Monitoring Blood-Brain Barrier Integrity Following Amyloid-β Immunotherapy Using Gadolinium-Enhanced MRI in a PDAPP Mouse Model.

Ines Blockx,Johan Van Audekerke,Marleen Verhoye,Wagner Zago,Annemie Van Der Linden,Dimitri Roose,Frederique Bard,Steve Einstein,Caroline Guglielmetti,Pieter-Jan Guns

doi:10.3233/jad-160023

Abstract

Amyloid-related imaging abnormalities (ARIA) have been reported with some anti-amyloid-β (Aβ) immunotherapy trials. They are detected with magnetic resonance imaging (MRI) and thought to represent transient accumulation of fluid/edema (ARIA-E) or microhemorrhages (ARIA-H). Although the clinical significance and pathophysiology are unknown, it has been proposed that anti-Aβimmunotherapy may affect blood-brain barrier (BBB) integrity. To examine vascular integrity in aged (12-16 months) PDAPP and wild type mice (WT), we performed a series of longitudinal in vivo MRI studies. Mice were treated on a weekly basis using anti-Aβimmunotherapy (3D6) and follow up was done longitudinally from 1-12 weeks after treatment. BBB-integrity was assessed using both visual assessment of T1-weighted scans and repeated T1 mapping in combination with gadolinium (Gd-DOTA). A subset of 3D6 treated PDAPP mice displayed numerous BBB disruptions, whereas WT and saline-treated PDAPP mice showed intact BBB integrity under the conditions tested. In addition, the contrast induced decrease in T1 value was observed in the meningeal and midline area. BBB disruption events occurred early during treatment (between 1 and 5 weeks), were transient, and resolved quickly. Finally, BBB-leakages associated with microhemorrhages were confirmed by Perls'Prussian blue histopathological analysis. Our preclinical findings support the hypothesis that 3D6 leads to transient leakage from amyloid-positive vessels. The current study has provided valuable insights on the time course of vascular alterations during immunization treatment and supports further research in relation to the nature of ARIA and the utility of in vivo repeated T1 MRI as a translational tool.

Highlights

Alzheimer’s disease (AD) is the most common cause of dementia and represents an unprecedented public health problem
To assess the feasibility of our approach and prior to the administration of any treatment, we compared the impact of the Gd-DOTA injections on aged PDAPP and wild type (WT) mice
Since amyloid is known to accumulate in the cortical vessels first, these findings suggested that small blood-brain barrier (BBB) disruptions in old, untreated PDAPP mice, below the limit of visual detection, were greater than in WT animals, even before treatment is considered (Figure 3)

Summary

Introduction

Alzheimer’s disease (AD) is the most common cause of dementia and represents an unprecedented public health problem. Since the accumulation of Aβ is generally believed to play a causative role in AD, the development of disease-modifying drugs aiming at reducing the Aβ levels in the brain has been a priority for many pharmaceutical companies. Bapineuzumab (and 3D6) is believed to clear Aβ centrally through both microglial phagocytosis [5] and neutralization of soluble aggregates [9]. In several Aβ immunotherapy clinical trials, abnormalities have been detected by brain MR imaging [10, 11] - so called Amyloid-. Amyloid-related imaging abnormalities (ARIA) have been reported with some anti-A immunotherapy trials. They are detected with magnetic resonance imaging (MRI) and thought to represent transient accumulation of fluid/edema (ARIA-E) or microhemorrhages (ARIA-H). The clinical significance and pathophysiology are unknown, it has been proposed that anti-A immunotherapy may affect blood-brain barrier (BBB) integrity

Methods

Results

Conclusion