Objectives

The main objective within this workpakage is to determine the role of P-gp function in the pathophysiology of Alzheimer’s disease (AD) with the ultimate aim to develop novel probes for early diagnosis and novel therapeutic strategies specifically aimed to enhance clearance through the BBB. First, P-gp activity will be determined in patients with probable AD using (R)-[11C]-verapamil and Positron Emission Tomography. Then the regional distribution of P-gp activity will be related in patients with probable AD to amyloid depositions typical for AD as measured using [11C]PIB. The last objective of this work package it to investigate if there is an association between P-gp function and other parameters for AD, such as medial temporal lobe atrophy, glucose metabolism, apoE genotype, CSF Aß levels as well as P-gp genotype.

 

Workpackage description

Although the pathogenesis of AD is currently unknown, there is an increasing consensus that the production and accumulation of amyloid-beta (Aß) is central to the pathogenesis of AD and it has been postulated that the accumulation of Aß may result from an imbalance between Aß production and Aß clearance. The mechanisms of Aß clearance from the brain are not yet fully understood. Several proteins have been shown to be involved in Aß clearance, including recently P-glycoprotein (P-gp). P-gp is highly expressed on the luminal surface of brain capillary endothelial cells and functions as an efflux pump. Indeed, ablation of P-gp at the BBB enhances Aß deposition and there is evidence that P-gp-expression at the BBB is inversely correlated with the number of Aß-plaques in the medial temporal lobe of elderly non-demented humans. These data suggest that there may be a direct link between P-gp and Aß metabolism in-vivo, and that P-gp-activity at the BBB could affect risk for developing AD. As such, P-gp-activity may provide a novel diagnostic and therapeutic target.
Verapamil is a substrate for P-gp. When labelled with the positron emitter carbon-11, verapamil can be used to assess P-gp-function using positron emission tomography (PET). In addition, it has recently become possible to image amyloid deposits in-vivo using the novel high-potential amyloid-imaging tracer [11C]PIB. Recently we have performed a pilot study with (R)-[11C]verapamil in three patients with AD and four healthy age-matched controls, and this pilot study suggests global reduced P-glycoprotein function in AD. Building upon these pilot data, we will perform a larger study period to assess whether P-gp function is affected in AD patients compared to age matched normal controls. Using (R)-[11C]verapamil, 20 patients with probable AD will be compared to 20 age and sex matched healthy controls at the VU University Medical Centre (VUmc) in Amsterdam, and 10 patients with probably AD will be scanned at Vienna. Five subjects from each centre will be scanned twice to compare test-retest variability with that in healthy controls. In addition, the regional distribution of P-gp activity in patients with probable AD will be related to amyloid depositions as measured using [11C]PIB. Therefore, in addition to (R)-[11C]-verapamil PET scans, 10 subjects from VUmc will also undergo a [11C]-PIB scan.

Furthermore, the association between P-gp function and other parameters for AD will be evaluated at VUmc. All patients will undergo a standardized structural MRI, [18F]FDG PET, lumbar punction and neuropsychological assessment. As such, P-gp function can be correlated with other validated parameters for AD (medial temporal lobe atrophy, glucose metabolism, apoE genotype, CSF Aß levels. Finally, explorative analysis of the MDR1-genotype will also be performed to explore the relation between MDR1-genotype and P-gp function.