Affiliations: [a] Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium
| [b]
Janssen Research and Development, Titusville, NJ, USA
| [c] Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA, USA
| [d] Expert Group Antwerp Molecular Imaging (EGAMI), University of Antwerp, Antwerp, Belgium
| [e] Prothena Biosciences Inc, South San Francisco, CA, USA
Correspondence:
[*]
Correspondence to: Frederique Bard, Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA, USA. Tel.: +11 8583203323; E-mail: fbard@its.jnj.com..
Note: [1] These authors contributed equally to this work.
Abstract: Background: 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. Objective: 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. Methods: 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). Results: 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. Conclusion: 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.
Keywords: Alzheimer’s disease, amyloid-related imaging abnormalities, blood-brain barrier, immunotherapy, magnetic resonance imaging, neuroimaging, transgenic mouse model
