Noninvasive quantification of ascorbate and glutathione concentration in the elderly human brain

Emir, Uzay E.; Raatz, Susan K.; McPherson, Susan; Hodges, James S.; Torkelson, Carolyn J.; Tawfik, Pierre; White, Tonya; Terpstra, Melissa

doi:10.1002/nbm.1646

Cited by 98 publications

(99 citation statements)

References 53 publications

(68 reference statements)

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“…Although not reaching statistical significance, we observed 21% lower GSH in the aged cortex. Emir et al (2011) have previously documented lower GSH, but not Asc, in the occipital cortex of elderly humans. Because Asc is found at higher concentrations in neurons, whereas GSH predominates in astrocytes (Rice and Russo-Menna, 1998), we speculate that accumulating reactive oxygen species in aging may selectively target neurons in the hippocampus (resulting in lower hippocampal Asc), while having a relatively larger effect on glial cells in other cortical areas (resulting in lower cortical GSH).…”

Section: Discussionmentioning

confidence: 88%

“…Our investigation of the neurometabolic effects of age focused on brain regions subserving memory and motor function, systems which show progressive functional impairment with age (Schuff et al, 1999; Seidler et al, 2010; West, 1993). Previous in vivo spectroscopy studies in humans and animal models have quantified 7 neurochemicals in the aging brain (Driscoll et al, 2006; Emir et al, 2011; Haga et al, 2009; Katz-Brull et al, 2002). We have measured an additional 13 neurochemicals that have not been reported in the aging brain in vivo: Ala, Asp, Cr, PCr, GABA, Glc, GPC, PCho, MM, NAAG, PE, Ser, and Tau.…”

Section: Discussionmentioning

confidence: 99%

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High-field proton magnetic resonance spectroscopy reveals metabolic effects of normal brain aging

Harris

Swerdlow

Choi

et al. 2014

Neurobiology of Aging

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Altered brain metabolism is likely to be an important contributor to normal cognitive decline and brain pathology in elderly individuals. To characterize the metabolic changes associated with normal brain aging, we used high-field proton magnetic resonance spectroscopy in vivo to quantify 20 neurochemicals in the hippocampus and sensorimotor cortex of young adult and aged rats. We found significant differences in the neurochemical profile of the aged brain when compared with younger adults, including lower aspartate, ascorbate, glutamate, and macromolecules, and higher glucose, myo-inositol, N-acetylaspartylglutamate, total choline, and glutamine. These neurochemical biomarkers point to specific cellular mechanisms that are altered in brain aging, such as bioenergetics, oxidative stress, inflammation, cell membrane turnover, and endogenous neuroprotection. Proton magnetic resonance spectroscopy may be a valuable translational approach for studying mechanisms of brain aging and pathology, and for investigating treatments to preserve or enhance cognitive function in aging.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

High-field proton magnetic resonance spectroscopy reveals metabolic effects of normal brain aging

Harris

Swerdlow

Choi

et al. 2014

Neurobiology of Aging

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“…This study did not distinguish between gray and white matter and assumed a %CSF contribution to the MR voxel based on prior data from our group (12). Glucose concentrations in gray and white matter were found to be the same in one prior study (35) and different in another (6).…”

Section: E1046 Cerebral Glucose Transport and Metabolism Bymentioning

confidence: 85%

“…2 also takes into account the contribution of cerebrospinal fluid (CSF) and blood glucose to the acquired MR signal. The CSF contribution to the VOI was assumed to be 9% based on our prior data acquired from an identical voxel in young, healthy volunteers (12), and the vascular contribution was assumed to be 3.5% (34). Whereas at steady state the Glc concentration in CSF can be assumed to be ϳ0.65 times Glc concentration in plasma (6,22), under non-steady-state conditions where plasma glucose is increased in a step function, the time course of CSF glucose has to be estimated because equilibration of glucose between plasma and CSF is not rapid (13).…”

Section: Methodsmentioning

confidence: 99%

Simultaneous measurement of glucose transport and utilization in the human brain

Shestov

Emir

Kumar

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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cose is the primary fuel for brain function, and determining the kinetics of cerebral glucose transport and utilization is critical for quantifying cerebral energy metabolism. The kinetic parameters of cerebral glucose transport, K M t and V max t , in humans have so far been obtained by measuring steady-state brain glucose levels by proton ( 1 H) NMR as a function of plasma glucose levels and fitting steady-state models to these data. Extraction of the kinetic parameters for cerebral glucose transport necessitated assuming a constant cerebral metabolic rate of glucose (CMRglc) obtained from other tracer studies, such as 13 C NMR. Here we present new methodology to simultaneously obtain kinetic parameters for glucose transport and utilization in the human brain by fitting both dynamic and steady-state 1 H NMR data with a reversible, non-steady-state Michaelis-Menten model. Dynamic data were obtained by measuring brain and plasma glucose time courses during glucose infusions to raise and maintain plasma concentration at ϳ17 mmol/l for ϳ2 h in five healthy volunteers. Steady-state brain vs. plasma glucose concentrations were taken from literature and the steady-state portions of data from the five volunteers. In addition to providing simultaneous measurements of glucose transport and utilization and obviating assumptions for constant CMRglc, this methodology does not necessitate infusions of expensive or radioactive tracers. Using this new methodology, we found that the maximum transport capacity for glucose through the blood-brain barrier was nearly twofold higher than maximum cerebral glucose utilization. The glucose transport and utilization parameters were consistent with previously published values for human brain. magnetic resonance spectroscopy; metabolic modeling; blood-brain barrier; blood-cerebrospinal fluid barrier GLUCOSE IS THE PRIMARY FUEL for brain function. It is transported from the blood to the brain via facilitated diffusion through the lumenal and ablumenal endothelial membranes of the bloodbrain barrier (BBB) by the GLUT1 glucose transporter protein (23,30). Following entry into the brain, glucose is transported from the interstitial fluid into neurons primarily via GLUT3 and into glia primarily via GLUT1 transporters (37). This transport into the intracellular compartment is relatively rapid, making the BBB the rate-limiting barrier for glucose entry into brain cells (2,16,23). Therefore, glucose has been traditionally considered a single pool past the BBB, as also evidenced by its homogeneous distribution in the brain tissue (32). Once inside the cells, a fraction of the glucose molecules gets irreversibly phosphorylated to glucose 6-phosphate by hexokinase, enters the glycolytic pathway, and is almost completely oxidized to CO 2 and H 2 O in the TCA cycle. Under normal physiology, glucose transport is not rate limiting for phosphorylation, which is saturated at the euglycemic brain glucose levels of 1-1.5 mmol/l due to a hexokinase K M of ϳ50 mol/l.Quantifying the kinetics of glucose transp...

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“…The unsuppressed water signal was used as an internal reference assuming 80% brain-water content and 9% CSF fraction within the VOI. 22 The metabolite concentrations were also corrected for relaxation effects during the echo time of 26 ms using simplified approximations (water T 2 = 64 ms and metabolites T 2 = 107 ms). For all metabolites except Glc, only concentration values quantified with Cramèr-Rao lower bounds (CRLBs) below 50% were included into further analysis.…”

Section: Fmrs Data Analysismentioning

confidence: 99%

Neurochemical and BOLD Responses during Neuronal Activation Measured in the Human Visual Cortex at 7 Tesla

Bednařík

Tkáč

Giove

et al. 2015

J Cereb Blood Flow Metab

168

250

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Several laboratories have consistently reported small concentration changes in lactate, glutamate, aspartate, and glucose in the human cortex during prolonged stimuli. However, whether such changes correlate with blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) signals have not been determined. The present study aimed at characterizing the relationship between metabolite concentrations and BOLD-fMRI signals during a block-designed paradigm of visual stimulation. Functional magnetic resonance spectroscopy (fMRS) and fMRI data were acquired from 12 volunteers. A short echo-time semi-LASER localization sequence optimized for 7 Tesla was used to achieve full signal-intensity MRS data. The group analysis confirmed that during stimulation lactate and glutamate increased by 0.26 ± 0.06 μmol/g (~30%) and 0.28 ± 0.03 μmol/g (~3%), respectively, while aspartate and glucose decreased by 0.20 ± 0.04 μmol/g (~5%) and 0.19 ± 0.03 μmol/g (~16%), respectively. The single-subject analysis revealed that BOLD-fMRI signals were positively correlated with glutamate and lactate concentration changes. The results show a linear relationship between metabolic and BOLD responses in the presence of strong excitatory sensory inputs, and support the notion that increased functional energy demands are sustained by oxidative metabolism. In addition, BOLD signals were inversely correlated with baseline γ-aminobutyric acid concentration. Finally, we discussed the critical importance of taking into account linewidth effects on metabolite quantification in fMRS paradigms. Journal of Cerebral Blood INTRODUCTIONFunctional magnetic resonance spectroscopy (fMRS) is a powerful tool that allows quantifying the dynamic of brain metabolite concentrations in the working brain in vivo. Different laboratories have recently used fMRS at ultra-high magnetic field (7 Tesla (7 T)) to measure the neurochemical responses occurring during stimulation of the human visual cortex. [1][2][3][4] The results of these studies were highly consistent with concentration changes in the order of 0.2 μmol/g being reported for aspartate (Asp), glutamate (Glu), glucose (Glc), and lactate (Lac) during prolonged visual stimuli. Similar changes of Glu and Lac have also been reported in the motor cortex. 5 The observed functional changes of metabolite concentrations support an overall increase in oxidative energy metabolism during neuronal activation. 6 In particular, the opposite changes in Glc and Lac concentrations are thought to reflect increased metabolic rate of Glc utilization and activation of the aerobic glycolytic pathway in brain cells. [7][8][9] The observed decrease in Asp and increase in Glu have been interpreted as a consequence of an increased rate of the malate-aspartate shuttle, which is associated with the increased flux into the tricarboxylic acid (TCA) cycle.

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Noninvasive quantification of ascorbate and glutathione concentration in the elderly human brain

Cited by 98 publications

References 53 publications

High-field proton magnetic resonance spectroscopy reveals metabolic effects of normal brain aging

High-field proton magnetic resonance spectroscopy reveals metabolic effects of normal brain aging

Simultaneous measurement of glucose transport and utilization in the human brain

Neurochemical and BOLD Responses during Neuronal Activation Measured in the Human Visual Cortex at 7 Tesla

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