Amyloid-related imaging abnormalities-haemosiderin (ARIA-H) in patients with Alzheimer's disease treated with bapineuzumab: a historical, prospective secondary analysis

Abstract

BackgroundAmyloid-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.ObjectiveOur 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.MethodsTwo 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.ResultsSeveral 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.ConclusionsARIA-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 registrationNCT00112073 and NCT00606476.

Recent Developments in Understanding Brain Aging: Implications for Alzheimer’s Disease and Vascular Cognitive Impairment

“…Also, bapineuzumab, a humanized monoclonal antibody directed against amyloid β was associated with enhanced amyloid-related magnetic resonance imaging abnormalities due to hemosiderin deposition (ARIA-H) that appears to be related to impaired vascular integrity (6). In their study Arrighi et al (6) concluded that presence of the apolipoprotein (APOE) ε4 allele or preexisting hemosiderin deposition, as well as treatment with bapineuzumab and use of antithrombotic agents increased risk for ARIA-H, probably resulting from loss of integrity of cerebral vessels due to amyloid burden. In addition, a Phase II trial of a promising inhibitor of the beta-site amyloid precursor proteincleaving enzyme (BACE1, LY2886721) was suspended due to liver toxicity.…”

Chronic Verubecestat Treatment Suppresses Amyloid Accumulation in Advanced Aged Tg2576-AβPPswe Mice Without Inducing Microhemorrhage

“…At the time this study was initiated, several investigative passive anti-Aβ immunotherapies already were shown to be associated with increased ARIA-E and ARIA-H in AD patients [ 12 ]. In the case of N-terminally directed anti-Aβ antibody, bapineuzimab, it was unclear whether the ARIA findings in humans were solely adverse or a direct consequence of the pharmacological activity of the antibody to bind to and mobilize clearance of amyloid plaque [ 9, 14 ]. However, the dose-related increase in the incidence and severity of symptomatic ARIA events in AD patients receiving bapineuzimab was sufficiently severe to force dose capping at 0.5 mg/kg, a dose well below the originally targeted top dose of 5 mg/kg [ 8, 9 ].…”

“…ARIA events may be mechanistically related to the physical removal of amyloid deposits from within or around brain blood vessels by anti-amyloid antibodies or by shifts in the equilibrium from insoluble aggregates to soluble Aβ that could occur with BACE1 inhibition [ 23, 34 ]. Indeed, doses of bapineuzimab that induced ARIA are associated with plaque clearance [ 9, 14 ]. Therefore, to explore the relationship between ARIA-H profiles as a function of treatment on the status of amyloid pathology, we measured multiple biochemical and histological endpoints related to amyloid accumulation.…”

Central Review of Amyloid-Related Imaging Abnormalities in Two Phase III Clinical Trials of Bapineuzumab in Mild-To-Moderate Alzheimer’s Disease Patients

“…Clinical studies of bapineuzumab and several clinical trials of therapies directed at lowering the fibrillar cerebral Aβ burden in AD were associated with findings on magnetic resonance imaging (MRI) abnormalities [6][7][8]. These amyloid-related imaging abnormalities (ARIA) were of two types: a) ARIA-E, parenchymal and/or sulcal hyperintensities seen on fluidattenuation inversion recovery (FLAIR) MRI scans consistent with edema or sulcal effusion (extravasated proteinaceous fluid in leptomeninges and sulcal space), in some cases associated gyral swelling [8]; and b) ARIA-H, foci of signal void on T2*-weighted gradient-echo (GRE) brain MRI pulse sequences [9] due to magnetic susceptibility effects of hemosiderin.…”