Amyloid-related imaging abnormalities: manifestations, metrics and mechanisms

Three monoclonal antibodies directed against specific forms of the amyloid-β (Aβ) peptide have been granted accelerated or traditional approval by the FDA as treatments for Alzheimer disease, representing the first step towards bringing disease-modifying treatments for this disease into clinical practice. Here, we review the detection, underlying pathophysiological mechanisms and clinical implications of amyloid-related imaging abnormalities (ARIA), the most impactful adverse effect of anti-Aβ immunotherapy. ARIA appears as regions of oedema or effusions (ARIA-E) in brain parenchyma or sulci or as haemorrhagic lesions (ARIA-H) in the form of cerebral microbleeds, convexity subarachnoid haemorrhage, cortical superficial siderosis or intracerebral haemorrhage. Analysis of the radiographic appearance of ARIA, its clinical risk factors and underlying neuropathology, and results from animal models point to a central role for cerebral amyloid angiopathy — a condition characterized by cerebrovascular Aβ deposits — as a key component, either as a direct target for antibody-mediated inflammation or as recipient of Aβ mobilized from plaques in the Alzheimer brain parenchyma. The great majority of ARIA occurrences are associated with mild or no clinical symptoms. However, ~5% of all ARIA events are severe enough to result in hospitalization, permanent disability or death and thus raise challenging clinical questions regarding patient selection and use of concomitant agents. Therefore, identifying novel approaches to predicting, modelling, preventing and treating ARIA remains a key step towards allowing safe use of anti-Aβ immunotherapy for the world’s rapidly ageing population.