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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References
Haussinger D, Laubenberger J, vom Dahl S, Ernst T, Bayer S, Langer M, et al. Proton magnetic resonance spectroscopy studies on human brain myo-inositol in hypo-osmolarity and hepatic encephalopathy. Gastroenterology 1994;107:1475–80.
Haussinger D, Kircheis G, Fischer R, Schliess F, vom Dahl S. Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral oedema? J Hepatol 2000;32:1035–8.
Haussinger D, Schliess F. Astrocyte swelling and protein tyrosine nitration in hepatic encephalopathy. Neurochem Int 2005;47:64–70.
Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy-definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 2002;35:716–21.
Butterworth RF. Pathogenesis of hepatic encephalopathy: new insights from neuroimaging and molecular studies. J Hepatol 2003;39:278–85.
Butterworth R. Metabolic encephalopathies. In: Siegel GJ, Albers RW, Brady ST, Price DL, editors. Basic neurochemistry: molecular, cellular, and medical aspects. 7th ed. San Diego: Academic; 2006. p. 596–8.
Timmermann L, Gross J, Butz M, Kircheis G, Haussinger D, Schnitzler A. Mini-asterixis in hepatic encephalopathy induced by pathologic thalamo-motor-cortical coupling. Neurology 2003;61:689–92.
Lockwood AH, Weissenborn K, Bokemeyer M, Tietge U, Burchert W. Correlations between cerebral glucose metabolism and neuropsychological test performance in nonalcoholic cirrhotics. Metab Brain Dis 2002;17:29–40.
Zafiris O, Kircheis G, Rood HA, Boers F, Haussinger D, Zilles K. Neural mechanism underlying impaired visual judgement in the dysmetabolic brain: an fMRI study. Neuroimage 2004;22:541–52.
Kircheis G, Wettstein M, Timmermann L, Schnitzler A, Haussinger D. Critical flicker frequency for quantification of low-grade hepatic encephalopathy. Hepatology 2002;35:357–66.
O’Carroll RE, Hayes PC, Ebmeier KP, Dougall N, Murray C, Best JJ, et al. Regional cerebral blood flow and cognitive function in patients with chronic liver disease. Lancet 1991;337:1250–3.
Shawcross D, Jalan R. Dispelling myths in the treatment of hepatic encephalopathy. Lancet 2005;365:431–33.
Riordan SM, Williams R. Treatment of hepatic encephalopathy. N Engl J Med 1997;337:473–9.
Song G, Dhodda VK, Blei AT, Dempsey RJ, Rao VL. GeneChip analysis shows altered mRNA expression of transcripts of neurotransmitter and signal transduction pathways in the cerebral cortex of portacaval shunted rats. J Neurosci Res 2002;68:730–7.
Brambilla D, Chapman D, Greene R. Adenosine mediation of presynaptic feedback inhibition of glutamate release. Neuron 2005;46:275–83.
Jodynis-Liebert J, Flieger J, Matuszewska A, Juszczyk J. Serum metabolite/caffeine ratios as a test for liver function. J Clin Pharmacol 2004;44:338–47.
Basheer R, Strecker RE, Thakkar MM, McCarley RW. Adenosine and sleep–wake regulation. Prog Neurobiol 2004;73:379–96.
Cordoba J, Cabrera J, Lataif L, Penev P, Zee P, Blei AT. High prevalence of sleep disturbance in cirrhosis. Hepatology 1998;27:339–45.
Schneider C, Fulda S, Schulz H. Daytime variation in performance and tiredness/sleepiness ratings in patients with insomnia, narcolepsy, sleep apnea and normal controls. J Sleep Res 2004;13:373–83.
Dunwiddie TV, Masino SA. The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci 2001;24:31–55.
Santschi LA, Zhang XL, Stanton PK. Activation of receptors negatively coupled to adenylate cyclase is required for induction of long-term synaptic depression at Schaffer collateral-CA1 synapses. J Neurobiol 2006;66:205–19.
Rodrigo R, Montoliu C, Chatauret N, Butterworth R, Behrends S, Del Olmo JA, et al. Alterations in soluble guanylate cyclase content and modulation by nitric oxide in liver disease. Neurochem Int 2004;45:947–53.
Holschbach MH, Olsson RA, Bier D, Wutz W, Sihver W, Schuller M, et al. Synthesis and evaluation of no-carrier-added 8-cyclopentyl-3-(3-[(18)F]fluoropropyl)-1-propylxanthine ([(18)F]CPFPX): a potent and selective A(1)-adenosine receptor antagonist for in vivo imaging. J Med Chem 2002;45:5150–56.
Conn HO. Quantifying the severity of hepatic encephalopathy. In: Conn HO, Bircher J, editors. Hepatic encephalopathy: syndromes and therapies. East Lansing, MI: Medi-Ed; 1993. p. 13–26.
Burger C, Buck A. Requirements and implementation of a flexible kinetic modeling tool. J Nucl Med 1997;38:1818–23.
Meyer PT, Elmenhorst D, Boy C, Winz O, Matusch A, Zilles K, et al. Effect of aging on cerebral A(1) adenosine receptors: A [(18)F]CPFPX PET study in humans. Neurobiol Aging 2006; DOI 10.1016/j.neurobiolaging.2006.08.005.
Svenningsson P, Hall H, Sedvall G, Fredholm BB. Distribution of adenosine receptors in the postmortem human brain: an extended autoradiographic study. Synapse 1997;27:322–35.
Logan J, Fowler JS, Volkow ND, Wang GJ, Ding YS, Alexoff DL. Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 1996;16:834–40.
Bauer A, Holschbach MH, Meyer PT, Boy C, Herzog H, Olsson RA, et al. In vivo imaging of adenosine A1 receptors in the human brain with [18F]CPFPX and positron emission tomography. Neuroimage 2003;19:1760–9.
Meyer PT, Elmenhorst D, Bier D, Holschbach MH, Matusch A, Coenen HH, et al. Quantification of cerebral A1 adenosine receptors in humans using [18F]CPFPX and PET: an equilibrium approach. Neuroimage 2005;24:1192–204.
Meyer PT, Bier D, Holschbach MH, Boy C, Olsson RA, Coenen HH, et al. Quantification of cerebral A1 adenosine receptors in humans using [18F]CPFPX and PET. J Cereb Blood Flow Metab 2004;24:323–33.
Meyer PT, Elmenhorst D, Matusch A, Winz O, Zilles K, Bauer A. A1 adenosine receptor PET using [18F]CPFPX: displacement studies in humans. Neuroimage 2006;32:1100–5.
Meyer PT, Elmenhorst D, Zilles K, Bauer A. Simplified quantification of cerebral A1 adenosine receptors using [18F]CPFPX and PET: analyses based on venous blood sampling. Synapse 2005;55:212–23.
Elmenhorst D, Meyer PT, Matusch A, Winz OH, Zilles K, Bauer A. Test–retest stability of cerebral A(1) adenosine receptor quantification using [(18)F]CPFPX and PET. Eur J Nucl Med Mol Imaging 2007;34:1061–70.
Matusch A, Meyer PT, Bier D, Holschbach MH, Woitalla D, Elmenhorst D, et al. Metabolism of the A1 adenosine receptor PET ligand [18F]CPFPX by CYP1A2: implications for bolus/infusion PET studies. Nucl Med Biol 2006;33:891–8.
Kril JJ, Butterworth RF. Diencephalic and cerebellar pathology in alcoholic and nonalcoholic patients with end-stage liver disease. Hepatology 1997;26:837–41.
Meerlo P, Roman V, Farkas E, Keijser JN, Nyakas C, Luiten PG. Ageing-related decline in adenosine A1 receptor binding in the rat brain: an autoradiographic study. J Neurosci Res 2004;78:742–8.
Shah NJ, Neeb H, Zaitsev M, Steinhoff S, Kircheis G, Amunts K, et al. Quantitative T1 mapping of hepatic encephalopathy using magnetic resonance imaging. Hepatology 2003 Nov;38:1219–26.
Kril JJ, Halliday GM. Brain shrinkage in alcoholics: a decade on and what have we learned? Prog Neurobiol 1999;58:381–7.
Gao Z, Robeva AS, Linden J. Purification of A1 adenosine receptor-G-protein complexes: effects of receptor down-regulation and phosphorylation on coupling. Biochem J 1999;338:729–36.
Palomero-Gallagher N, Reiffenberger G, Kostopulos G, Kircheis G, Haussinger D, Zilles K. Neurotransmitter receptor alterations in hepatic encephalopathy. In: Haussinger D, Kirchels G, Schliess F, editors. Hepatic encephalopathy and nitrogen metabolism. Dordrecht: Springer; 2006. p. 255–72.
Keiding S, Sorensen M, Bender D, Munk OL, Ott P, Vilstrup H. Brain metabolism of 13N-ammonia during acute hepatic encephalopathy in cirrhosis measured by positron emission tomography. Hepatology 2006;43:42–50.
Vogels BA, Maas MA, Daalhuisen J, Quack G, Chamuleau RA. Memantine, a noncompetitive NMDA receptor antagonist improves hyperammonemia-induced encephalopathy and acute hepatic encephalopathy in rats. Hepatology 1997;25:820–7.
Erceg S, Monfort P, Hernandez-Viadel M, Rodrigo R, Montoliu C, Felipo V. Oral administration of sildenafil restores learning ability in rats with hyperammonemia and with portacaval shunts. Hepatology 2005;41:299–306.
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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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