title: Blood-brain barrier P-glycoprotein function in Alzheimer's disease.
abstract: A major pathological hallmark of Alzheimer's disease is accumulation of amyloid-β in senile plaques in the brain. Evidence is accumulating that decreased clearance of amyloid-β from the brain may lead to these elevated amyloid-β levels. One of the clearance pathways of amyloid-β is transport across the blood-brain barrier via efflux transporters. P-glycoprotein, an efflux pump highly expressed at the endothelial cells of the blood-brain barrier, has been shown to transport amyloid-β. P-glycoprotein function can be assessed in vivo using (R)-[(11)C]verapamil and positron emission tomography. The aim of this study was to assess blood-brain barrier P-glycoprotein function in patients with Alzheimer's disease compared with age-matched healthy controls using (R)-[(11)C]verapamil and positron emission tomography. In 13 patients with Alzheimer's disease (age 65 ± 7 years, Mini-Mental State Examination 23 ± 3), global (R)-[(11)C]verapamil binding potential values were increased significantly (P = 0.001) compared with 14 healthy controls (aged 62 ± 4 years, Mini-Mental State Examination 30 ± 1). Global (R)-[(11)C]verapamil binding potential values were 2.18 ± 0.25 for patients with Alzheimer's disease and 1.77 ± 0.41 for healthy controls. In patients with Alzheimer's disease, higher (R)-[(11)C]verapamil binding potential values were found for frontal, parietal, temporal and occipital cortices, and posterior and anterior cingulate. No significant differences between groups were found for medial temporal lobe and cerebellum. These data show altered kinetics of (R)-[(11)C]verapamil in Alzheimer's disease, similar to alterations seen in studies where P-glycoprotein is blocked by a pharmacological agent. As such, these data indicate that P-glycoprotein function is decreased in patients with Alzheimer's disease. This is the first direct evidence that the P-glycoprotein transporter at the blood-brain barrier is compromised in sporadic Alzheimer's disease and suggests that decreased P-glycoprotein function may be involved in the pathogenesis of Alzheimer's disease.
authors: Department of Nuclear Medicine and PET Research, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. d.vanassema@vumc.nl
authors: Daniëlle M E
authors: DM
authors: van Assema
authors: Mark
authors: M
authors: Lubberink
authors: Martin
authors: M
authors: Bauer
authors: Wiesje M
authors: WM
authors: van der Flier
authors: Robert C
authors: RC
authors: Schuit
authors: Albert D
authors: AD
authors: Windhorst
authors: Emile F I
authors: EF
authors: Comans
authors: Nikie J
authors: NJ
authors: Hoetjes
authors: Nelleke
authors: N
authors: Tolboom
authors: Oliver
authors: O
authors: Langer
authors: Markus
authors: M
authors: Müller
authors: Philip
authors: P
authors: Scheltens
authors: Adriaan A
authors: AA
authors: Lammertsma
authors: Bart N M
authors: BN
authors: van Berckel
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000368:Aged; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D011877:Radionuclide Imaging; D014700:Verapamil / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014700:Verapamil