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Advanced Neurology Insights on ARIA

Vascular risk factors such as hypertension, amyloid-targeting monoclonal antibodies, indicating that
hyperlipidemia, and diabetes do not seem to be risk a higher level of Aβ clearance leads to a higher incidence
factors for ARIA-E . Furthermore, baseline biomarkers of ARIA [26,32,39] . Third, with the continuous use of amyloid-
[33]
of amyloid positron emission tomography imaging, targeting monoclonal antibodies and the continuous
volumetric MRI measures, and most cerebrospinal fluid removal of Aβ, the structural integrity of vessel walls
biomarkers also have no associations with ARIA-E, and the efficiency of perivascular drainage may improve,
although lower baseline cerebrospinal fluid levels of thereby gradually reducing the incidence of ARIA [26,42] .
Aβ in APOE ε4 noncarriers has been associated with a Similar results have been reported in animal models. Zago
42
higher risk of ARIA-E . The correlation between baseline et al. found that the clearance of vascular Aβ was spatially
[38]
microhemorrhages and ARIA is also debatable; current and temporally associated with microhemorrhage when
studies have reported inconsistent results [26,32,36] . an AD mouse model was treated with amyloid-targeting
Despite the relatively high incidence rate of ARIA antibodies; this microhemorrhage was transient and
[41]
in subjects who used amyloid-targeting monoclonal improved with the restoration of vascular morphology .
antibodies compared with subjects who used placebo, there Capillary amyloid deposition and alterations of the
is no need to be pessimistic. Most ARIA is asymptomatic blood–brain barrier are also likely to be involved in
(see section 2.1), and a dose titration strategy is likely to ARIA. The solubilization of parenchymal Aβ leads to its
reduce the occurrence of ARIA to a certain extent . In accumulation in capillaries, while capillary Aβ deposits
[39]
addition, standardized management protocols can also can change the normal tight structures of astrocytic endfeet
enable clinicians to make early decisions . Moreover, the surrounding endothelial cells . Similar results have
[24]
[41]
cumulative risk of ARIA decreases with multiple infusions been reported in the brains of participants who received
of antibodies [25,26,32,36,40,41] . For example, in patients treated immunotherapy; researchers found that astrocytic endfeet
with bapineuzumab, the incidence rate of ARIA-H was may be damaged with the progression of capillary amyloid-
elevated in the initial 6 months of active treatment only, related angiopathy, thus causing uncontrolled fluid influx
and declined after this interval to a rate similar to that to the perineural space, leading to ARIA-E . In another
[44]
observed in the group treated with placebo . Similar study, Blockx et al. directly observed disruptions of the
[36]
results were obtained with aducanumab . blood–brain barrier using a series of repeated gadolinium-
[25]
enhanced T1-weighted scans and a T1 mapping model.
4. Mechanisms of ARIA Notably, the disruption events were also transient and
[45]
While the mechanisms underlying ARIA are not resolved quickly . Aquaporin-4 is a bidirectional water
completely understood, it is likely that the coexistence channel that facilitates the reabsorption of excess fluid
of multiple pathways leads to the occurrence of ARIA. during conditions of brain edema. In animal models,
Clinical trials have demonstrated a significant correlation capillary Aβ deposits also downregulate and redistribute
[41]
between ARIA-E and ARIA-H , indicating that they may aquaporin-4 channels ; however, inconsistent results
[37]
[44]
have a common pathophysiological mechanism. have been reported in the human cerebral cortex .
The current mainstream view is that ARIA results from Neuroinflammation may also play an important role
a large amount of Aβ being cleared in a short period of in ARIA. Some researchers believe that ARIA is a type of
time . More specifically, the solubilization of Aβ caused CAA-ri based on their similar clinical manifestations, risk
[42]
by amyloid-targeting monoclonal antibodies overwhelms factors (such as the APOE ε4 allele), and neuroimaging
the capacity for Aβ clearance through the perivascular features [46,47] . Pathological examinations of the brains
pathways, leading to amyloid deposition in the arterial wall of CAA-ri patients revealed that microglia, T cells, and
and accelerated the development of CAA. Furthermore, Aβ-containing multinucleated giant cells accumulate
specific therapies also target vascular Aβ and thus disrupt around the amyloid-laden vessels, suggesting the
vessel integrity, contributing to vascular leakage. As a occurrence of a spontaneous anti-Aβ autoimmune
[46]
result, patients show ARIA on neuroimaging when liquid response . In addition, anti-Aβ autoantibodies are
components, proteins, or cellular components leak into the specifically increased in the cerebrospinal fluid and directly
surrounding tissues. This viewpoint is also supported by correlate with Aβ mobilization during the acute phase of
the following line of evidence. First, ApoE ε4 carriers have CAA-ri . Immunosuppressive treatment helps to improve
[48]
more severe Aβ deposition than ApoE-ε4 non-carriers ; symptoms , which further supports the hypothesis
[47]
[43]
multiple studies have demonstrated a positive association that the pathogenesis of CAA-ri is likely mediated by a
between APOE ε4 allele dose and ARIA incidence [32,36] . selective autoimmune reaction against cerebrovascular
Second, the risk of ARIA increases with the dose of Aβ. Therefore, the administration of exogenous amyloid-

Volume 1 Issue 1 (2022) 5 https://doi.org/10.36922/an.v1i1.2