Article Text

Research paper
Amyloid-related imaging abnormalities-haemosiderin (ARIA-H) in patients with Alzheimer's disease treated with bapineuzumab: a historical, prospective secondary analysis
  1. H Michael Arrighi1,
  2. Jerome Barakos2,3,
  3. Frederik Barkhof4,5,
  4. Donatella Tampieri6,
  5. Clifford Jack Jr7,
  6. Denis Melançon7,
  7. Kristen Morris8,9,
  8. Nzeera Ketter1,
  9. Enchi Liu1,
  10. H Robert Brashear1
  1. 1Janssen Research & Development, South San Francisco, California, USA
  2. 2California Pacific Medical Center, San Francisco, California, USA
  3. 3Synarc, Newark, California, USA
  4. 4Department of Radiology, Image Analysis Centre, VU University Medical Center, Amsterdam, The Netherlands
  5. 5Department of Diagnostic Radiology, VU University Medical Center, Amsterdam, The Netherlands
  6. 6NeuroRx Research, Montreal, Canada
  7. 7Mayo Clinic, Rochester, Minnesota, USA
  8. 8Janssen Alzheimer Immunotherapy R&D, South San Francisco, California, USA
  9. 9BioMarin, San Rafael, California, USA
  1. Correspondence to Dr H Michael Arrighi, Janssen Pharmaceuticals Research & Development, 40 King Street, Mill Valley, South San Francisco, CA 94941, USA; marrighi{at}its.jnj.com

Abstract

Background Amyloid-related imaging abnormalities due to haemosiderin deposition (ARIA-H) occur in patients with mild to moderate dementia due to Alzheimer's disease (AD) and have been reported with increased incidence in clinical trials of amyloid-lowering therapies under development for AD.

Objective Our objective was to explore the relationship between the incidences of ARIA-H during treatment with placebo and different doses of bapineuzumab, a humanised monoclonal antibody directed against amyloid β.

Methods Two neuroradiologists independently reviewed 2572 GRE/T2* MRI sequences from 262 participants in two phase two clinical trials of bapineuzumab and an open-label extension study. Readers were blinded to the participant's therapy, APOE ε4 genotype and medical history.

Results Several risk factors for small ARIA-H <10 mm (microhaemorrhages) were identified: APOE ε4, bapineuzumab treatment, pre-existing small ARIA-H and use of antithrombotics. The HR (95%CI) for incident ARIA-H <10 mm associated with the number of APOE ε4 alleles was 11.9 (3.3 to 42.5) for 2 versus no alleles and 3.5 (1.0 to 12.0) for 1 versus no allele. The HR for bapineuzumab therapy was 3.5 (1.0 to 12.0); for the presence of baseline ARIA-H <10 mm, it was 3.5 (1.6 to 7.8), and for the use of antithrombotic agents it was 2.2 (1.0 to 4.8). The incidence rate for ARIA-H <10 mm was elevated only in the initial 6 months of active treatment and declined after this interval to a rate similar to that observed in the group treated with placebo.

Conclusions ARIA-H represents a spectrum of MRI findings due to haemosiderin deposition that appears to be related to impaired vascular integrity. The increased risk for ARIA-H associated with APOE ε4 allele frequency, pre-existing ARIA-H, treatment with bapineuzumab and use of antithrombotic agents provides additional support for this hypothesis of loss of integrity of cerebral vessels due to amyloid burden.

Trial registration NCT00112073 and NCT00606476.

  • ALZHEIMER'S DISEASE
  • AMYLOID
  • NEUROEPIDEMIOLOGY
  • MRI

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Files in this Data Supplement: