Department of Radiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. James A R Nicoll, Division of Clinical Neurosciences, Clinical and Experimental Sciences, University of Southampton, Southampton SO16 6YD, UK. angiopathy. There is a great need to conceptually link the evident synergistic interplay associated with AM 1220 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. AM 1220 With the availability of approved amyloid- 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: amyloid-related imaging abnormalities, Alzheimers disease, cerebral amyloid angiopathy, anti-amyloid monoclonal antibodies, disease-modifying therapies Hampel review amyloid-related imaging abnormalitiesARIAassociated with the use of monoclonal antibodies that target A, including radiological features, detection/classification challenges, pathophysiology, underlying mechanism(s), and associated risk factors and predictors. Introduction Historical background and definition of ARIA Alzheimers disease is a primary neurodegenerative disease leading to a clinical dementia syndrome, which is projected to affect 152.8 million people by 2050 worldwide.1 Translational studies support a descriptive hypothetical model of Alzheimers disease pathophysiology, characterized by the accumulation of aggregated amyloid- (A) species into plaques. This precedes clinical manifestations by 20C30 years, neuroinflammation and the spreading of phosphorylated tau and neuronal loss.2,3 Currently, monoclonal antibodies that remove A from the brain are in several late-stage Ctsb randomized clinical trials (RCTs).4-6 The use of anti-A antibodies has been associated with treatment-emergent MRI signal abnormalities,7 coined amyloid-related imaging abnormalities (ARIAs) at the Alzheimers Association Research Roundtable in 2011.8 ARIA covers two classes of MRI signal AM 1220 abnormalities: ARIA-oedema/effusion (ARIA-E) refers to the extravasation of fluid resulting in interstitial vasogenic oedema or sulcal effusion in the leptomeningeal/subpial space.8,9 These manifest as hyperintense parenchymal or sulcal abnormalities such as changes to cortical folds on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequence images (representative MRI images of ARIA-E shown in Fig. 1).8-10 ARIA-haemosiderosis/microhaemorrhages (ARIA-H) refers to microhaemorrhages (mH) or macrohaemorrhages observed as hypointense haemosiderin deposition. These reflect iron accumulation following the breakdown of extravasated haemoglobin on gradient recalled echo (GRE)/T2* images or with enhanced visualization processing by susceptibility weighting imaging (SWI) sequences.8,11,14 Under the rigorous protocols and conditions of clinical trials, ARIA-E/H have generally been asymptomatic and have usually resolved within 3C4 months with dose adjustment, suspension or discontinuation.15-17 In the minority of cases when ARIA-E was symptomatic, most were of mild or moderate severity. Rare serious or severe neurological symptoms may require hospitalization and specific monitoring and management (e.g. AM 1220 intensive care unit admission, EEG, corticosteroids, antiepileptics).7,15-17 The recent accelerated approvals of anti-A antibodies by the US Food and Drug Administration (FDA)18,19 underscores the importance of safety monitoring and effectively managing ARIA in the real-world clinical setting. This state-of-the-art review provides an overview of the radiological features, detection and classification challenges, pathophysiology, and risk factors/predictors associated with ARIA. Open in a separate window Figure 1 Main characteristics.
Department of Radiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
