| 1. |
- van Assema, Danielle M. E., et al.
(författare)
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Blood-brain barrier P-glycoprotein function in Alzheimer's disease
- 2012
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 135, s. 181-189
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Tidskriftsartikel (refereegranskat)abstract
- A major pathological hallmark of Alzheimer's disease is accumulation of amyloid-beta in senile plaques in the brain. Evidence is accumulating that decreased clearance of amyloid-beta from the brain may lead to these elevated amyloid-beta levels. One of the clearance pathways of amyloid-beta 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-beta. P-glycoprotein function can be assessed in vivo using (R)-[C-11]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)-[C-11]verapamil and positron emission tomography. In 13 patients with Alzheimer's disease (age 65 +/- 7 years, Mini-Mental State Examination 23 +/- 3), global (R)-[C-11]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)-[C-11]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)-[C-11]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)-[C-11]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.
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| 2. |
- van Assema, Danielle M. E., et al.
(författare)
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No evidence for additional blood-brain barrier P-glycoprotein dysfunction in Alzheimer's disease patients with microbleeds
- 2012
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 32:8, s. 1468-1471
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Tidskriftsartikel (refereegranskat)abstract
- Decreased blood-brain barrier P-glycoprotein (Pgp) function has been shown in Alzheimer's disease (AD) patients using positron emission tomography (PET) with the radiotracer (R)-[C-11] verapamil. Decreased Pgp function has also been hypothesized to promote cerebral amyloid angiopathy (CAA) development. Here, we used PET and (R)-[C-11] verapamil to assess Pgp function in eighteen AD patients, of which six had microbleeds (MBs), presumably reflecting underlying CAA. No differences were found in binding potential and nonspecific volume of distribution of (R)-[C-11] verapamil between patient groups. These results provide no evidence for additional Pgp dysfunction in AD patients with MBs.
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| 3. |
- van Assema, Danielle M. E., et al.
(författare)
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P-Glycoprotein Function at the Blood-Brain Barrier : Effects of Age and Gender
- 2012
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Ingår i: Molecular Imaging and Biology. - : Springer Science and Business Media LLC. - 1536-1632 .- 1860-2002. ; 14:6, s. 771-776
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Tidskriftsartikel (refereegranskat)abstract
- PurposeP-glycoprotein (Pgp) is an efflux transporter involved in transport of several compounds across the blood–brain barrier (BBB). Loss of Pgp function with increasing age may be involved in the development of age-related disorders, but this may differ between males and females. Pgp function can be quantified in vivo using (R)-[11C]verapamil and positron emission tomography. The purpose of this study was to assess global and regional effects of both age and gender on BBB Pgp function.ProceduresThirty-five healthy men and women in three different age groups were included. Sixty minutes dynamic (R)-[11C]verapamil scans with metabolite-corrected arterial plasma input curves were acquired. Grey matter time–activity curves were fitted to a validated constrained two-tissue compartment plasma input model, providing the volume of distribution (V T) of (R)-[11C]verapamil as outcome measure.ResultsIncreased V T of (R)-[11C]verapamil with aging was found in several large brain regions in men. Young and elderly women showed comparable V T values. Young women had higher V T compared with young men.ConclusionsDecreased BBB Pgp is found with aging; however, effects of age on BBB Pgp function differ between men and women.
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