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Amyloid-Related Imaging Abnormalities and β-Amyloid–Targeting AntibodiesA Systematic Review

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To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  What is the association of amyloid-related imaging abnormalities (ARIAs) with treatment regimens consisting of anti–β-amyloid monoclonal antibodies in patients with Alzheimer disease?

Findings  In this systematic review of 34 studies and 15 508 patients, ARIAs were a frequent finding of randomized clinical trials, prompting centralized and structured magnetic resonance imaging reporting, and incidence of ARIAs was associated with apolipoprotein E ε4 genotype and antibody dosage. In most cases, ARIAs were asymptomatic and resolved with dose adjustment or withdrawal; in some cases, severe neurological symptoms occurred, requiring hospitalization and specific treatments (eg, corticosteroids).

Meaning  These findings suggest that there is still a need for information about whether specific components of ARIAs are associated with clinical management and treatment response.


Importance  After more than a decade of research and development of clinical trials testing anti–β-amyloid monoclonal antibodies (mAbs), extensive experience has been gained regarding the effects of these treatments in patients with Alzheimer disease (AD). On the verge of an expected large-scale introduction in the clinical setting after the recent US Food and Drug Administration approval of aducanumab, shared knowledge regarding amyloid-related imaging abnormalities (ARIAs) is of paramount importance.

Objective  To summarize available evidence on ARIAs from randomized clinical trials (RCTs) testing anti–β-amyloid mAbs in patients with AD and to provide a comprehensive update about risk factors, clinical correlates, and implications for withholding and reinitiating treatment.

Evidence Review  In this systematic review, a literature search of MEDLINE/PubMed, Embase, and Cochrane Library and a search of ClinicalTrials.gov were conducted through September 15, 2021. Publications describing RCTs, secondary analyses of RCT data, and case reports of ARIAs were included. Strengths of clinical data were graded according to the Oxford Centre for Evidence-Based Medicine.

Findings  Twenty-two RCTs, 11 secondary analyses of RCTs, and 1 case report, including in total 15 508 adult patients (8483 women [54.7%]; mean [SD] age, 69.6 [8.3] years) were selected for inclusion. Signal alterations that included parenchymal edema and sulcal effusion leading to transient hyperintensities on fluid-attenuated inversion recovery and T2-weighted sequences were termed ARIA-E, whereas those consisting of hemosiderin deposits, including parenchymal microhemorrhages and leptomeningeal superficial siderosis, were termed ARIA-H. Apolipoprotein E (ApoE) ε4 genotype was the main risk factor for both ARIA types; ARIA-E incidence was further associated with treatment dose, affecting the 55% of ApoE ε4 carriers in the high-dose aducanumab treatment group. Both ARIA types manifested early during study course, and symptomatic cases accounted for the 6.1% to 39.3% of ARIA-E cases at higher treatment doses across RCTs, whereas ARIA-H cases were generally asymptomatic. Most ARIA-E cases resolved with treatment withholding, although corticosteroid administration was required anecdotally. ARIA-E recurrence after dose reinitiation or adjustment varied from 13.8% to 25.6% across RCTs.

Conclusions and Relevance  Evidence suggests that ARIAs are frequent, mostly asymptomatic collateral events of amyloid-modifying therapies, highlighting the need for standardized clinical and neuroradiological management protocols in real-world clinical settings.

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Article Information

Accepted for Publication: October 22, 2021.

Published Online: January 31, 2022. doi:10.1001/jamaneurol.2021.5205

Corresponding Author: Massimo Filippi, MD, Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132 Milan, Italy (filippi.massimo@hsr.it).

Author Contributions: Drs Cecchetti and Spinelli had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Filippi, Cecchetti, Vezzulli, Falini, Agosta.

Acquisition, analysis, or interpretation of data: Cecchetti, Spinelli, Agosta.

Drafting of the manuscript: Filippi, Cecchetti, Spinelli, Vezzulli.

Critical revision of the manuscript for important intellectual content: Filippi, Cecchetti, Spinelli, Falini, Agosta.

Statistical analysis: Spinelli.

Administrative, technical, or material support: Spinelli.

Supervision: Filippi, Spinelli, Falini.

Other: Vezzulli.

Other (literature review, figure creation): Cecchetti.

Conflict of Interest Disclosures: Dr Filippi reported receiving personal fees from Alexion Pharmaceuticals, Almirall SA, Bayer AG, Biogen Inc, Celgene Corporation, Eli Lilly & Company, Genzyme, Merck Serono, Novartis International AG, La Roche AG, Sanofi SA, Takeda Pharmaceutical Company Limited, and Teva Pharmaceutical Industries Ltd; receiving institutional grants from Biogen Idec, Merck Serono, Novartis International AG, La Roche AG, and Teva Pharmaceutical Industries Ltd outside the submitted work; and serving as editor-in-chief of the Journal of Neurology, associate editor of Human Brain Mapping, associate editor of Radiology, and associate editor of Neurological Sciences. Dr Agosta reported receiving personal fees for consulting services and/or speaking activities from F. Hoffmann-La Roche AG, Biogen Inc, and Philips outside the submitted work; serving as the associate editor of NeuroImage: Clinical; and receiving research support from Italian Ministry of Health, AriSLA (Fondazione Italiana di Ricerca per la SLA), and the European Research Council. No other disclosures were reported.

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