Elsevier

NeuroImage

Volume 20, Issue 3, November 2003, Pages 1894-1898
NeuroImage

Case report
Resting-state brain glucose utilization as measured by PET is directly related to regional synaptophysin levels: a study in baboons

https://doi.org/10.1016/j.neuroimage.2003.07.002Get rights and content

Abstract

It is classically recognized that regional cerebral glucose consumption (CMRglc), as measured by positron emission tomography (PET) and [18F]-2-fluorodeoxyglucose (FDG), is a precise index of the integrated local neuronal activity. However, despite extensive use of the FDG-PET method, the significance of the measured CMRglc has been little addressed so far. In the present study, we aimed for the first time to test whether resting-state CMRglc is directly related to synaptic density. To this end, we investigated in the baboon the relationships between CMRglc and the levels of synaptophysin (SY), a presynaptic protein classically used to assess synaptic density. CMRglc, measured in vivo by FDG-PET at the resting-state, and SY levels, assessed postmortem by the Western blot technique, were quantified in seven brain areas of five baboons. By applying these two techniques to the same animals, we found significant positive correlations between CMRglc and SY levels, across all regions and all animals, as well as within individual baboons. These findings strongly support the hypothesis that resting-state CMRglc reflects integrated synaptic activity.

Introduction

Among functional brain imaging techniques, positron emission tomography (PET) with the use of [18F]-2-fluorodeoxyglucose (FDG) is unique as it allows local estimation of cerebral glucose consumption (CMRglc). It is one of the most commonly used methods to assess resting-state functional brain activity in both research and clinical settings. Over the past two decades, investigations with FDG-PET at resting state have afforded valuable insights into the pathophysiology of brain diseases as prevalent as Alzheimer's disease, Parkinson's disease, epilepsy, and schizophrenia (for review, see Iacoboni et al., 1999). Nevertheless, despite widespread use of this method, the significance of the PET-measured CMRglc has remained little addressed.

Using the [14C]-2-deoxy-d-glucose (2DG) technique during changes in brain functional activity in rats and monkeys, an ex vivo autoradiographic technique later applied to in vivo FDG-PET studies, Sokoloff (1981) provided clear evidence of a close coupling between CMRglc and local functional activity. The increased glucose uptake in response to functional stimulation has been shown to be primarily localized in regions enriched in axon terminals (Kadekaro et al., 1987). The cellular and molecular mechanisms involved in this coupling and in generating this metabolic signal were subsequently clarified Pellerin and Magistretti, 1994, Sibson et al., 1998. In the resting state, in which FDG-PET studies are commonly performed, about 80% of basal glucose use is related to basal neuronal activity, the remaining glucose use being associated with basal cellular function, independent from synaptic activity. Although it is classically acknowledged that CMRglc can be considered as an index of the integrated local synaptic activity (for review, see Barinaga, 1997, Magistretti et al., 1999, the relationship between glucose uptake and synapse density has never been directly investigated. It has been reported that the pattern of distribution of the rates of glucose consumption on 2DG autoradiographs from monkey striate cortex coincided closely with the density of cytoarchitectural layers on thionin- and myelin-stained sections (Kennedy et al., 1976). However, quantitative assessment of both CMRglc and synaptic density in the same subjects has never been performed, albeit crucial for interpreting the human PET data.

Although there is no specific marker of synaptic activity so far, synaptic proteins are valid candidates for the postmortem assessment of synaptic density/activity. Thus, synaptophysin (SY), one of the major presynaptic vesicle membrane proteins that is abundantly, ubiquitously, and uniformly expressed throughout the brain Jahn et al., 1985, Wiedenmann and Franke, 1985, Sudhof et al., 1987, is classically used as a marker of synaptic density (Calhoun et al., 1996).

In the present study, we aimed for the first time to test whether CMRglc, as measured in vivo by FDG-PET, is directly related to synaptic density. To this end, we investigated in baboons the relationships between PET-measured CMRglc in the resting state and levels of SY, as assessed postmortem by the Western blot technique, in corresponding brain regions.

Section snippets

Animals

Five young adult male Papio anubis baboons (14–17 kg) were used.

CMRglc and SY levels were quantified in each subject in seven right-sided brain regions of similar location for both PET and biochemical techniques: anterior cingulate, primary occipital, posterior parietal, inferior temporal, dorsolateral prefrontal and orbitofrontal cortices, and hippocampal region (Fig. 1). This sample purposely included regions with low (e.g., primary occipital and hippocampal region) and high (e.g.,

Results

As shown in Fig. 2A, a significant positive correlation was found between normalized CMRglc values and SY levels across the five animals and the seven brain regions (r = 0.61, P < 0.0001; Pearson's test). This result was strengthened by the fact that significant positive correlations were also found in three out of the five baboons with within subject analysis (0.79 ≤ r ≤ 0.82, P ≤ 0.05; Spearman's tests; Fig. 2B).

Discussion

Our findings are of interest for the significance of resting-state regional CMRglc. Widely used as a marker for synaptic density (Calhoun et al., 1996), SY has been shown to be involved in several synaptic functions. Thus, SY regulates exocytosis Calakos and Scheller, 1994, Edelmann et al., 1995, Bacci et al., 2001, induces synaptic vesicles formation (Thiele et al., 2000), and plays a role in synaptic vesicles recycling (Daly and Ziff, 2002). Concerning synaptic activity, the implication of SY

Acknowledgements

This research was supported by INSERM, CEA, and University of Caen. A.B.R. was further supported by Région Basse-Normandie, Association France-Alzheimer and Aventis Laboratories under a Ph.D. program. We thank K. Meguro as well as the radiochemistry, cyclotron, and PET camera teams for technical assistance.

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