TY - JOUR
T1 - Amyloid-related imaging abnormalities-haemosiderin (ARIA-H) in patients with Alzheimer's disease treated with bapineuzumab
T2 - A historical, prospective secondary analysis
AU - Arrighi, H. Michael
AU - Barakos, Jerome
AU - Barkhof, Frederik
AU - Tampieri, Donatella
AU - Jack, Clifford
AU - Melançon, Denis
AU - Morris, Kristen
AU - Ketter, Nzeera
AU - Liu, Enchi
AU - Brashear, H. Robert
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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.
AB - 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.
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U2 - 10.1136/jnnp-2014-309493
DO - 10.1136/jnnp-2014-309493
M3 - Article
C2 - 25669746
AN - SCOPUS:84956581698
SN - 0022-3050
VL - 87
SP - 106
EP - 112
JO - Journal of Neurology, Neurosurgery and Psychiatry
JF - Journal of Neurology, Neurosurgery and Psychiatry
IS - 1
ER -