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Abstract

Purpose

The cerebral mechanisms underlying hepatic encephalopathy (HE) are poorly understood. Adenosine, a neuromodulator that pre- and postsynaptically modulates neuronal excitability and release of classical neurotransmitters via A1 adenosine receptors (A1AR), is likely to be involved. The present study investigates changes of cerebral A1AR binding in cirrhotic patients by means of positron emission tomography (PET) and [18F]CPFPX, a novel selective A1AR antagonist.

Methods

PET was performed in cirrhotic patients (n = 10) and healthy volunteers (n = 10). Quantification of in vivo receptor density was done by Logan’s non-invasive graphical analysis (pons as reference region). The outcome parameter was the apparent binding potential (aBP, proportional to B max/K D).

Results

Cortical and subcortical regions showed lower A1AR binding in cirrhotic patients than in controls. The aBP changes reached statistical significance vs healthy controls (p < 0.05, U test with Bonferroni-Holm adjustment for multiple comparisons) in cingulate cortex (−50.0%), precentral gyrus (−40.9%), postcentral gyrus (−38.6%), insular cortex (−38.6%), thalamus (−32.9%), parietal cortex (−31.7%), frontal cortex (−28.6), lateral temporal cortex (−28.2%), orbitofrontal cortex (−27.9%), occipital cortex (−24.6), putamen (−22.7%) and mesial temporal lobe (−22.4%).

Conclusion

Regional cerebral adenosinergic neuromodulation is heterogeneously altered in cirrhotic patients. The decrease of cerebral A1AR binding may further aggravate neurotransmitter imbalance at the synaptic cleft in cirrhosis and hepatic encephalopathy. Different pathomechanisms may account for these alterations including decrease of A1AR density or affinity, as well as blockade of the A1AR by endogenous adenosine or exogenous xanthines.

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Acknowledgements

This study was supported by grants from the German Research Foundation (DFG) through the Collaborative Research Centre 575 (Experimental Hepatology, C5), and the Federal Ministry of Education and Research (Neuroimaging, Brain Imaging Centre West). The authors thank E. Theelen, S. Schaden, L. Tellmann, B. Elghahwagi, K. H. Beyer, and G. Oeffler (Institute of Medicine), M. Lang, B. Palm, and E. Wabbals (Institute of Nuclear Chemistry) for excellent technical assistance and Dr. W. Meyer (Central Institute for Applied Mathematics, Research Centre Jülich) for statistical consultation.

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Correspondence to Andreas Bauer.

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Christian Boy and Philipp T. Meyer contributed equally to this work.

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Boy, C., Meyer, P.T., Kircheis, G. et al. Cerebral A1 adenosine receptors (A1AR) in liver cirrhosis. Eur J Nucl Med Mol Imaging 35, 589–597 (2008). https://doi.org/10.1007/s00259-007-0586-z

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  • DOI: https://doi.org/10.1007/s00259-007-0586-z

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