Amyloid-Related Imaging Abnormalities with Emerging Alzheimer Disease Therapeutics: Detection and Reporting Recommendations for Clinical Practice

Abstract

Monoclonal antibodies are emerging disease-modifying therapies for Alzheimer disease that require brain MR imaging for eligibility assessment as well as for monitoring for amyloid-related imaging abnormalities. Amyloid-related imaging abnormalities result from treatment-related loss of vascular integrity and may occur in 2 forms. Amyloid-related imaging abnormalities with edema or effusion are transient, treatment-induced edema or sulcal effusion, identified on T2-FLAIR. Amyloid-related imaging abnormalities with hemorrhage are treatment-induced microhemorrhages or superficial siderosis identified on T2* gradient recalledecho. As monoclonal antibodies become more widely available, treatment screening and monitoring brain MR imaging examinations may greatly increase neuroradiology practice volumes. Radiologists must become familiar with the imaging appearance of amyloidrelated imaging abnormalities, how to select an appropriate imaging protocol, and report findings in clinical practice. On the basis of clinical trial literature and expert experience from clinical trial imaging, we summarize imaging findings of amyloid-related imaging abnormalities, describe potential interpretation pitfalls, and provide recommendations for a standardized imaging protocol and an amyloid-related imaging abnormalities reporting template. Standardized imaging and reporting of these findings are important because an amyloid-related imaging abnormalities severity score, derived from the imaging findings, is used along with clinical status to determine patient management and eligibility for continued monoclonal antibody dosing.

Brain Shrinkage in Anti–β-Amyloid Alzheimer Trials

“…Bulk plaque amyloid-β removal seems like a plausible but an unlikely explanation. 6 It is also possible that other mechanisms such as off-target reductions in inflammatory responses 7 or alterations in CSF dynamics 8 could account for brain volume changes that are not due to neurodegeneration. Paradoxical changes in brain volume due to anti-inflammatory effects have been observed in multiple sclerosis therapeutics and are referred to as pseudoatrophy.…”

Amyloid‐Related Imaging Abnormalities in the DIAN‐TU‐001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease

“…Potential reasons suggested for this lack of success include treating too late in the disease course, inadequate dosing, and lack of target engagement 1 . Doses may not have been high enough (given the low level of blood–brain barrier penetrance – <1%) due to concern about dose‐related Aβ‐related imaging abnormalities (ARIA) – the most common side effect associated with this drug class 10, 11 …”

“…1 Doses may not have been high enough (given the low level of blood-brain barrier penetrance -<1%) due to concern about dose-related Aβrelated imaging abnormalities (ARIA)the most common side effect associated with this drug class. 10,11 Recent trials of anti-amyloid monoclonal antibodies in sAD populations report ARIA episodes at a wide range of incidence rates. 4,8,12,13 Two types of ARIA have been defined on magnetic resonance imaging (MRI): (1) the edema type or ARIA-E, seen as increased signal intensity on fluid attenuated inversion recovery (FLAIR) sequence in the parenchyma and/or sulcal space, which can be reversible on MRI, and (2) the hemosiderin type or ARIA-H, seen as signal loss on T2*-weighted MRI or susceptibility weighted imaging (SWI) sequence in the parenchyma for microhemorrhages (mH) and in the subarachnoid space for superficial siderosis, which corresponds to long-lasting hemoglobin residual lesions on MRI.…”

“… 1 Doses may not have been high enough (given the low level of blood–brain barrier penetrance – <1%) due to concern about dose‐related Aβ‐related imaging abnormalities (ARIA) – the most common side effect associated with this drug class. 10 , 11 …”

Study on the Effect of 40 Hz Non-Invasive Light Therapy System. A Protocol for a Randomized, Double-Blinded, Placebo-Controlled Clinical Trial.

“…Even though this is an important progression in nding treatment options, the approval has not been without controversy and the safety, costs, and clinical relevance to patients and caregivers are discussed [4,5]. Amyloid-modifying therapeutic agents have been found to carry the risk of causing Amyloid-related imaging abnormalities (ARIA) with edema or effusions [6,7] which have also been reported with Lecanemab [3,4]. Consequently, new and safe treatment options are still needed.…”