Kinetic analysis of blood-brain barrier transport of d-glucose in man: Quantitative evaluation in the presence of tracer backflux and capillary heterogeneity

Knudsen, Gitte M.; Pettigrew, Karen D.; Paulson, Olaf B.; Hertz, Marianne M.; Patlak, Clifford S.

doi:10.1016/0026-2862(90)90057-x

Cited by 36 publications

(30 citation statements)

References 26 publications

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“…Glu labeling curves. Many studies have measured the kinetics of glucose transport (Knudsen et al, 1990;Pardridge, 1994;Van Zijl et al, 1997) given that the dominant method to measure cerebral glucose consumption is by measuring the activity accumulated in the phosphorylation product of a glucose analog, such as the widely used autoradiography of deoxyglucose, or the non-invasive fluoro-deoxy-glucose positron emission tomography (Tyler et al, 1988). In vivo NMR spectroscopy stands out among these methods in that it can provide a direct, localized measurement of brain glucose content (Choi et al, 2001;Gruetter et al, 1992a;Gruetter et al, 1998b) as well as the diffusion behavior of glucose (Pfeuffer et al, 2000).…”

Section: Glucose Transportmentioning

confidence: 99%

In vivo 13C NMR studies of compartmentalized cerebral carbohydrate metabolism

Gruetter

2002

Neurochemistry International

110

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Localized 13 C nuclear magnetic resonance (NMR) spectroscopy provides a unique window for studying cerebral carbohydrate metabolism through, e.g. the completely non-invasive measurement of cerebral glucose and glycogen metabolism. In addition, label incorporation into amino acid neurotransmitters such as glutamate (Glu), GABA and aspartate can be measured providing information on Krebs cycle flux and oxidative metabolism. Given the compartmentation of key enzymes such as pyruvate carboxylase and glutamine synthetase, the detection of label incorporation into glutamine indicated that neuronal and glial metabolism can be measured in vivo. The purpose of this paper is to provide a critical overview of these recent advances into measuring compartmentation of brain energy metabolism using localized in vivo 13 C NMR spectroscopy. The studies reviewed herein showed that anaplerosis is significant in brain, as is oxidative ATP generation in glia and the rate of glial glutamine synthesis attributed to the replenishment of the neuronal Glu pool and that brain glycogen metabolism is slow under resting conditions. This new modality promises to provide a new investigative tool to study aspects of normal and diseased brain hitherto unaccessible, such as the interplay between glutamatergic action, glucose and glycogen metabolism during brain activation, and the derangements thereof in patients with hepatic encephalopathy, neurodegenerative diseases and diabetes.

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Section: Glucose Transportmentioning

confidence: 99%

In vivo 13C NMR studies of compartmentalized cerebral carbohydrate metabolism

Gruetter

2002

Neurochemistry International

110

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“…7,8 Subsequent measurements using microtransillumination, 9 confocal, 10 and two-photon microscopy 11 also observed considerable heterogeneity in baseline blood cell velocity. In one of the few direct measurements, Villringer et al 10 observed a significant decrease in heterogeneity in response to hypercapnia-induced hyperemia.…”

Section: Introductionmentioning

confidence: 97%

Extra Permeability is Required to Model Dynamic Oxygen Measurements: Evidence for Functional Recruitment?

Barrett

Suresh

2013

J Cereb Blood Flow Metab

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Neural activation triggers a rapid, focal increase in blood flow and thus oxygen delivery. Local oxygen consumption also increases, although not to the same extent as oxygen delivery. This 'uncoupling' enables a number of widely-used functional neuroimaging techniques; however, the physiologic mechanisms that govern oxygen transport under these conditions remain unclear. Here, we explore this dynamic process using a new mathematical model. Motivated by experimental observations and previous modeling, we hypothesized that functional recruitment of capillaries has an important role during neural activation. Using conventional mechanisms alone, the model predictions were inconsistent with in vivo measurements of oxygen partial pressure. However, dynamically increasing net capillary permeability, a simple description of functional recruitment, led to predictions consistent with the data. Increasing permeability in all vessel types had the same effect, but two alternative mechanisms were unable to produce predictions consistent with the data. These results are further evidence that conventional models of oxygen transport are not sufficient to predict dynamic experimental data. The data and modeling suggest that it is necessary to include a mechanism that dynamically increases net vascular permeability. While the model cannot distinguish between the different possibilities, we speculate that functional recruitment could have this effect in vivo.

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“…58 In deriving the glucose metabolic rate from the uptake of a glucose analog, the kinetics of glucose transport is important and have been assessed in several studies. [59][60][61] In vivo NMR spectroscopy has the capability of providing a direct, localized measurement of brain glucose content non-invasively. 20,21,24 Of course, sensitivity for NMR is low compared with some radioactivity-based methods, and the relative sensitivity of 13 C NMR is even lower.…”

Section: Nmr Uniquementioning

confidence: 99%

Localized in vivo¹³C NMR spectroscopy of the brain

et al. 2003

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Localized 13C NMR spectroscopy provides a new investigative tool for studying cerebral metabolism. The application of 13 C NMR spectroscopy to living intact humans and animals presents the investigator with a number of unique challenges. This review provides in the first part a tutorial insight into the ingredients required for achieving a successful implementation of localized 13 C NMR spectroscopy. The difficulties in establishing 13 C NMR are the need for decoupling of the one-bond 13 C-1 H heteronuclear J coupling, the large chemical shift range, the low sensitivity and the need for localization of the signals. The methodological consequences of these technical problems are discussed, particularly with respect to (a) RF front-end considerations, (b) localization methods, (c) the low sensitivity, and (d) quantification methods. Lastly, some achievements of in vivo localized 13 C NMR spectroscopy of the brain are reviewed, such as: (a) the measurement of brain glutamine synthesis and the feasibility of quantifying glutamatergic action in the brain; (b) the demonstration of significant anaplerotic fluxes in the brain; (c) the demonstration of a highly regulated malate-aspartate shuttle in brain energy metabolism and isotope flux; (d) quantification of neuronal and glial energy metabolism; and (e) brain glycogen metabolism in hypoglycemia in rats and humans. We conclude that the unique and novel insights provided by 13 19-24 Most of these studies have involved the administration of a 13 C-enriched precursor. When the enriched 13 C label is transferred to molecules in the metabolic pathway, sensitivity can not only be increased, but important information on metabolic pathways can also be obtained. For example, recent studies showed that the information content of 13 C NMR spectroscopy can be amplified considerably, such as the resolved observation of GABA labeling in the human brain, as well as the first detection of lactate labeling in normal human brain. 8 In addition to its importance in assessing metabolism in intact brain, 13 C NMR spectroscopy has become an important and useful tool in assessing compartmentation of metabolism in brain cells using extracts. 25,26 In addition to its low sensitivity, 13 C NMR spectroscopy is methodologically more challenging than 1 H or even 31 P NMR spectroscopy. However, 13C NMR provides its own unique insight and advantages over 1 H NMR spectroscopy. The uniqueness of 13 C NMR stems mainly from its increased chemical shift dispersion, which can, for example, be used in two-dimensional NMR to increase spectral resolution following specific labeling of the protein. 27 As shall be elaborated further below, 13 C NMR spectroscopy in living tissue provides a unique window on in vivo metabolism as it occurs. In the

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Kinetic analysis of blood-brain barrier transport of d-glucose in man: Quantitative evaluation in the presence of tracer backflux and capillary heterogeneity

Cited by 36 publications

References 26 publications

In vivo 13C NMR studies of compartmentalized cerebral carbohydrate metabolism

In vivo 13C NMR studies of compartmentalized cerebral carbohydrate metabolism

Extra Permeability is Required to Model Dynamic Oxygen Measurements: Evidence for Functional Recruitment?

Localized in vivo¹³C NMR spectroscopy of the brain

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Kinetic analysis of blood-brain barrier transport of d-glucose in man: Quantitative evaluation in the presence of tracer backflux and capillary heterogeneity

Cited by 36 publications

References 26 publications

In vivo 13C NMR studies of compartmentalized cerebral carbohydrate metabolism

In vivo 13C NMR studies of compartmentalized cerebral carbohydrate metabolism

Extra Permeability is Required to Model Dynamic Oxygen Measurements: Evidence for Functional Recruitment?

Localized in vivo13C NMR spectroscopy of the brain

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Localized in vivo¹³C NMR spectroscopy of the brain