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Magnetic resonance spectroscopic imaging (MRSI) of the brain enables in vivo assessment of metabolic alterations in multiple sclerosis (MS). This provides complementary insights into lesion pathology that cannot be obtained via T1- and T2-weighted conventional magnetic resonance imaging (cMRI).The aims of this study were to assess focal metabolic alterations inside and at the periphery of lesions that are visible or invisible on cMRI, and to correlate their metabolic changes with T1 hypointensity and the distance of lesions to cortical gray matter (GM).A 7 T MRSI was performed on 51 patients with relapsing-remitting MS (30 female/21 male; mean age, 35.4 ± 9.9 years). Mean metabolic ratios were calculated for segmented regions of interest (ROIs) of normal-appearing white matter, white matter lesions, and focal regions of increased mIns/tNAA invisible on cMRI. A subgroup analysis was performed after subdividing based on T1 relaxation and distance to cortical GM. Metabolite ratios were correlated with T1 and compared between different layers around cMRI-visible lesions.Focal regions of, on average, 2.8-fold higher mIns/tNAA than surrounding normal-appearing white matter and with an appearance similar to that of MS lesions were found, which were not visible on cMRI (ie, ~4% of metabolic hotspots). T1 relaxation was positively correlated with mIns/tNAA (P ≤ 0.01), and negatively with tNAA/tCr (P ≤ 0.01) and tCho/tCr (P ≤ 0.01). mIns/tCr was increased outside lesions, whereas tNAA/tCr distributions resembled macroscopic tissue damage inside the lesions. mIns/tCr was -21% lower for lesions closer to cortical GM (P ≤ 0.05).7 T MRSI allows in vivo visualization of focal MS pathology not visible on cMRI and the assessment of metabolite levels in the lesion center, in the active lesion periphery and in cortical lesions. This demonstrated the potential of MRSI to image mIns as an early biomarker in lesion development.

Objectives: Advanced MR imaging of brain tumors is still mainly based on qualitative imaging. PET imaging offers additive metabolic information, and MR fingerprinting (MRF) offers a novel approach to quantitative data acquisition. The purpose of this study was to evaluate the ability of MRF to predict tumor regions and grading in combination with PET. Methods: Seventeen patients with histologically verified infiltrating gliomas and available amino-acid PET data were enrolled. ROIs for solid tumor parts (SPo), perifocal edema (ED1), and normal-appearing white matter (NAWM) were selected on conventional MRI sequences and aligned to the MRF and PET images. The predictability of gliomas by region and grading as well as intermodal correlations were assessed. Results: For MRF, we calculated an overall predictability by region (SPo, ED1, and NAWM) for all of the MRF parameters of 76.5%, 47.1%, and 94.1%, respectively. The overall ability to distinguish low- from high-grade gliomas using MRF was 88.9% for LGG and 75% for HGG, with an accuracy of 82.4%, a ppV of 85.71%, and an npV of 80%. PET positivity was found in 13/17 patients for solid tumor parts, and in 3/17 patients for the edema region. However, there was no significant difference in region-specific MRF values between PET positive and PET negative patients. Conclusions: MRF and PET provide quantitative measurements of the tumor tissue characteristics of gliomas, with good predictability. Nonetheless, the results are dissimilar, reflecting the different underlying mechanisms of each method.

IntroductionDeuterium metabolic imaging (DMI) and quantitative exchange label turnover (QELT) are novel MR spectroscopy techniques for non-invasive imaging of human brain glucose and neurotransmitter metabolism with high clinical potential. Following oral or intravenous administration of non-ionizing [6,6’-2H2]-glucose, its uptake and synthesis of downstream metabolites can be mapped via direct or indirect detection of deuterium resonances using2H MRSI (DMI) and1H MRSI (QELT), respectively.The purpose of this study was to compare the dynamics of spatially resolved brain glucose metabolism, i.e., estimated concentration enrichment of deuterium labeled Glx (glutamate+glutamine) and Glc (glucose) acquired repeatedly in the same cohort of subjects using DMI at 7T and QELT at clinical 3T.MethodsFive volunteers (4m/1f) were scanned in repeated sessions for 60 min after overnight fasting and 0.8g/kg oral [6,6’-2H2]-glucose administration using time-resolved 3D2H FID-MRSI with elliptical phase encoding at 7T and 3D1H FID-MRSI with a non-Cartesian concentric ring trajectory readout at clinical 3T.ResultsOne hour after oral tracer administration regionally averaged deuterium labeled Glx4concentrations and the dynamics were not significantly different over all participants between 7T2H DMI and 3T1H QELT data for GM (1.29±0.15 vs. 1.38±0.26 mM, p=0.65 & 21±3 vs. 26±3 µM/min, p=0.22) and WM (1.10±0.13 vs. 0.91±0.24 mM, p=0.34 & 19±2 vs. 17±3 µM/min, p=0.48). Also, the observed time constants of dynamic Glc6data in GM (24±14 vs. 19±7 min, p=0.65) and WM (28±19 vs. 18±9 min, p=0.43) dominated regions showed no significant differences.Between individual2H and1H data points a weak to moderate negative correlation was observed for Glx4concentrations in GM (r=-0.52, p6data GM (r=- 0.61, pConclusionThis study demonstrates that indirect detection of deuterium labeled compounds using1H QELT MRSI at widely available clinical 3T without additional hardware is able to reproduce absolute concentration estimates of downstream glucose metabolites and the dynamics of glucose uptake compared to2H DMI data acquired at 7T. This suggests significant potential for widespread application in clinical settings especially in environments with limited access to ultra-high field scanners and dedicated RF hardware.

Detailed results of dynamic contrast-enhanced MR imaging of the breast, DWI, 3D 1H-MRSI and 18FDG PET the assigned final MRI BI-RADS® classification for benign and malignant lesions.

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.

ROC curves illustrate the higher diagnostic accuracy that is reached by MP 18FDG-PET-MRI compared to assessment with a single parameter or with multiparametric MRI with combinations of two/three parameters.

Purpose: To assess whether multiparametric 18fluorodeoxyglucose positron emission tomography magnetic resonance imaging (MRI) (MP 18FDG PET-MRI) using dynamic contrast-enhanced MRI (DCE-MRI), diffusion-weighted imaging (DWI), three-dimensional proton MR spectroscopic imaging (3D 1H-MRSI), and 18FDG-PET enables an improved differentiation of benign and malignant breast tumors.Experimental Design: Seventy-six female patients (mean age, 55.7 years; range, 25–86 years) with an imaging abnormality (BI-RADS 0, 4–5) were included in this Institutional Review Board (IRB)-approved study. Patients underwent fused PET-MRI of the breast with 18FDG-PET/CT and MP MRI at 3T. The likelihood of malignancy was assessed for all single parameters, for MP MRI with two/three parameters, and for MP 18FDG PET-MRI. Histopathology was used as the standard of reference. Appropriate statistical tests were used to assess sensitivity, specificity, and diagnostic accuracy for each assessment combination.Results: There were 53 malignant and 23 benign breast lesions. MP 18FDG PET-MRI yielded a significantly higher area under the cure (AUC) of 0.935 than DCE-MRI (AUC, 0.86; P = 0.044) and the combination of DCE-MRI and another parameter (AUC, 0.761–0.826; P = 0.013–0.020). MP 18FDG PET-MRI showed slight further improvement to MP MRI with three parameters (AUC, 0.925; P = 0.317). Using MP 18FDG PET-MRI there would have been a reduction of the unnecessary breast biopsies recommended by MP imaging with one or two parameters (P = 0.002–0.011).Conclusion: This feasibility study shows that MP 18FDG PET-MRI enables an improved differentiation of benign and malignant breast tumors when several MRI and PET parameters are combined. MP 18FDG PET-MRI may lead to a reduction in unnecessary breast biopsies. Clin Cancer Res; 20(13); 3540–9. ©2014 AACR.

ObjectiveTo investigate the metabolic pattern of different types of iron accumulation in multiple sclerosis(MS) lesions, and compare metabolic alterations within and at the periphery of lesions and newly emerging lesionsin vivoaccording to iron deposition.Methods7T MR spectroscopic imaging and susceptibility-weighted-imaging was performed in 31 RRMS patients(16female/15male;mean age,36.9±10.3years). Mean metabolic ratio were calculated for regions of interest(ROI) of normal appearing white matter(NAWM), “non-iron”, and three distinct types of iron-laden lesions, and for lesion layers of “non-iron” and “rim” lesions. Furthermore, newly emerging “non-iron” and “iron” lesions were compared longitudinally.Results52% of iron-containing lesions showed no distinct paramagnetic rim. Of these, “area” lesions exhibited a 65% higher mIns/tNAA(p=0.035) than “rim” lesions. Comparing lesion layers of both “non-iron” and “rim” lesions, a steeper metabolic gradient of mIns/tNAA(“non-iron”+15%,”iron”+40%) and tNAA/tCr(“non-iron”-15%,”iron”-35%) was found in “iron” lesions, with the lesion core showing +22% higher mIns/tNAA(p=0.005) and -23% lower tNAA/tCr(p=0.048) in “iron” compared to “non-iron” lesions. In newly emerging lesions, 46% showed iron accumulation, with the drop in tNAA/tCr after lesion formation remaining significantly lower compared to pre-lesional tissue over time in “iron” lesions(year0:p=0.013,year1:p=0.041) as opposed to “non-iron” lesions(year0:p=0.022,year1:p=0.231).Conclusion7T MRSI allows in vivo characterization of different iron accumulation types showing metabolic differences. Furthermore, the larger extent of neuronal damage in lesions with a distinct iron rim was reconfirmed, but with metabolic differences in lesion development between (non)-iron-containing lesions. This highlights the ability of MRSI to further investigate different types of iron accumulation and suggests possible implications for disease monitoring.Clinical relevance statementThe clinical importance of differentiating various types of iron accumulation in MS lesions was shown, as contrasting metabolic profiles are likely associated with different levels of tissue damage.Key pointsIron-containing lesions were suggested as a biomarker for tissue damage, a more aggressive disease course, and worse clinical outcome, but related metabolic alterations are poorly understoodOur MRSI results confirm a higher extent of tissue damage within paramagnetic rim lesions. 46% of newly emerging lesions showed an iron accumulation, correlating with an altered metabolic behavior compared to non-iron lesionsOnly 48% of iron-containing lesions have a distinct rim-shaped iron accumulation, although most studies focus on these paramagnetic rim lesions. We showed highly different metabolic profiles in different iron accumulation types, highlighting the need for distinct classification of iron accumulation

Background We postulate that meningiomas undergo distinct metabolic reprogramming in tumorigenesis and unraveling their metabolic phenotypes provide new therapeutic insights. Glutamine catabolism is key to the growth and proliferation of tumors. Here, we investigated the metabolomics of freshly resected meningiomas and glutamine metabolism in patient-derived meningioma cells. Methods 1H NMR spectroscopy of tumor tissues from meningioma patients was used to differentiate the metabolite profiles of grade-I and grade-II meningiomas. Glutamine metabolism was examined using 13C/15N glutamine tracer, in 5 patient-derived meningioma cells. Results Alanine, lactate, glutamate, glutamine, and glycine were predominantly elevated only in grade-II meningiomas by 74%, 76%, 35%, 75%, and 33%, respectively, with alanine and glutamine levels being statistically significant (P ≤ .02). 13C/15N glutamine tracer experiments revealed that both grade-I and -II meningiomas actively metabolize glutamine to generate various key carbon intermediates including alanine and proline that are necessary for the tumor growth. Also, it is shown that glutaminase (GLS1) inhibitor, CB-839 is highly effective in downregulating glutamine metabolism and decreasing proliferation in meningioma cells. Conclusion Alanine and glutamine/glutamate are mainly elevated in grade-II meningiomas. Grade-I meningiomas possess relatively higher glutamine metabolism providing carbon/nitrogen for the biosynthesis of key nonessential amino acids. GLS1 inhibitor (CB-839) is very effective in downregulating glutamine metabolic pathways in grade-I meningiomas leading to decreased cellular proliferation.

ObjectivesNon-invasive, affordable, and reliable mapping of brain glucose metabolism is of critical interest for clinical research and routine application as metabolic impairment is linked to numerous pathologies e.g., cancer, dementia and depression. A novel approach to map glucose metabolism non-invasively in the human brain and separate normal oxidative from pathologic anaerobic pathways has been presented recently on experimental MR scanners using direct or indirect detection of deuterium-labeled glucose and downstream metabolites such as glutamate, glutamine and lactate.The aim of this study was to demonstrate the feasibility to non-invasively detect deuterium labeled downstream glucose metabolites indirectly in the human brain via 3D proton (1H) MR spectroscopic imaging on a clinical 3T MR scanner without additional hardware.Materials and MethodsThis prospective, institutional review board approved study was performed in seven healthy volunteers (mean age, 31±4 years, 5 m/ 2 f) following written informed consent. After overnight fasting and oral deuterium-labeled glucose administration 3D metabolic maps were acquired every ∼4 min with ∼0.24 ml isotropic spatial resolution using real-time motion-, shim- and frequency-corrected echo-less 3D1H-MR Spectroscopic Imaging. Time courses were analyzed using linear regression and non-parametric statistical tests. Deuterium labeled glucose and downstream metabolites were detected indirectly via their respective signal decrease in dynamic1H MR spectra due to deuterium to proton exchange in the molecules.ResultsSixty-five minutes after deuterium-labeled glucose administration, glutamate+glutamine (Glx) signal intensities decreased in gray/white matter (GM,WM) by -15±2%,(p=0.02)/-14±3%,(p=0.02), respectively. Strong negative correlation between Glx and time was observed in GM/WM (r=-0.71ppp=0.02) steeper slopes, indicating faster metabolic activity in GM compared to WM. Other non-labeled metabolites showed no significant changes.ConclusionOur approach translates deuterium metabolic imaging to widely available clinical routine MR scanners without specialized hardware offering a safe, affordable, and versatile (other substances than glucose can be labeled) approach for non-invasive imaging of glucose and neurotransmitter metabolism in the human brain.

Objectives Multiple sclerosis (MS) is an inflammatory demyelinating disease that may cause physical disabling as well as cognitive dysfunction. The presented study investigated how the neuropsychological status depends on the thalamus and hippocampus's metabolic processes, using γ-aminobutyric acid-edited magnetic resonance spectroscopy (GABA-edited 1H MRS) in patients with early MS, and how the results differ from healthy volunteers. Methods We recruited 36 relapsing-remitting (RRMS) MS patients and 22 controls (CON). In addition to common 1H MRS metabolites, such as N-acetyl-aspartate (tNAA), myoinositol (mIns), total choline and creatine (tCr, tCho), we also evaluated GABA and glutamate/glutamine (Glx). Metabolite ratios were correlated with the results of Single-Digit Modality Test (SDMT) and Expanded Disability Status Score (EDSS). Results In the thalamus, GABA ratios (GABA/tCr, GABA/tNAA) were significantly lower in RRMS patients than in CON. Both tCho- and mIns-ratios correlated with lower scores of SDMT but not with EDSS. Metabolic ratios in the hippocampus did not differ between RRMS and CON and did not correlate with any of performed tests. Discussion This study is the first to provide GABA-edited 1H MRS evidence for MS-related metabolic changes of the thalamus and hippocampus. The findings underline the importance of evaluating subcortical grey matter in MS patients to improve understanding of the clinical manifestations of MS and as a potential future target for treatment.

Background/Aims: Walking speed (WS) is an objective measure of physical capacity and a modifiable risk factor of morbidity and mortality in the elderly. In this study, we (i) determined effects of 3-month supervised aerobic-strength training on WS, muscle strength, and habitual physical activity; (ii) evaluated capacity of long-term (21 months) training to sustain higher WS; and (iii) identified determinants of WS in the elderly. Methods: Volunteers (F 48/M 14, 68.4 ± 7.1 years) completed either 3-month aerobic-strength (3 × 1 h/week, n = 48) or stretching (active control, n = 14) intervention (study A). Thirty-one individuals (F 24/M 7) from study A continued in supervised aerobic-strength training (2 × 1 h/week, 21 months) and 6 (F 5/M 1) became nonexercising controls. Results: Three-month aerobic-strength training increased preferred and maximal WS (10-m walk test, p < 0.01), muscle strength (p < 0.01) and torque (p < 0.01) at knee extension, and 24-h habitual physical activity (p < 0.001), while stretching increased only preferred WS (p < 0.03). Effect of training on maximal WS was most prominent in individuals with baseline WS between 1.85 and 2.30 m·s−1. Maximal WS measured before intervention correlated negatively with age (r = −0.339, p = 0.007), but this correlation was weakened by the intervention (r = −0.238, p = 0.06). WS progressively increased within the first 9 months of aerobic-strength training (p < 0.001) and remained elevated during 21-month intervention (p < 0.01). Cerebellar gray matter volume (MRI) was positively associated with maximal (r = 0.54; p < 0.0001) but not preferred WS and explained >26% of its variability, while age had only minor effect. Conclusions: Supervised aerobic-strength training increased WS, strength, and dynamics of voluntary knee extension as well as habitual physical activity in older individuals. Favorable changes in WS were sustainable over the 21-month period by a lower dose of aerobic-strength training. Training effects on WS were not limited by age, and cerebellar cortex volume was the key determinant of WS.

Cardiac autonomic dysfunction has been reported in patients with long-standing multiple sclerosis (MS); however, data in early disease are limited. The present study was aimed at evaluating cardiac autonomic function in patients with early MS in the context of white matter metabolic status, which could potentially affect functions of the autonomic brain centers. Cardiac sympathetic and baroreflex cardiovagal responses to the Valsalva maneuver, orthostatic test, and the Stroop test were evaluated in 16 early, treatment-naive patients with relapsing–remitting MS, and in 14 healthy participants. Proton magnetic resonance spectroscopic imaging (MRSI) of the brain was performed in eight of these MS patients and in eight controls. Valsalva maneuver outcomes were comparable between patients and controls. At baseline, norepinephrine levels were lower (p = 0.027) in MS patients compared to controls. The patients had higher heart rate (p = 0.034) and lower stroke volume (p = 0.008), but similar blood pressure, cardiac output and norepinephrine increments from baseline to 2 min of the orthostatic test compared to controls. MS patients and controls did not differ in responses to the Stroop test. MRSI showed lower total N-acetylaspartate/total creatine (p = 0.038) and higher myo-inositol/total creatine (p = 0.013) in MS lesions compared to non-lesional white matter. Our results show normal cardiac sympathetic and baroreflex cardiovagal function in MS patients with relapsing–remitting MS with lesions at the post-acute/early resolving stage. The study was registered at ClinicalTrials.gov under the Identifier: NCT 03052595 and complies with the STROBE checklist for cohort, case–control, and cross-sectional studies.

(1) Background: Recent developments in 7T magnetic resonance spectroscopic imaging (MRSI) made the acquisition of high-resolution metabolic images in clinically feasible measurement times possible. The amino acids glutamine (Gln) and glycine (Gly) were identified as potential neuro-oncological markers of importance. For the first time, we compared 7T MRSI to amino acid PET in a cohort of glioma patients. (2) Methods: In 24 patients, we co-registered 7T MRSI and routine PET and compared hotspot volumes of interest (VOI). We evaluated dice similarity coefficients (DSC), volume, center of intensity distance (CoI), median and threshold values for VOIs of PET and ratios of total choline (tCho), Gln, Gly, myo-inositol (Ins) to total N-acetylaspartate (tNAA) or total creatine (tCr). (3) Results: We found that Gln and Gly ratios generally resulted in a higher correspondence to PET than tCho. Using cutoffs of 1.6-times median values of a control region, DSCs to PET were 0.53 ± 0.36 for tCho/tNAA, 0.66 ± 0.40 for Gln/tNAA, 0.57 ± 0.36 for Gly/tNAA, and 0.38 ± 0.31 for Ins/tNAA. (4) Conclusions: Our 7T MRSI data corresponded better to PET than previous studies at lower fields. Our results for Gln and Gly highlight the importance of future research (e.g., using Gln PET tracers) into the role of both amino acids.

Purpose To explore the impact of temporal motion-induced coil sensitivity changes on CEST-MRI at 7T and its correction using interleaved volumetric EPI navigators, which are applied for real-time motion correction. Methods Five healthy volunteers were scanned via CEST. A 4-fold correction pipeline allowed the mitigation of (1) motion, (2) motion-induced coil sensitivity variations, Δ B 1 - , (3) motion-induced static magnetic field inhomogeneities, ΔB0 , and (4) spatially varying transmit RF field fluctuations, ΔB 1 + . Four CEST measurements were performed per session. For the first 2, motion correction was turned OFF and then ON in absence of voluntary motion, whereas in the other 2 controlled head rotations were performed. During post-processing Δ B 1 - was removed additionally for the motion-corrected cases, resulting in a total of 6 scenarios to be compared. In all cases, retrospective ∆B0 and - ΔB 1 + corrections were performed to compute artifact-free magnetization transfer ratio maps with asymmetric analysis (MTRasym ). Results Dynamic Δ B 1 - correction successfully mitigated signal deviations caused by head motion. In 2 frontal lobe regions of volunteer 4, induced relative signal errors of 10.9% and 3.9% were reduced to 1.1% and 1.0% after correction. In the right frontal lobe, the motion-corrected MTRasym contrast deviated 0.92%, 1.21%, and 2.97% relative to the static case for Δω = 1, 2, 3 ± 0.25 ppm. The additional application of Δ B 1 - correction reduced these deviations to 0.10%, 0.14%, and 0.42%. The fully corrected MTRasym values were highly consistent between measurements with and without intended head rotations. Conclusion Temporal Δ B 1 - cause significant CEST quantification bias. The presented correction pipeline including the proposed retrospective Δ B 1 - correction significantly reduced motion-related artifacts on CEST-MRI.

Purpose To develop a fat‐water imaging method that allows reliable separation of the two tissues, uses established robust reconstruction methods, and requires only one single‐echo acquisition. Theory and Methods The proposed method uses spectrally selective dual‐band excitation in combination with CAIPIRINHA to generate separate images of fat and water simultaneously. Spatially selective excitation without cross‐contamination is made possible by the use of spatial‐spectral pulses. Fat and water images can either be visualized separately, or the fat images can be corrected for chemical shift displacement and, in gradient echo imaging, for chemical shift‐related phase discrepancy, and recombined with water images, generating fat‐water images free of chemical shift effects. Gradient echo and turbo spin echo sequences were developed based on this Simultaneous Multiple Resonance Frequency imaging (SMURF) approach and their performance was assessed at 3Tesla in imaging of the knee, breasts, and abdomen. Results The proposed method generated well‐separated fat and water images with minimal unaliasing artefacts or cross‐excitation, evidenced by the near absence of water signal attributed to the fat image and vice versa. The separation achieved was similar to or better than that using separate acquisitions with water‐ and fat‐saturation or Dixon methods. The recombined fat‐water images provided similar image contrast to conventional images, but the chemical shift effects were eliminated. Conclusion Simultaneous Multiple Resonance Frequency imaging is a robust fat‐water imaging technique that offers a solution to imaging of body regions with significant amounts of fat.

(1) Background: Advanced MR imaging (MRI) of brain tumors is mainly based on qualitative contrast images. MR Fingerprinting (MRF) offers a novel approach. The purpose of this study was to use MRF-derived T1 and T2 relaxation maps to differentiate diffuse gliomas according to isocitrate dehydrogenase (IDH) mutation. (2) Methods: Twenty-four patients with histologically verified diffuse gliomas (14 IDH-mutant, four 1p/19q-codeleted, 10 IDH-wildtype) were enrolled. MRF T1 and T2 relaxation times were compared to apparent diffusion coefficient (ADC), relative cerebral blood volume (rCBV) within solid tumor, peritumoral edema, and normal-appearing white matter (NAWM), using contrast-enhanced MRI, diffusion-, perfusion-, and susceptibility-weighted imaging. For perfusion imaging, a T2* weighted perfusion sequence with leakage correction was used. Correlations of MRF T1 and T2 times with two established conventional sequences for T1 and T2 mapping were assessed (a fast double inversion recovery-based MR sequence (‘MP2RAGE’) for T1 quantification and a multi-contrast spin echo-based sequence for T2 quantification). (3) Results: MRF T1 and T2 relaxation times were significantly higher in the IDH-mutant than in IDH-wildtype gliomas within the solid part of the tumor (p = 0.024 for MRF T1, p = 0.041 for MRF T2). MRF T1 and T2 relaxation times were significantly higher in the IDH-wildtype than in IDH-mutant gliomas within peritumoral edema less than or equal to 1cm adjacent to the tumor (p = 0.038 for MRF T1 mean, p = 0.010 for MRF T2 mean). In the solid part of the tumor, there was a high correlation between MRF and conventionally measured T1 and T2 values (r = 0.913, p < 0.001 for T1, r = 0.775, p < 0.001 for T2), as well as between MRF and ADC values (r = 0.813, p < 0.001 for T2, r = 0.697, p < 0.001 for T1). The correlation was weak between the MRF and rCBV values (r = −0.374, p = 0.005 for T2, r = −0.181, p = 0.181 for T1). (4) Conclusions: MRF enables fast, single-sequence based, multi-parametric, quantitative tissue characterization of diffuse gliomas and may have the potential to differentiate IDH-mutant from IDH-wildtype gliomas.

(1) Background: Advanced MR imaging (MRI) of brain tumors is mainly based on qualitative contrast images. MR Fingerprinting (MRF) offers a novel approach. The purpose of this study was to use MRF-derived T1 and T2 relaxation maps to differentiate diffuse gliomas according to isocitrate dehydrogenase (IDH) mutation. (2) Methods: Twenty-four patients with histologically verified diffuse gliomas (14 IDH-mutant, four 1p/19q-codeleted, 10 IDH-wildtype) were enrolled. MRF T1 and T2 relaxation times were compared to apparent diffusion coefficient (ADC), relative cerebral blood volume (rCBV) within solid tumor, peritumoral edema, and normal-appearing white matter (NAWM), using contrast-enhanced MRI, diffusion-, perfusion-, and susceptibility-weighted imaging. For perfusion imaging, a T2* weighted perfusion sequence with leakage correction was used. Correlations of MRF T1 and T2 times with two established conventional sequences for T1 and T2 mapping were assessed (a fast double inversion recovery-based MR sequence (‘MP2RAGE’) for T1 quantification and a multi-contrast spin echo-based sequence for T2 quantification). (3) Results: MRF T1 and T2 relaxation times were significantly higher in the IDH-mutant than in IDH-wildtype gliomas within the solid part of the tumor (p = 0.024 for MRF T1, p = 0.041 for MRF T2). MRF T1 and T2 relaxation times were significantly higher in the IDH-wildtype than in IDH-mutant gliomas within peritumoral edema less than or equal to 1cm adjacent to the tumor (p = 0.038 for MRF T1 mean, p = 0.010 for MRF T2 mean). In the solid part of the tumor, there was a high correlation between MRF and conventionally measured T1 and T2 values (r = 0.913, p < 0.001 for T1, r = 0.775, p < 0.001 for T2), as well as between MRF and ADC values (r = 0.813, p < 0.001 for T2, r = 0.697, p < 0.001 for T1). The correlation was weak between the MRF and rCBV values (r = −0.374, p = 0.005 for T2, r = −0.181, p = 0.181 for T1). (4) Conclusions: MRF enables fast, single-sequence based, multi-parametric, quantitative tissue characterization of diffuse gliomas and may have the potential to differentiate IDH-mutant from IDH-wildtype gliomas.

Impaired brain glucose metabolism characterizes most severe brain diseases. Recent studies have proposed deuterium (2H)-Magnetic Resonance Spectroscopic Imaging (MRSI) as a reliable, non-invasive, and safe method to quantify the human metabolism of 2H-labeled substrates such as glucose and their downstream metabolism (e.g., aerobic/anaerobic glucose utilization and neurotransmitter synthesis) and address the major drawbacks of positron emission tomography (PET) or carbon (13C)-MRS. Here, for the first time, we show an indirect dynamic proton (1H)-MRSI technique in humans, which overcomes four critical 2H-MRSI limitations. Our innovative approach provides higher sensitivity with improved spatial/temporal resolution and higher chemical specificity to differentiate glutamate (Glu4), glutamine (Gln4), and gamma-aminobutyric acid (GABA2) deuterated at specific molecular positions while allowing simultaneous mapping of both labeled and unlabeled metabolites without the need for specialized hardware. Our novel method demonstrated significant Glu4, Gln4, and GABA2 decreases, with 18% faster Glu4 reduction in the gray matter than white matter after ingestion of deuterated glucose. Thus, robustly detected downstream glucose metabolism utilizing clinically available MR hardware without the need for radioactive tracers and PET.

PURPOSE Lactate is a key metabolite in skeletal muscle and whole-body physiology. Its MR visibility in muscle is affected by overlapping lipid signals and fiber orientation. Double-quantum filtered (DQF) 1 H MRS selectively detects lactate at 1.3 ppm, but at ultra-high field the efficiency of slice-selective 3D-localization with conventional RF pulses is limited by bandwidth. This novel 3D-localized 1 H DQF MRS sequence uses adiabatic refocusing pulses to unambiguously detect lactate in skeletal muscle at 7 T. METHODS Lactate double-quantum coherences were 3D-localized using slice-selective Shinnar-Le Roux optimized excitation and adiabatic refocusing pulses (similar to semi-LASER). DQF MR spectra were acquired at 7 T from lactate phantoms, meat specimens with injected lactate (exploring multiple TEs and fiber orientations), and human gastrocnemius in vivo during and after exercise (without cuff ischemia). RESULTS Lactate was readily detected, achieving the full potential of 50% signal with a DQF, in solution. The effects of fiber orientation and TE on the lactate doublet (peak splitting, amplitude, and phase) were in good agreement with theory and literature. Exercise-induced lactate accumulation was detected with 30 s time resolution. CONCLUSION This novel 3D-localized 1 H DQF MRS sequence can dynamically detect glycolytically generated lactate in muscle during exercise and recovery at 7 T.

Sex hormones affect the GABAergic and glutamatergic neurotransmitter system as demonstrated in animal studies. However, human research has mostly been correlational in nature. Here, we aimed at substantiating causal interpretations of the interaction between sex hormones and neurotransmitter function by using magnetic resonance spectroscopy imaging (MRSI) to study the effect of gender-affirming hormone treatment (GHT) in transgender individuals.Fifteen trans men (TM) with a DSM-5 diagnosis of gender dysphoria, and 15 age-matched cisgender women (CW) underwent MRSI before and after at least 12 weeks of GHT. Additionally, sex differences in neurotransmitter levels were evaluated in an independent sample of 80 cisgender men and 79 cisgender women. Mean GABA+ (a combination of GABA and macromolecules) and Glx (a combination of glutamate and glutamine) ratios to total creatine (GABA+/tCr, Glx/tCr) were calculated in five predefined regions-of-interest (hippocampus, insula, pallidum, putamen and thalamus).Linear mixed models analysis revealed a significant measurement by gender identity effect (pcorr. = 0.048) for GABA+/tCr ratios in the hippocampus, with the TM cohort showing decreased GABA+/tCr levels after GHT compared to CW. Moreover, analysis of covariance showed a significant sex difference in insula GABA+/tCr ratios (pcorr. = 0.049), indicating elevated GABA levels in cisgender women compared to cisgender men.Our study demonstrates GHT treatment-induced GABA+/tCr reductions in the hippocampus, indicating hormone receptor activation on GABAergic cells and testosterone-induced neuroplastic processes within the hippocampus. Moreover, elevated GABA levels in the female compared to the male insula highlight the importance of including sex as factor in future MRS studies.

Lactate is a key metabolite in skeletal muscle and whole-body physiology. Its MR visibility in muscle is affected by overlapping lipid signals and fiber orientation. Double-quantum filtered (DQF)Lactate double-quantum coherences were 3D-localized using slice-selective Shinnar-Le Roux optimized excitation and adiabatic refocusing pulses (similar to semi-LASER). DQF MR spectra were acquired at 7 T from lactate phantoms, meat specimens with injected lactate (exploring multiple TEs and fiber orientations), and human gastrocnemius in vivo during and after exercise (without cuff ischemia).Lactate was readily detected, achieving the full potential of 50% signal with a DQF, in solution. The effects of fiber orientation and TE on the lactate doublet (peak splitting, amplitude, and phase) were in good agreement with theory and literature. Exercise-induced lactate accumulation was detected with 30 s time resolution.This novel 3D-localized

MR spectroscopic imaging (MRSI) noninvasively maps the metabolism of human brains. In particular, the imaging of D-2-hydroxyglutarate (2HG) produced by glioma isocitrate dehydrogenase (IDH) mutations has become a key application in neuro-oncology. However, the performance of full field-of-view MRSI is limited by B0 spatial nonuniformity and lipid artifacts from tissues surrounding the brain. Array coils that multiplex RF-receive and B0 -shim electrical currents (AC/DC mixing) over the same conductive loops provide many degrees of freedom to improve B0 uniformity and reduce lipid artifacts. AC/DC coils are highly efficient due to compact design, requiring low shim currents (

MR spectroscopic imaging (MRSI) noninvasively maps the metabolism of human brains. In particular, the imaging of D-2-hydroxyglutarate (2HG) produced by glioma isocitrate dehydrogenase (IDH) mutations has become a key application in neuro-oncology. However, the performance of full field-of-view MRSI is limited by B(0) spatial nonuniformity and lipid artifacts from tissues surrounding the brain. Array coils that multiplex RF-receive and B(0)-shim electrical currents (AC/DC mixing) over the same conductive loops provide many degrees of freedom to improve B(0) uniformity and reduce lipid artifacts. AC/DC coils are highly efficient due to compact design, requiring low shim currents (

Purpose Heating of gradient coils and passive shim components is a common cause of instability in the B0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites. Method A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC). Results Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI. Discussion This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.

PURPOSE Recently, a 3D-concentric ring trajectory (CRT)-based free induction decay (FID)-MRSI sequence was introduced for fast high-resolution metabolic imaging at 7 T. This technique provides metabolic ratio maps of almost the entire brain within clinically feasible scan times, but its robustness has not yet been thoroughly investigated. Therefore, we have assessed quantitative concentration estimates and their variability in healthy volunteers using this approach. METHODS We acquired whole-brain 3D-CRT-FID-MRSI at 7 T in 15 min with 3.4 mm nominal isometric resolution in 24 volunteers (12 male, 12 female, mean age 27 ± 6 years). Concentration estimate maps were calculated for 15 metabolites using internal water referencing and evaluated in 55 different regions of interest (ROIs) in the brain. Data quality, mean metabolite concentrations, and their inter-subject coefficients of variation (CVs) were compared for all ROIs. RESULTS Of 24 datasets, one was excluded due to motion artifacts. The concentrations of total choline, total creatine, glutamate, myo-inositol, and N-acetylaspartate in 44 regions were estimated within quality thresholds. Inter-subject CVs (mean over 44 ROIs/minimum/maximum) were 9%/5%/19% for total choline, 10%/6%/20% for total creatine, 11%/7%/24% for glutamate, 10%/6%/19% for myo-inositol, and 9%/6%/19% for N-acetylaspartate. DISCUSSION We defined the performance of 3D-CRT-based FID-MRSI for metabolite concentration estimate mapping, showing which metabolites could be robustly quantified in which ROIs with which inter-subject CVs expected. However, the basal brain regions and lesser-signal metabolites in particular remain as a challenge due susceptibility effects from the proximity to nasal and auditory cavities. Further improvement in quantification and the mitigation of B0 /B1 -field inhomogeneities will be necessary to achieve reliable whole-brain coverage.