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Quantitative assessment of brain glucose metabolic rates using in vivo deuterium magnetic resonance spectroscopy.

ABSTRACT: Quantitative assessment of cerebral glucose consumption rate (CMR_glc) and tricarboxylic acid cycle flux (V_TCA) is crucial for understanding neuroenergetics under physiopathological conditions. In this study, we report a novel in vivo Deuterium (²H) MRS (DMRS) approach for simultaneously measuring and quantifying CMR_glc and V_TCA in rat brains at 16.4 Tesla. Following a brief infusion of deuterated glucose, dynamic changes of isotope-labeled glucose, glutamate/glutamine (Glx) and water contents in the brain can be robustly monitored from their well-resolved ²H resonances. Dynamic DMRS glucose and Glx data were employed to determine CMR_glc and V_TCA concurrently. To test the sensitivity of this method in response to altered glucose metabolism, two brain conditions with different anesthetics were investigated. Increased CMR_glc (0.46 vs. 0.28?µmol/g/min) and V_TCA (0.96 vs. 0.6?µmol/g/min) were found in rats under morphine as compared to deeper anesthesia using 2% isoflurane. This study demonstrates the feasibility and new utility of the in vivo DMRS approach to assess cerebral glucose metabolic rates at high/ultrahigh field. It provides an alternative MRS tool for in vivo study of metabolic coupling relationship between aerobic and anaerobic glucose metabolisms in brain under physiopathological states.

SUBMITTER: Lu M

PROVIDER: S-EPMC5669347 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Quantitative assessment of brain glucose metabolic rates using in vivo deuterium magnetic resonance spectroscopy.

Lu Ming M Zhu Xiao-Hong XH Zhang Yi Y Mateescu Gheorghe G Chen Wei W

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20170515 11

Quantitative assessment of cerebral glucose consumption rate (CMRglc) and tricarboxylic acid cycle flux (VTCA) is crucial for understanding neuroenergetics under physiopathological conditions. In this study, we report a novel in vivo Deuterium (2H) MRS (DMRS) approach for simultaneously measuring and quantifying CMRglc and VTCA in rat brains at 16.4 Tesla. Following a brief infusion of deuterated glucose, dynamic changes of isotope-labeled g ...[more]

PMID: 28503999

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Project description:ObjectivesGlioblastoma multiforme (GBM), the most aggressive glial brain tumors, can metabolize glucose through glycolysis and mitochondrial oxidation pathways. While specific dependencies on those pathways are increasingly associated with treatment response, detecting such GBM subtypes in vivo remains elusive. Here, we develop a dynamic glucose-enhanced deuterium spectroscopy (DGE 2H-MRS) approach for differentially assessing glucose turnover rates through glycolysis and mitochondrial oxidation in mouse GBM and explore their association with histologic features of the tumor and its microenvironment.Materials and methodsGL261 and CT2A glioma allografts were induced in immunocompetent mice and scanned in vivo at 9.4 Tesla, harnessing DGE 2H-MRS with volume selection and Marchenko-Pastur PCA (MP-PCA) denoising to achieve high temporal resolution. Each tumor was also classified by histopathologic analysis and assessed for cell proliferation (Ki67 immunostaining), while the respective cell lines underwent in situ extracellular flux analysis to assess mitochondrial function.ResultsMP-PCA denoising of in vivo DGE 2H-MRS data significantly improved the time-course detection (~2-fold increased Signal-to-Noise Ratio) and fitting precision (-19 ± 1 % Cramér-Rao Lower Bounds) of 2H-labelled glucose, and glucose-derived glutamate-glutamine (Glx) and lactate pools in GL261 and CT2A orthotopic tumors. Kinetic modeling further indicated inter-tumor heterogeneity of glucose consumption rate for glycolysis and oxidation during a defined epoch of active proliferation in both cohorts (19 ± 1 days post-induction), with consistent volumes (38.3 ± 3.4 mm3) and perfusion properties prior to marked necrosis. Histopathologic analysis of these tumors revealed clear differences in tumor heterogeneity between the two GBM models, aligned with metabolic differences of the respective cell lines monitored in situ. Importantly, glucose oxidation (i.e. Glx synthesis and elimination rates: 0.40 ± 0.08 and 0.12 ± 0.03 mM min-1, respectively) strongly correlated with cell proliferation across the pooled cohorts (R = 0.82, p = 0.001; and R = 0.80, p = 0.002, respectively), regardless of tumor morphologic features or in situ metabolic characteristics of each GBM model.ConclusionsOur fast DGE 2H-MRS enables the quantification of glucose consumption rates through glycolysis and mitochondrial oxidation in mouse GBM, which is relevant for assessing their modulation in vivo according to tumor microenvironment features such as cell proliferation. This novel application augurs well for non-invasive metabolic characterization of glioma or other cancers with mitochondrial oxidation dependencies.

Project description:Medulloblastoma (MB) is the most common malignant brain tumor occurring in childhood and rarely found in adult. Based on transcriptome profile MB are currently classified into four major molecular groups reflecting a considerable biological heterogeneity: WNT-activated, SHH-activated, group 3 and group 4. Recently, DNA methylation profiling allowed the identification of additional subgroups within the four major molecular groups associated with different clinic-pathological and molecular features. Isocitrate Dehydrogenase-1 (IDH1) mutations have been described in several tumours, including gliomas, while in MB are exceptionally reported and not routinely investigated. By mean of magnetic resonance spectroscopy (MRS) we unequivocally assessed the presence the oncometabolite D-2-Hydroxyglutarate (2HG), a marker of IDH1 and IDH2 mutation, in a case of adult MB. Immunophenotypical work-up and methylation profiling assigned the diagnosis of MB, subclass SHH-A, and molecular testing revealed the presence of the non-canonical somatic IDH1(p.R132C) mutation and an additional GNAS mutation, also exceptionally described in MB. To our knowledge this is the first reported case of MB harboring both mutations together. Of note, tumour exhibited a heterogeneous phenotype with a tumour component displaying glial differentiation, with robust GFAP expression, and a component with conventional MB features and selective presence of GNAS mutation, suggesting coexistence of two different major tumour clones. These findings draw attention to the need of a deeper genetic characterization of MB in order to get insights into their biology and improve stratification and clinical management of the patients. Moreover, reported data underling the importance of performing MRS for the identification of IDH mutations in non-glial tumours. The use of throughput molecular profiling analysis and advanced medical imaging technology will certainly increase the frequency with which rare tumour entities will be identified. Whether they have any particular therapeutic implications or prognostic relevance requires further investigations.

Dataset Information

Quantitative assessment of brain glucose metabolic rates using in vivo deuterium magnetic resonance spectroscopy.

Publications

Quantitative assessment of brain glucose metabolic rates using in vivo deuterium magnetic resonance spectroscopy.

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