Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics

Abstract

Excess accumulation and aggregation of toxic soluble and insoluble amyloid-β species in the brain are a major hallmark of Alzheimer's disease. Randomized clinical trials show reduced brain amyloid-β deposits using monoclonal antibodies that target amyloid-β and have identified MRI signal abnormalities called amyloid-related imaging abnormalities (ARIA) as possible spontaneous or treatment-related adverse events. This review provides a comprehensive state-of-the-art conceptual review of radiological features, clinical detection and classification challenges, pathophysiology, underlying biological mechanism(s) and risk factors/predictors associated with ARIA. We summarize the existing literature and current lines of evidence with ARIA-oedema/effusion (ARIA-E) and ARIA-haemosiderosis/microhaemorrhages (ARIA-H) seen across anti-amyloid clinical trials and therapeutic development. Both forms of ARIA may occur, often early, during anti-amyloid-β monoclonal antibody treatment. Across randomized controlled trials, most ARIA cases were asymptomatic. Symptomatic ARIA-E cases often occurred at higher doses and resolved within 3-4 months or upon treatment cessation. Apolipoprotein E haplotype and treatment dosage are major risk factors for ARIA-E and ARIA-H. Presence of any microhaemorrhage on baseline MRI increases the risk of ARIA. ARIA shares many clinical, biological and pathophysiological features with Alzheimer's disease and cerebral amyloid angiopathy. There is a great need to conceptually link the evident synergistic interplay associated with such underlying conditions to allow clinicians and researchers to further understand, deliberate and investigate on the combined effects of these multiple pathophysiological processes. Moreover, this review article aims to better assist clinicians in detection (either observed via symptoms or visually on MRI), management based on appropriate use recommendations, and general preparedness and awareness when ARIA are observed as well as researchers in the fundamental understanding of the various antibodies in development and their associated risks of ARIA. To facilitate ARIA detection in clinical trials and clinical practice, we recommend the implementation of standardized MRI protocols and rigorous reporting standards. With the availability of approved amyloid-β therapies in the clinic, standardized and rigorous clinical and radiological monitoring and management protocols are required to effectively detect, monitor, and manage ARIA in real-world clinical settings.

Keywords: Alzheimer’s disease; amyloid-related imaging abnormalities; anti-amyloid monoclonal antibodies; cerebral amyloid angiopathy; disease-modifying therapies.

Figure 1

Main characteristics of ARIA. Figure reproduced with permission from Barakos et al. and Cogswell et al. ARIA are MRI signal abnormalities that present as oedema/effusion (ARIA-E) or microhaemorrhage/superficial siderosis (ARIA-H). ARIA-E refers to the leakage of proteinaceous fluid while ARIA-H refers to leakage of small amounts of iron-containing blood products. Three main risk factors across both ARIA classes include exposure to anti-Aβ antibody treatment, presence of pretreatment microhaemorrhages, and APOE-ε4 carrier status. Biomarkers (i.e. CSF, PET) as potential predictors of future ARIA require further investigation. Aβ = amyloid-β; FLAIR = fluid-attenuated inversion recovery; GRE = gradient recalled echo.

Figure 2

Proposed pathophysiological mechanisms for ARIA. ARIA may occur due to the pathological deposition of amyloid in cerebral blood vessel walls (also known as cerebral amyloid angiopathy, CAA) or upon introduction of monoclonal antibodies that remove Aβ plaque.^,, The loss of vascular integrity and impaired clearance often leads to an immune response (inflammation) in the vessel wall. Such effects transiently weaken the vessels leading to leakage of proteinaceous fluid and blood, resulting in ARIA-E or ARIA-H, respectively. Some evidence suggests that with repeated immunization, the risk of extravasation tends to decrease, subsequently decreasing the risk of ARIA.^,, sAβ = soluble amyloid-β.

Figure 3

MRI protocols for detection of ARIA in an anti-amyloid therapy clinical trial. Owing to the limited availability of higher field units in certain centres, the use of 1.5 T scanners is suggested as a minimum standard despite the greater sensitivity often found with high-field strength scanners. The implementation of more sensitive MRI measures e.g. susceptibility weighting imaging (SWI) to detect ARIA-H should be balanced against the clinical importance of such findings. While a brain MRI obtained within the past year may be acceptable if there have been no clinical changes since the scan was performed, it is preferable to obtain a brain MRI when initiating treatment or within 3–4 months of beginning treatment. GRE = gradient recalled echo; TE = echo time.