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Cerebral Ketones Detected by 3T MR Spectroscopy in Patients with High-Grade Glioma on an Atkins-Based Diet.
Berrington, A, Schreck, KC, Barron, BJ, Blair, L, Lin, DDM, Hartman, AL, Kossoff, E, Easter, L, Whitlow, CT, Jung, Y, et al
AJNR. American journal of neuroradiology. 2019;(11):1908-1915
Abstract
BACKGROUND AND PURPOSE Ketogenic diets are being explored as a possible treatment for several neurological diseases, but the physiologic impact on the brain is unknown. The objective of this study was to evaluate the feasibility of 3T MR spectroscopy to monitor brain ketone levels in patients with high-grade gliomas who were on a ketogenic diet (a modified Atkins diet) for 8 weeks. MATERIALS AND METHODS Paired pre- and post-ketogenic diet MR spectroscopy data from both the lesion and contralateral hemisphere were analyzed using LCModel software in 10 patients. RESULTS At baseline, the ketone bodies acetone and β-hydroxybutyrate were nearly undetectable, but by week 8, they increased in the lesion for both acetone (0.06 ± 0.03 ≥ 0.27 ± 0.06 IU, P = .005) and β-hydroxybutyrate (0.07 ± 0.07 ≥ 0.79 ± 0.32 IU, P = .046). In the contralateral brain, acetone was also significantly increased (0.041 ± 0.01 ≥ 0.16 ± 0.04 IU, P = .004), but not β-hydroxybutyrate. Acetone was detected in 9/10 patients at week 8, and β-hydroxybutyrate, in 5/10. Acetone concentrations in the contralateral brain correlated strongly with higher urine ketones (r = 0.87, P = .001) and lower fasting glucose (r = -0.67, P = .03). Acetoacetate was largely undetectable. Small-but-statistically significant decreases in NAA were also observed in the contralateral hemisphere at 8 weeks. CONCLUSIONS This study suggests that 3T MR spectroscopy is feasible for detecting small cerebral metabolic changes associated with a ketogenic diet, provided that appropriate methodology is used.
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Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate.
Andronesi, OC, Arrillaga-Romany, IC, Ly, KI, Bogner, W, Ratai, EM, Reitz, K, Iafrate, AJ, Dietrich, J, Gerstner, ER, Chi, AS, et al
Nature communications. 2018;(1):1474
Abstract
Inhibitors of the mutant isocitrate dehydrogenase 1 (IDH1) entered recently in clinical trials for glioma treatment. Mutant IDH1 produces high levels of 2-hydroxyglurate (2HG), thought to initiate oncogenesis through epigenetic modifications of gene expression. In this study, we show the initial evidence of the pharmacodynamics of a new mutant IDH1 inhibitor in glioma patients, using non-invasive 3D MR spectroscopic imaging of 2HG. Our results from a Phase 1 clinical trial indicate a rapid decrease of 2HG levels by 70% (CI 13%, P = 0.019) after 1 week of treatment. Importantly, inhibition of mutant IDH1 may lead to the reprogramming of tumor metabolism, suggested by simultaneous changes in glutathione, glutamine, glutamate, and lactate. An inverse correlation between metabolic changes and diffusion MRI indicates an effect on the tumor-cell density. We demonstrate a feasible radiopharmacodynamics approach to support the rapid clinical translation of rationally designed drugs targeting IDH1/2 mutations for personalized and precision medicine of glioma patients.
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Diagnostic accuracy of 2-hydroxyglutarate magnetic resonance spectroscopy in newly diagnosed brain mass and suspected recurrent gliomas.
Zhou, M, Zhou, Y, Liao, H, Rowland, BC, Kong, X, Arvold, ND, Reardon, DA, Wen, PY, Lin, AP, Huang, RY
Neuro-oncology. 2018;(9):1262-1271
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Abstract
BACKGROUND Isocitrate dehydrogenase (IDH) mutations result in abnormal accumulation of 2-hydroxyglutarate (2HG) in gliomas that can be detected by MRS. We examined the diagnostic accuracy of 2HG single-voxel spectroscopy (SVS) and chemical shift imaging (CSI) in both newly diagnosed and posttreatment settings. METHODS Long echo time (97 ms) SVS and CSI were acquired in 85 subjects, including a discovery cohort of 39 patients who had postoperative residual or recurrent glioma with confirmed IDH-mutation status and 6 normal volunteers, a prospective preoperative validation cohort of 24 patients with newly diagnosed brain mass, and a prospective recurrent-lesion validation cohort of 16 previously treated IDH-mutant glioma patients with suspected tumor recurrence. The optimal thresholds for both methods in diagnosing IDH status were determined by receiver operating characteristic analysis in the discovery cohort and then applied to the 2 validation cohorts to assess the diagnostic performance. RESULTS The optimal 2HG/creatine thresholds of SVS and 75th percentile CSI for IDH mutations were 0.11 and 0.23, respectively. When applied to the validation sets, the sensitivity, specificity, and accuracy in distinguishing IDH-mutant gliomas in the preoperative cohort were 85.71%, 100.00%, and 94.12% for SVS, and 100.00%, 69.23%, and 81.82% for CSI, respectively. In the recurrent-lesion cohort, the sensitivity, specificity, and accuracy for discriminating IDH-positive recurrent gliomas were 40.00%, 62.50%, and 53.85% for SVS, and 66.67%, 100.00%, and 86.67% for CSI, respectively. CONCLUSIONS 2HG MRS provides diagnostic utility for IDH-mutant gliomas both preoperatively and at time of suspected tumor recurrence. SVS has a better diagnostic performance for untreated IDH-mutant gliomas, whereas CSI demonstrates greater performance in identifying recurrent tumors.
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Monitoring creatine and phosphocreatine by (13)C MR spectroscopic imaging during and after (13)C4 creatine loading: a feasibility study.
Janssen, BH, Lassche, S, Hopman, MT, Wevers, RA, van Engelen, BG, Heerschap, A
Amino acids. 2016;(8):1857-66
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Abstract
Creatine (Cr) supplementation to enhance muscle performance shows variable responses among individuals and different muscles. Direct monitoring of the supplied Cr in muscles would address these differences. In this feasibility study, we introduce in vivo 3D (13)C MR spectroscopic imaging (MRSI) of the leg with oral ingestion of (13)C4-creatine to observe simultaneously Cr and phosphocreatine (PCr) for assessing Cr uptake, turnover, and the ratio PCr over total Cr (TCr) in individual muscles. (13)C MRSI was performed of five muscles in the posterior thigh in seven subjects (two males and two females of ~20 years, one 82-year-old male, and two neuromuscular patients) with a (1)H/(13)C coil in a 3T MR system before, during and after intake of 15 % (13)C4-enriched Cr. Subjects ingested 20 g Cr/day for 4 days in four 5 g doses at equal time intervals. The PCr/TCr did not vary significantly during supplementation and was similar for all subjects and investigated muscles (average 0.71 ± 0.07), except for the adductor magnus (0.64 ± 0.03). The average Cr turnover rate, assessed in male muscles, was 2.1 ± 0.7 %/day. The linear uptake rates of Cr were variable between muscles, although not significantly different. This assessment was possible in all investigated muscles of young male volunteers, but less so in muscles of the other subjects due to lower signal-to-noise ratio. Improvements for future studies are discussed. In vivo (13)C MRSI after (13)C-Cr ingestion is demonstrated for longitudinal studies of Cr uptake, turnover, and PCr/TCr ratios of individual muscles in one exam.
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Simple and effective exercise design for assessing in vivo mitochondrial function in clinical applications using (31)P magnetic resonance spectroscopy.
Sleigh, A, Lupson, V, Thankamony, A, Dunger, DB, Savage, DB, Carpenter, TA, Kemp, GJ
Scientific reports. 2016;:19057
Abstract
The growing recognition of diseases associated with dysfunction of mitochondria poses an urgent need for simple measures of mitochondrial function. Assessment of the kinetics of replenishment of the phosphocreatine pool after exercise using (31)P magnetic resonance spectroscopy can provide an in vivo measure of mitochondrial function; however, the wider application of this technique appears limited by complex or expensive MR-compatible exercise equipment and protocols not easily tolerated by frail participants or those with reduced mental capacity. Here we describe a novel in-scanner exercise method which is patient-focused, inexpensive, remarkably simple and highly portable. The device exploits an MR-compatible high-density material (BaSO4) to form a weight which is attached directly to the ankle, and a one-minute dynamic knee extension protocol produced highly reproducible measurements of post-exercise PCr recovery kinetics in both healthy subjects and patients. As sophisticated exercise equipment is unnecessary for this measurement, our extremely simple design provides an effective and easy-to-implement apparatus that is readily translatable across sites. Its design, being tailored to the needs of the patient, makes it particularly well suited to clinical applications, and we argue the potential of this method for investigating in vivo mitochondrial function in new cohorts of growing clinical interest.
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Skeletal muscle ATP synthesis and cellular H(+) handling measured by localized (31)P-MRS during exercise and recovery.
Fiedler, GB, Schmid, AI, Goluch, S, Schewzow, K, Laistler, E, Niess, F, Unger, E, Wolzt, M, Mirzahosseini, A, Kemp, GJ, et al
Scientific reports. 2016;:32037
Abstract
(31)P magnetic resonance spectroscopy (MRS) is widely used for non-invasive investigation of muscle metabolism dynamics. This study aims to extend knowledge on parameters derived from these measurements in detail and comprehensiveness: proton (H(+)) efflux, buffer capacity and the contributions of glycolytic (L) and oxidative (Q) rates to ATP synthesis were calculated from the evolutions of phosphocreatine (PCr) and pH. Data are reported for two muscles in the human calf, for each subject and over a wide range of exercise intensities. 22 subjects performed plantar flexions in a 7T MR-scanner, leading to PCr changes ranging from barely noticeable to almost complete depletion, depending on exercise protocol and muscle studied by localized MRS. Cytosolic buffer capacity was quantified for the first time non-invasively and individually, as was proton efflux evolution in early recovery. Acidification started once PCr depletion reached 60-75%. Initial and end-exercise L correlated with end-exercise levels of PCr and approximately linear with pH. Q calculated directly from PCr and pH derivatives was plausible, requiring fewer assumptions than the commonly used ADP-model. In conclusion, the evolution of parameters describing cellular energy metabolism was measured over a wide range of exercise intensities, revealing a relatively complete picture of muscle metabolism.
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Blood Metabolome Changes Before and After Bariatric Surgery: A (1)H NMR-Based Clinical Investigation.
Lopes, TI, Geloneze, B, Pareja, JC, Calixto, AR, Ferreira, MM, Marsaioli, AJ
Omics : a journal of integrative biology. 2015;(5):318-27
Abstract
Excessive body fat and obesity have adverse health effects and result in significant morbidity such as type 2 diabetes mellitus. The health burden of obesity can be reduced with the Roux-en-Y gastric bypass (RYGB) weight-loss bariatric surgery. Little is known on the molecular changes that occur at the metabolome level before and after bariatric surgery, with a view to clinical biomarker development. Hence, we employed a metabolomics approach in 10 obese diabetic patients who underwent bariatric surgery. Metabolomics data were obtained by T2- and diffusion-edited hydrogen nuclear magnetic resonance ((1)H NMR) spectra to monitor the metabolic and lipoprotein profiles, and gas chromatography-mass spectrometry (CG-MS) to access the fatty acid profile before and 12 months after RYGB. Using hierarchical partial least squares discriminant analysis, we found that RYGB induces several key metabolic alterations associated with glucose homeostasis, as well as fatty acid and amino acid metabolism. The levels of lactate (Krebs' intermediate cycle) decreased after RYGB. The leucine, isoleucine, valine, lactate, and glucose levels were higher in the samples before RYGB (p<0.05). Additionally, the levels of very low-density lipoprotein, unsaturated lipids, and N-acetyl-glycoprotein were higher before RYGB. By contrast, levels of the high-density lipoprotein and phosphatidylcholine were higher after bariatric surgery. These results collectively offer important holistic integrative biology data to develop future clinically relevant metabolomics biomarkers related to bariatric surgery in connection with obesity.
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Evaluation of the lactate-to-N-acetyl-aspartate ratio defined with magnetic resonance spectroscopic imaging before radiation therapy as a new predictive marker of the site of relapse in patients with glioblastoma multiforme.
Deviers, A, Ken, S, Filleron, T, Rowland, B, Laruelo, A, Catalaa, I, Lubrano, V, Celsis, P, Berry, I, Mogicato, G, et al
International journal of radiation oncology, biology, physics. 2014;(2):385-93
Abstract
PURPOSE Because lactate accumulation is considered a surrogate for hypoxia and tumor radiation resistance, we studied the spatial distribution of the lactate-to-N-acetyl-aspartate ratio (LNR) before radiation therapy (RT) with 3D proton magnetic resonance spectroscopic imaging (3D-(1)H-MRSI) and assessed its impact on local tumor control in glioblastoma (GBM). METHODS AND MATERIALS Fourteen patients with newly diagnosed GBM included in a phase 2 chemoradiation therapy trial constituted our database. Magnetic resonance imaging (MRI) and MRSI data before RT were evaluated and correlated to MRI data at relapse. The optimal threshold for tumor-associated LNR was determined with receiver-operating-characteristic (ROC) curve analysis of the pre-RT LNR values and MRI characteristics of the tumor. This threshold was used to segment pre-RT normalized LNR maps. Two spatial analyses were performed: (1) a pre-RT volumetric comparison of abnormal LNR areas with regions of MRI-defined lesions and a choline (Cho)-to- N-acetyl-aspartate (NAA) ratio ≥ 2 (CNR2); and (2) a voxel-by-voxel spatial analysis of 4,186,185 voxels with the intention of evaluating whether pre-RT abnormal LNR areas were predictive of the site of local recurrence. RESULTS A LNR of ≥ 0.4 (LNR-0.4) discriminated between tumor-associated and normal LNR values with 88.8% sensitivity and 97.6% specificity. LNR-0.4 voxels were spatially different from those of MRI-defined lesions, representing 44% of contrast enhancement, 64% of central necrosis, and 26% of fluid-attenuated inversion recovery (FLAIR) abnormality volumes before RT. They extended beyond the overlap with CNR2 for most patients (median: 20 cm(3); range: 6-49 cm(3)). LNR-0.4 voxels were significantly predictive of local recurrence, regarded as contrast enhancement at relapse: 71% of voxels with a LNR-0.4 before RT were contrast enhanced at relapse versus 10% of voxels with a normal LNR (P<.01). CONCLUSIONS Pre-RT LNR-0.4 in GBM indicates tumor areas that are likely to relapse. Further investigations are needed to confirm lactate imaging as a tool to define additional biological target volumes for dose painting.
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3.0 T MRI arterial spin labeling and magnetic resonance spectroscopy technology in the application of Alzheimer's disease.
Zou, JX, Wang, MJ, Lei, XJ, Chen, XG
Experimental gerontology. 2014;:31-6
Abstract
The purpose of this study was to investigate the changes in the cerebral blood flow (CBF) and spectrum variables in the posterior cingulate region of patients with AD under the detection of arterial spin labeling (ASL) and magnetic resonance spectroscopy (MRS). A total of 20 AD patients (8 males and 12 females; mean age, 64.84±8.82 years) and 20 healthy controls (9 males and 11 females; mean age, 64.94±7.93 years) were included in this study for analysis. All images were obtained using a 3.0-T MR imager and an 8-channel head array receiving coil. MRS measurements were conducted exploring variables of metabolite ratios. Statistical analyses were conducted with the SPSS 11.0 statistical software package. Findings in the present study revealed a significant difference in the mean MMSE scores between the AD group and the healthy control group (16.21±4.01 vs. 27.35±1.01, P<0.01). Compared with the healthy control group, CBF in the bilateral frontal region showed a significant decrease in the AD group (right frontal: 83.5±7.2 vs. 110±11.5, P<0.05; left frontal: 85.6±8.1 vs. 108.7±12.2, P<0.05, respectively), and a similar association was also observed in the TL, TPJ, parietal, and hippocampal regions (all P<0.05). MRS imaging in the posterior cingulate region showed a significant reduction in the NAA/Cr ratio in the AD group (1.43±0.1 vs. 1.49±0.0, P<0.05). Additionally, we found that the MI/Cr and Cho/Cr ratios were higher than normal controls in patients with AD (all P<0.05). Our results suggested that 3D ASL detection combined with MRS in studying AD could show the regional hypo-perfusion with the decrease of CBF and the abnormal metabolic changes of the posterior cingulate cortex.
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The effect of insulin infusion on the metabolites in cerebral tissues assessed with proton magnetic resonance spectroscopy in young healthy subjects with high and low insulin sensitivity.
Karczewska-Kupczewska, M, Tarasów, E, Nikolajuk, A, Stefanowicz, M, Matulewicz, N, Otziomek, E, Górska, M, Straczkowski, M, Kowalska, I
Diabetes care. 2013;(9):2787-93
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Abstract
OBJECTIVE Insulin may play important roles in brain metabolism. Proton magnetic resonance spectroscopy ((1)H-MRS) of the central nervous system gives information on neuronal viability, cellular energy, and membrane status. To elucidate the specific role of insulin action in the brain, we estimated neurometabolites with (1)H-MRS and assessed their regulation by insulin infusion and their relationship with insulin sensitivity. RESEARCH DESIGN AND METHODS We studied 16 healthy young men. (1)H-MRS was performed at baseline and after 240 min of euglycemic-hyperinsulinemic clamp. Voxels were positioned in the left frontal lobe, left temporal lobe, and left thalamus. The ratios of N-acetylaspartate (NAA), choline-containing compounds (Cho), myo-inositol, and glutamate/glutamine/γ-aminobutyric acid complex (Glx) to creatine (Cr) and nonsuppressed water signal were determined. The participants were divided into subgroups of high (high IS) and low (low IS) insulin sensitivity. RESULTS Baseline neurometabolic substrates were not different between the groups. Insulin infusion resulted in an increase in frontal NAA/Cr and NAA/H2O and frontal and temporal Glx/Cr and Glx/H2O and a decrease in frontal Cho/Cr and temporal Cho/H2O and myo-inositol/H2O (all P < 0.05, except temporal Glx/H2O, P = 0.054, NS) in the high-IS, but not in the low-IS, group. Insulin sensitivity correlated positively with frontal NAA/Cr and NAA/H2O and temporal Glx/H2O and negatively with temporal myo-inositol/Cr and myo-inositol/H2O assessed during the second (1)H-MRS (all P < 0.05). CONCLUSIONS Insulin might influence cerebral metabolites, and this action is impaired in subjects with low whole-body insulin sensitivity. Thus, our results provide a potential link between insulin resistance and altered metabolism of the central nervous system.