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Advanced Neurologyurology
Advanced Ne Insights on ARIA

alone reached US $248.71 billion in 2020 [6,7] , placing a large Clinicians and radiologists need to fully understand ARIA
burden on the country, society, and families. Consequently, before popularizing these amyloid-targeting monoclonal
effective anti-AD drugs are urgently needed to prevent the antibodies, such as aducanumab. Therefore, the main aims
progression of this disease. of this recommendation are to introduce the mechanisms,
AD is a complex and progressive disease characterized recognition, and management of ARIA in the hope that
by the extracellular deposition of anti-β-amyloid (Aβ), patients with AD will benefit in the near future.
in the form of neuritic plaques, and intraneuronal 2. Identification of ARIA
neurofibrillary tangles, which are composed of aggregated
hyperphosphorylated tau proteins . The journey of drug 2.1. Clinical features
[8]
development for AD has not been a smooth one. Only Most ARIA events have no clear accompanying
six drugs had been approved by the US Food and Drug symptoms and can only be detected by imaging. For
Administration (FDA) before 2021, and each one only example, the results of aducanumab Phase III studies
improves AD symptoms [9,10] . Based on the “amyloid indicated that approximately 74% of participants with
cascade hypothesis” and real-world studies, Aβ is regarded ARIA were asymptomatic [24,25] . Furthermore, among
as the earliest abnormal change in AD. This is followed by those with symptomatic ARIA, symptoms were mild
the aggregation of cortical tau tangles, ultimately resulting in 67.7%, moderate in 28.3%, and severe in just 4%.
in neurodegeneration and cognitive decline [8,11-14] . The most common symptoms reported were confusion
Furthermore, the latest research framework of the National or altered mental status (5%), dizziness (4%), visual
Institute on Aging–Alzheimer’s Association states that disturbances (2%), and nausea (2%). Notably, the ARIA
individuals with evidence of abnormal Aβ biomarkers are episodes generally resolved within 4 – 16 weeks, and the
on the Alzheimer’s continuum , indicating an increased majority of patients who experienced ARIA were able to
[15]
risk of cognitive decline compared with individuals with continue treatments; only 6.2% patients discontinued
normal levels of Aβ biomarkers . It is, therefore, not the trial. Similar results have been reported with other
[16]
surprising that most anti-AD drugs target amyloid . drugs, such as bapineuzumab; 78% of participants
[17]
The FDA recently conditionally approved aducanumab did not report ARIA-associated symptoms, and the
as an anti-amyloid drug for AD treatment, which comes adverse events reported in symptomatic patients mainly
approximately 17 years after the approval of memantine included headache, confusion, and neuropsychiatric and
in 2003. Aducanumab is a typical representative passive gastrointestinal symptoms . In general, ARIA needs to
[26]
anti-Aβ immunotherapy and is currently the only drug be distinguished from pathologies such as stroke (ischemic
that directly targets the clearance of Aβ pathology in AD . or hemorrhagic), subarachnoid hemorrhage, reversible
[18]
The approval of aducanumab paves the way for the further posterior encephalopathy syndrome, and cerebral amyloid
development of amyloid-targeting monoclonal antibodies angiopathy-related inflammation (CAA-ri). There are
and offers hope to patients with AD. many similarities between ARIA and CAA-ri, and their
In addition to effectiveness, safety is an important differentiation mainly depends on each patient’s medical
evaluation index for the approval of new drugs. Amyloid- history. Typical idiopathic CAA-ri usually occurs naturally;
related imaging abnormalities (ARIA) are the most that is, it is not drug induced . In addition, in CAA-ri,
[21]
important adverse effect of amyloid-targeting therapies. the number of microhemorrhages in the edema area of the
This term refers specifically to abnormal imaging brain parenchyma is usually higher than in ARIA.
manifestations (rather than clinical manifestations). ARIA
was first reported in a clinical trial of bapineuzumab in 2.2. Recognition sequences
[19]
2009 ; subsequently, it has been found to be generally Although some ARIA can be identified using computed
related to other monoclonal antibodies, including tomography, magnetic resonance imaging (MRI) remains
aducanumab . An “ARIA paradox” has been proposed, the main identification method . MRI studies for ARIA
[20]
[23]
which assumes that Aβ mobilization may be casually should include T2-weighted/fluid-attenuated inversion
linked to both efficacy and ARIA risk . The spectrum of recovery (FLAIR), T2* gradient refocused echo (GRE),
[21]
ARIA includes vasogenic edema and/or sulcal effusion — and rapid diffusion-weighted imaging (DWI). Depending
this is termed ARIA-edema (ARIA-E), and its exudative on the type of MRI available, an optional fourth sequence
components are mainly protein liquid components — as could be either three-dimensional (3D) T1 or 3D T2
well as microhemorrhage and/or superficial siderosis sampling perfection with application-optimized contrasts
— this is termed ARIA-hemorrhage (ARIA-H), and its using different flip angle evolutions (SPACE) [23,24] . In clinical
exudative components are mainly hemosiderin [22,23] . trials of amyloid-targeting monoclonal antibodies, the

Volume 1 Issue 1 (2022) 2 https://doi.org/10.36922/an.v1i1.2