Age dependency of cerebral P-gp function measured with (R)-[11C]verapamil and PET
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The aim of this study was to assess the influence of age on the functional activity of the multidrug efflux transporter P-glycoprotein (P-gp) at the human blood-brain barrier.
Seven young (mean age: 27 ± 4 years) and six elderly (mean age: 69 ± 9 years) healthy volunteers underwent dynamic (R)-[11C]verapamil (VPM) positron emission tomography (PET) scans and arterial blood sampling. Parametric distribution volume (DV) images were generated using Logan linearisation, and age groups were compared with statistical parametric mapping (SPM). Brain regions that SPM analysis had shown to be most affected by age were analysed by a region of interest (ROI)-based approach using a maximum probability brain atlas, before and after partial volume correction (PVC).
SPM analysis revealed significant clusters of DV increases in cerebellum, temporal and frontal lobe of elderly compared to younger subjects. In the ROI-based analysis, elderly subjects showed significant DV increases in amygdala (+30%), insula (+26%) and cerebellum (+25%) before PVC, and in insula (+33%) after PVC.
Increased VPM DV values in the brains of elderly subjects suggest a decrease in cerebral P-gp function with increasing age.
KeywordsP-glycoprotein Blood-brain barrier Age (R)-[11C]verapamil Positron emission tomography
The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement number 201380 and from the Austrian Science Fund (FWF) project ‘Transmembrane Transporters in Health and Disease’ (SFB F35). This study would not have been possible without the excellent support of Rainer Bartosch (Department of Nuclear Medicine), and Edith Lackner and Johann Stanek (Department of Clinical Pharmacology). The authors wish to thank Gert Luurtsema, Mark Lubberink and Adriaan Lammertsma from the VU University Medical Center (Amsterdam, The Netherlands) for help with setting up the (R)-[11C]verapamil PET procedure in their laboratory. Alexander Hammers from the MRC Clinical Sciences Centre (London, UK) and Marie-Claude Asselin and Rainer Hinz from the Wolfson Molecular Imaging Centre (Manchester, UK) are gratefully acknowledged for providing help in establishing the brain atlas analysis approach.
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