Association of Microglial Activation With Spontaneous ARIA-E and CSF Levels of Anti-Aβ Autoantibodies

Abstract

Background and Objectives:Amyloid-related imaging abnormalities suggestive of vasogenic edema or sulcal effusion (ARIA-E) are the most common adverse events complicating Alzheimer’s disease (AD) immunotherapy with anti-amyloid-beta (Aβ) monoclonal antibodies (mAbs). ARIA-E can also occur spontaneously in cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare autoimmune encephalopathy associated with increased cerebrospinal fluid (CSF) levels of anti-Aβ autoantibodies. Although the pathophysiological mechanisms of ARIA-E remain to be fully elucidated, experimental evidence from ex-vivo studies suggest that gantenerumab and aducanumab enable microglial activation. However, the in vivo evidence for a direct association between neuroinflammation and ARIA-E in patients with high CSF anti-Aβ (auto)antibody levels has never been demonstrated.Methods:Spatial distribution and temporal variations of microglial activation associated with ARIA-E and CSF anti-Aβ autoantibody levels at (sub)acute presentation and after corticosteroid therapy, in a longitudinal case series of patients with CAA-ri, an increasingly recognized spontaneous model of the iatrogenic ARIA-E in AD immunotherapy. Multimodal and multiparametric magnetic resonance imaging (MRI) for CAA and ARIA-E quantification, as measured with validated MRI scoring systems; CSF testing for anti-Aβ autoantibodies and AD biomarkers; 11C-PK11195 positron emission tomography (PET) for activated microglia.Results:At (sub)acute presentation, we found focal peaks of microglial activation having a greater spatial co-localization with ARIA-E compared to chronic age-related white matter change (ARWMC) imaging abnormalities. The severity of ARIA-E and the magnitude of the associated microglial activation was greater in patients having AD and severe CAA concomitant disease, compared to patients having CAA only. CSF anti-Aβ autoantibodies at presentation were high in all patients and markedly decreased at post-treatment follow-up, in parallel with clinical resolution of acute symptoms, reduced ARIA-E severity, and reduced microglial activation.Discussion:Our findings extend the current notion of ARIA-E by providing the first in vivo11C-PK11195-PET evidence for an association between microglial activation and the magnitude and severity of ARIA-E in patients with increased CSF concentration of anti-Aβ autoantibodies and comorbid AD and CAA disease..Our results highlight CSF testing for anti-Aβ autoantibodies as a promising diagnostic, prognostic, and therapy response biomarker to help guide future treatment and management decisions in real clinical practice and clinical trials.

Clearance of interstitial fluid (ISF) and CSF (CLIC) group‐part of Vascular Professional Interest Area (PIA), updates in 2022‐2023. Cerebrovascular disease and the failure of elimination of Amyloid‐β from the brain and retina with age and Alzheimer's disease: Opportunities for therapy

“…[3][4][5] In this framework, therapy-induced ARIA are becoming increasingly recognized as the iatrogenic manifestation of CAA-ri. 8,9 ARIA is an umbrella term used to generally define the detection of two types of (sub)acute image abnormalities on magnetic resonance imaging (MRI): (i) ARIA-edema (ARIA-E), defined as cortical hyperintensities in the brain parenchyma or sulcal effusion in the leptomeninges/sulci, on T2 weighted fluid-attenuated inversion recovery (FLAIR) sequences; (ii) ARIA-hemorrhage (ARIA-H), defined as microhemorrhages or cortical superficial siderosis, on T2* or susceptibility weighted imaging (SWI). 10 Notably, the term ARIA is not intended to provide any information concerning the associated manifestations of clinical symptoms.…”

“…13 This finding is in accordance with the "ARIA paradox" ethiopathogenic model, which posits that Aβ mobilization achieved by mAbs targeting plaques may be causally linked to both efficacy and ARIA risk in a dose-dependent fashion. 14 Although the optimal balance between dose regimens to minimize risk of ARIA and maximize efficacy has yet to be determined, this is generating concerns over the potential of mAbs to aggravate CAA at the sites of greater plaque removal 8,15 (Figure 1). Moving beyond ARIA incidence, describing individual ARIA cases based on longitudinal biomarker variations will be instrumental in solidifying our understanding of ARIA mechanisms and risk factors.…”

“…With respect to CAA-ri, the integration of multimodal and multiparametric longitudinal testing for CSF and imaging biomarkers revealed a specific regional and temporal association between focal areas of microglia activation and ARIA-E only in patients with coexisting CAA and AD pathology, with subsequent in-time presentation of ARIA-H after the first ARIA-E index event. 8 In clinical trials, the precise pathophysiology of ARIA is not fully understood, but several mechanisms have been postulated. 4,16 Therapy-induced ARIA is associated with mAbs that rely on Fc receptor-mediated phagocytosis of Aβ aggregates by immune cells.…”

“…5,11,15,23 The data collected within the setting of anti-Aβ clinical trials should make it possible to evaluate the correlation between the location of ARIA events, the regional changes in Aβ burden and the regional presence of both hemorrhagic and non-hemorrhagic markers of CAA. 8,24,25 Such an integrated analysis will help clarify the relative risk of ARIA associated with the local vascular load of Aβ and its removal. Although less common, ARIA-E recurrent events, in particular their location will cast light on the intrinsic recovery ability of vessels affected by ARIA and ultimately increase confidence to restart therapy after the resolution of ARIA-E. 8 Post mortem neuropathological follow-up of individuals with and without ARIA will complement the image-based assessments by increasing confidence in diagnosis and providing insights about ARIA-induced neuropathological alterations of the blood vessels.…”

“…8,24,25 Such an integrated analysis will help clarify the relative risk of ARIA associated with the local vascular load of Aβ and its removal. Although less common, ARIA-E recurrent events, in particular their location will cast light on the intrinsic recovery ability of vessels affected by ARIA and ultimately increase confidence to restart therapy after the resolution of ARIA-E. 8 Post mortem neuropathological follow-up of individuals with and without ARIA will complement the image-based assessments by increasing confidence in diagnosis and providing insights about ARIA-induced neuropathological alterations of the blood vessels. 26 The lack of ARIA-E animal models and human samples from clinical trials for independent research is still representing one of the main road blocks to fill current knowledge gaps in our understanding of ARIA.…”