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

Ban Ke¹  David A. Mankoff¹  Jeanne M. Link¹  Todd L. Richards¹  Peng Hsiao¹  Satoshi Minoshima¹  Jashvant D. Unadkat¹  Karen Domino¹  Anand K. Deo¹  Janet F. Eary¹  Soo Borson¹  Finbarr O’Sullivan¹  Ken Maravilla¹  Sara Eyal¹ 

关键词: Alzheimer’s disease;    blood–brain barrier;    P-glycoprotein activity;    PET imaging;    relative extraction ratio;   

DOI  :  10.2967/jnumed.113.130161

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

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.

【 授权许可】

Unknown