuals as used to generate the altered data) and spectra from five other individuals were compared with the synthetically altered spectra to investigate the reliability of the quantification of GSH concentration. Using STEAM spectroscopy at 7 T, GSH concentration differences on the order of 20% were detected between test and retest studies, as well as between differing populations in a small sample (n = 5) with high accuracy (R(2) > 0.99) and certainty (p ≤ 0.01). Both increases and decreases in GSH concentration were reliably quantified with small impact on the quantification of ascorbate and γ-aminobutyric acid. These results show the feasibility of using short-TE (1)H MRS to measure biologically relevant changes and differences in human brain GSH concentration. Although these outcomes are specific to the experimental approach used and the spectral quality achieved, this study serves as a template for the analogous scrutiny of quantification reliability for other compounds, methodologies and spectral qualities.