Original research

EJNMMI Research

, 2:57

Open Access This content is freely available online to anyone, anywhere at any time.

Blood–brain barrier P-glycoprotein function in healthy subjects and Alzheimer's disease patients: effect of polymorphisms in the ABCB1 gene

  • Daniëlle ME van AssemaAffiliated withDepartment of Neurology and Alzheimer Center, VU University Medical Center Email author 
  • , Mark LubberinkAffiliated withPET Centre, Uppsala University Hospital
  • , Patrizia RizzuAffiliated withDepartment of Clinical Genetics, VU University Medical Center
  • , John C van SwietenAffiliated withDepartment of Neurology, University Medical Center Rotterdam
  • , Robert C SchuitAffiliated withDepartment of Nuclear Medicine and PET Research, VU University Medical Center
  • , Jonas ErikssonAffiliated withPET Centre, Uppsala University Hospital
  • , Philip ScheltensAffiliated withDepartment of Neurology and Alzheimer Center, VU University Medical Center
  • , Matthias KoeppAffiliated withInstitute of Neurology, University College London
  • , Adriaan A LammertsmaAffiliated withDepartment of Nuclear Medicine and PET Research, VU University Medical Center
    • , Bart NM van BerckelAffiliated withDepartment of Nuclear Medicine and PET Research, VU University Medical Center

Abstract

Background

P-glycoprotein is a blood–brain barrier efflux transporter involved in the clearance of amyloid-beta from the brain and, as such, might be involved in the pathogenesis of Alzheimer's disease. P-glycoprotein is encoded by the highly polymorphic ABCB1 gene. Single-nucleotide polymorphisms in the ABCB1 gene have been associated with altered P-glycoprotein expression and function. P-glycoprotein function at the blood–brain barrier can be quantified in vivo using the P-glycoprotein substrate tracer (R)-[11C]verapamil and positron emission tomography (PET). The purpose of this study was to assess the effects of C1236T, G2677T/A and C3435T single-nucleotide polymorphisms in ABCB1 on blood–brain barrier P-glycoprotein function in healthy subjects and patients with Alzheimer's disease.

Methods

Thirty-two healthy subjects and seventeen patients with Alzheimer's disease underwent 60-min dynamic (R)-[11C]verapamil PET scans. The binding potential of (R)-[11C]verapamil was assessed using a previously validated constrained two-tissue plasma input compartment model and used as outcome measure. DNA was isolated from frozen blood samples and C1236T, G2677T/A and C3435T single-nucleotide polymorphisms were amplified by polymerase chain reaction.

Results

In healthy controls, binding potential did not differ between subjects without and with one or more T present in C1236T, G2677T and C3435T. In contrast, patients with Alzheimer's disease with one or more T in C1236T, G2677T and C3435T had significantly higher binding potential values than patients without a T. In addition, there was a relationship between binding potential and T dose in C1236T and G2677T.

Conclusions

In Alzheimer's disease patients, C1236T, G2677T/A and C3435T single-nucleotide polymorphisms may be related to changes in P-glycoprotein function at the blood–brain barrier. As such, genetic variations in ABCB1 might contribute to the progression of amyloid-beta deposition in the brain.

Keywords

Blood–brain barrier P-glycoprotein ABCB1 MDR1 Polymorphisms (R)-[11C]verapamil PET