Spectrum of amyloid-related imaging abnormalities associated with aducanumab treatment: a case series report

Amyloid-related imaging abnormalities (ARIA) observed on magnetic resonance imaging (MRI) are known adverse events associated with beta-amyloid plaque-lowering monoclonal antibodies. A spectrum of radiographic and clinical presentations of ARIA have been observed. ARIA-E refer to vasogenic edema in the brain parenchyma and/or leptomeningeal/subpial sulcal effusion; ARIA-H refer to hemosiderin deposits including cerebral microhemorrhage and localized superficial siderosis. With clinical availability of anti-amyloid therapies for treatment of early clinical stage Alzheimer's disease, there is an important need for better awareness of ARIA and education among a diversity of clinicians and practice settings.

To illustrate the wide spectrum of ARIA, we present the clinical history, course, and MRI findings as well as summarize learnings and implications of 10 ARIA-E cases from the aducanumab phase 3 clinical trials EMERGE and ENGAGE (ClinicalTrials.gov identifiers NCT02484547 and NCT02477800). Monitoring and management of ARIA, including criteria and timing of MRI, and drug dosing actions were defined per protocol and based upon radiographic severity and clinical symptoms associated with ARIA. ARIA were detected by MRI performed at pre-specified intervals or in response to symptoms or for safety follow-up reasons.

The majority of ARIA-E events were asymptomatic. Most ARIA-E events occurred within the first 8 aducanumab doses and generally resolved within 3-4 months whether dosing was continued (i.e. when ARIA-E was asymptomatic and of mild radiographic severity) or whether dosing was suspended or discontinued. Occasionally, ARIA-E were recurrent. ARIA-H (microhemorrhages and superficial siderosis) most commonly occurred concurrently with ARIA-E. However, ARIA-H without ARIA-E, termed isolated ARIA-H, occurred at a similar frequency in aducanumab- and placebo-treated groups. 10% of participants with ARIA in the 10 mg/kg group had accompanying symptoms. When present, symptoms of ARIA most frequently included headache, nausea, fatigue, dizziness, confusional state, and visual disturbance. Serious symptoms associated with ARIA were uncommon (occurring in 0.3% of the participants treated with the 10 mg/kg dose regimen).

These illustrative cases provide learnings into the nature and factors associated with ARIA that can increase knowledge for clinicians and trialists regarding the varied radiographic and clinical presentations and evolution of ARIA.

Clinical Trials NCT02484547, registered June 18, 2015, https://clinicaltrials.gov/study/NCT02484547 . Clinical Trials NCT02477800, registered June 18, 2015, https://clinicaltrials.gov/study/NCT02477800 .