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

Research output: Contribution to journalArticle

67 Citations (Scopus)

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
StatePublished - Jul 1 2014
Externally publishedYes

Fingerprint

P-Glycoprotein
Blood-Brain Barrier
Amyloid
Cerebrovascular Circulation
Alzheimer Disease
Regional Blood Flow
Verapamil
Brain
Gyrus Cinguli
Radioactivity
Hippocampus
Water

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)

Cite this

Activity of P-glycoprotein, a β-amyloid transporter at the blood-brain barrier, is compromised in patients with mild Alzheimer disease. / Deo, Anand K.; Borson, Soo; Link, Jeanne; Domino, Karen; Eary, Janet F.; Ke, Ban; Richards, Todd L.; Mankoff, David A.; Minoshima, Satoshi; O'Sullivan, Finbarr; Eyal, Sara; Hsiao, Peng; Maravilla, Ken; Unadkat, Jashvant D.

In: Journal of Nuclear Medicine, Vol. 55, No. 7, 01.07.2014, p. 1106-1111.

Research output: Contribution to journalArticle

Deo, AK, Borson, S, Link, J, Domino, K, Eary, JF, Ke, B, Richards, TL, Mankoff, DA, Minoshima, S, O'Sullivan, F, Eyal, S, Hsiao, P, Maravilla, K & Unadkat, JD 2014, 'Activity of P-glycoprotein, a β-amyloid transporter at the blood-brain barrier, is compromised in patients with mild Alzheimer disease', Journal of Nuclear Medicine, vol. 55, no. 7, pp. 1106-1111. https://doi.org/10.2967/jnumed.113.130161
Deo, Anand K. ; Borson, Soo ; Link, Jeanne ; Domino, Karen ; Eary, Janet F. ; Ke, Ban ; Richards, Todd L. ; Mankoff, David A. ; Minoshima, Satoshi ; O'Sullivan, Finbarr ; Eyal, Sara ; Hsiao, Peng ; Maravilla, Ken ; Unadkat, Jashvant D. / Activity of P-glycoprotein, a β-amyloid transporter at the blood-brain barrier, is compromised in patients with mild Alzheimer disease. In: Journal of Nuclear Medicine. 2014 ; Vol. 55, No. 7. pp. 1106-1111.
@article{36323b122e7b4475bdd8ac8177616dd5,
title = "Activity of P-glycoprotein, a β-amyloid transporter at the blood-brain barrier, is compromised in patients with mild Alzheimer disease",
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.",
keywords = "Alzheimer's disease, Blood-brain barrier, P-glycoprotein activity, PET imaging, Relative extraction ratio",
author = "Deo, {Anand K.} and Soo Borson and Jeanne Link and Karen Domino and Eary, {Janet F.} and Ban Ke and Richards, {Todd L.} and Mankoff, {David A.} and Satoshi Minoshima and Finbarr O'Sullivan and Sara Eyal and Peng Hsiao and Ken Maravilla and Unadkat, {Jashvant D.}",
year = "2014",
month = "7",
day = "1",
doi = "10.2967/jnumed.113.130161",
language = "English (US)",
volume = "55",
pages = "1106--1111",
journal = "Journal of Nuclear Medicine",
issn = "0161-5505",
publisher = "Society of Nuclear Medicine Inc.",
number = "7",

}

TY - JOUR

T1 - Activity of P-glycoprotein, a β-amyloid transporter at the blood-brain barrier, is compromised in patients with mild Alzheimer disease

AU - Deo, Anand K.

AU - Borson, Soo

AU - Link, Jeanne

AU - Domino, Karen

AU - Eary, Janet F.

AU - Ke, Ban

AU - Richards, Todd L.

AU - Mankoff, David A.

AU - Minoshima, Satoshi

AU - O'Sullivan, Finbarr

AU - Eyal, Sara

AU - Hsiao, Peng

AU - Maravilla, Ken

AU - Unadkat, Jashvant D.

PY - 2014/7/1

Y1 - 2014/7/1

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - Blood-brain barrier

KW - P-glycoprotein activity

KW - PET imaging

KW - Relative extraction ratio

UR - http://www.scopus.com/inward/record.url?scp=84904100818&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84904100818&partnerID=8YFLogxK

U2 - 10.2967/jnumed.113.130161

DO - 10.2967/jnumed.113.130161

M3 - Article

VL - 55

SP - 1106

EP - 1111

JO - Journal of Nuclear Medicine

JF - Journal of Nuclear Medicine

SN - 0161-5505

IS - 7

ER -