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.

Trial registration: NCT00112073 and NCT00606476.

Keywords: ALZHEIMER'S DISEASE; AMYLOID; MRI; NEUROEPIDEMIOLOGY.

Figure 1

Total count on initial scan with a change from baseline in the number of amyloid-related imaging abnormalities-haemosiderin (ARIA-H) <10 mm, plotted by the amount of change relative to the date of first treatment with active therapy. For placebo subjects who did not transition to active therapy, the first placebo infusion date was set at month −18. Each participant only appears once.

Figure 2

Crude rate ratios for incident amyloid-related imaging abnormalities-haemosiderin (ARIA-H) <10 mm. Hypertension is defined by the use of an antihypertensive therapy, systolic blood pressure greater than 140 mm Hg or diastolic blood pressure greater than 90 mm Hg.

Figure 3

HRs for incident amyloid-related imaging abnormalities-haemosiderin (ARIA-H) <10 m from the multivariate proportional hazards model, log scale.

Figure 4

Example of changes in amyloid-related imaging abnormalities-haemosiderin (ARIA-H) seen on T2*/GRE MRI in an APOE ε4 homozygote patient with Alzheimer's dementia. (A) MRI at baseline showed no ARIA-H <10 mm. (B) At week 13 after one infusion of active therapy, MRI reveals several mHs (ARIA-H <10 mm); modest cortical hyperintensity for ARIA-E (ARIA-edema) can be seen as ‘shine through’. (C) MRI at week 77 shows resolution of both ARIA-H <10 mm and ARIA-E.