Activity of P-glycoprotein, a β-amyloid transporter at the blood-brain barrier, is compromised in patients with mild Alzheimer disease

Anand K. Deo, Soo Borson, Jeanne Link, Karen Domino, Janet F. Eary, Ban Ke, Todd L. Richards, David A. Mankoff, Satoshi Minoshima, Finbarr O'Sullivan, Sara Eyal, Peng Hsiao, Ken Maravilla, Jashvant D. Unadkat

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73 Scopus citations

Abstract

Studies in animals and postmortem human brain tissue support a role for P-glycoprotein in clearance of cerebral β-amyloid across the blood-brain barrier (BBB). We tested the hypothesis that BBB P-glycoprotein activity is diminished in Alzheimer disease (AD) by accounting for an AD-related reduction in regional cerebral blood flow (rCBF). Methods: We compared P-glycoprotein activity in mild-AD patients (n = 9) and cognitively normal, age-matched controls (n = 9) using PET with a labeled P-glycoprotein substrate, 11C-verapamil, and 15O-water to measure rCBF. BBB P-glycoprotein activity was expressed as the 11C-verapamil radioactivity extraction ratio (11C-verapamil brain distributional clearance, K1/rCBF). Results: Compared with controls, BBB P-glycoprotein activity was significantly lower in the parietotemporal, frontal, and posterior cingulate cortices and hippocampus of mild AD subjects. Conclusion: BBB P-glycoprotein activity in brain regions affected by AD is reduced and is independent of rCBF. This study improves on prior work by eliminating the confounding effect that reduced rCBF has on assessment of BBB P-glycoprotein activity and suggests that impaired P-glycoprotein activity may contribute to cerebral β-amyloid accumulation in AD. P-glycoprotein induction or activation to increase cerebral β-amyloid clearance could constitute a novel preventive or therapeutic strategy for AD.

Original languageEnglish (US)
Pages (from-to)1106-1111
Number of pages6
JournalJournal of Nuclear Medicine
Volume55
Issue number7
DOIs
Publication statusPublished - Jul 1 2014
Externally publishedYes

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Keywords

  • Alzheimer's disease
  • Blood-brain barrier
  • P-glycoprotein activity
  • PET imaging
  • Relative extraction ratio

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Medicine(all)

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