title: Amyloid-related imaging abnormalities-haemosiderin (ARIA-H) in patients with Alzheimer's disease treated with bapineuzumab: a historical, prospective secondary analysis.
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.
  
  
  BACKGROUND
  NCT00112073 and NCT00606476.
authors: Janssen Research & Development, South San Francisco, California, USA.
authors: H Michael
authors: HM
authors: Arrighi
authors: California Pacific Medical Center, San Francisco, California, USA Synarc, Newark, California, USA.
authors: Jerome
authors: J
authors: Barakos
authors: Department of Radiology, Image Analysis Centre, VU University Medical Center, Amsterdam, The Netherlands Department of Diagnostic Radiology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Frederik
authors: F
authors: Barkhof
authors: NeuroRx Research, Montreal, Canada.
authors: Donatella
authors: D
authors: Tampieri
authors: Mayo Clinic, Rochester, Minnesota, USA.
authors: Clifford
authors: http://orcid.org/0000-0001-7916-622X
authors: C
authors: Jack
authors: Mayo Clinic, Rochester, Minnesota, USA.
authors: Denis
authors: D
authors: Melançon
authors: Janssen Alzheimer Immunotherapy R&D, South San Francisco, California, USA BioMarin, San Rafael, California, USA.
authors: Kristen
authors: K
authors: Morris
authors: Janssen Research & Development, South San Francisco, California, USA.
authors: Nzeera
authors: N
authors: Ketter
authors: Janssen Research & Development, South San Francisco, California, USA.
authors: Enchi
authors: E
authors: Liu
authors: Janssen Research & Development, South San Francisco, California, USA.
authors: H Robert
authors: HR
authors: Brashear
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D053327:Apolipoprotein E4 / Q000097:blood; D017322:Clinical Trials, Phase II as Topic; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006485:Hemosiderin / Q000032:analysis*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D059906:Neuroimaging; D018697:Nootropic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D058225:Plaque, Amyloid / Q000473:pathology*; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D020521:Stroke / Q000150:complications / Q000453:epidemiology; D066127:White Matter / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D061067:Antibodies, Monoclonal, Humanized; D053327:Apolipoprotein E4; D005343:Fibrinolytic Agents; D018697:Nootropic Agents; D006485:Hemosiderin; C545458:bapineuzumab
keywords: ALZHEIMER'S DISEASE; AMYLOID; MRI; NEUROEPIDEMIOLOGY