Detection and Management of Amyloid-Related Imaging Abnormalities in Patients with Alzheimer’s Disease Treated with Anti-Amyloid Beta Therapy

Barakos, Jerome; Purcell, Derk D.; Suhy, Joyce; Chalkias, Spyros; Burkett, Paul A.; Grassi, C; Castrillo‐Viguera, Carmen; Rubino, Ivana; Vijverberg, Everard G.B.

doi:10.14283/jpad.2022.21

Cited by 54 publications

(103 citation statements)

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Section: Discussionmentioning

confidence: 88%

“…The exact mechanisms of ARIA-E remain to be fully elucidated. The review of lessons learned from the last decade of research confirmed the ARIA Paradox as the most accredited pathophysiological model to explain the biological complexity of ARIA-E. 1,4,10,12,23,43 According to this model, ARIA-E is a complex and multifactorial phenomenon resulting from the imbalance between the removal of Aβ deposited in plaques, which is attributed to the dose, time, and type of anti-Aβ (auto)antibodies, and the downstream effects that an excessive mobilization of Aβ can cause on intramural periarterial drainage pathways, 44 , which may account for increased transient CAA, cerebrovascular impairment, greater vascular permeability, and an easier extravasation of proteinaceous fluid and VE, particularly in ApoE ε4 carriers. 1,2,10,12,[45][46][47] In this proof of principle study, we extend the understanding of ARIA-E biology by providing the first in vivo evidence for an association between ARIA-E and microglial activation through multimodal and multiparametric MRI, CSF testing for anti-Aβ autoantibodies and AT(N) biomarkers, and 11 C-PK11195-PET longitudinal assessments in patients with CAA-ri, a spontaneous human model of the iatrogenic ARIA-E of AD immunotherapy.…”

Section: Discussionmentioning

confidence: 88%

“… 1 , 2 Evidence from a large cohort registry study of inpatients with CAA-ri showed that the natural history of spontaneous ARIA-E shares striking clinical, radiologic, and biological similarities with the iatrogenic ARIA-E reported in up to 50% of patients with AD exposed to several anti-Aβ monoclonal antibodies (mAbs) tested in clinical trials. 1 , 3 – 5 …”

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confidence: 99%

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

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 88%

mentioning

confidence: 99%

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

et al. 2022

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“…Both active and passive immunizations are being explored and are at different stages of clinical trials [ 3 ]. The recent approval of aducanumab is under debate in the scientific community and the improvement in cognition was statistically significant in only a subset of patients who received the highest dose of aducanumab, a fully human IgG1 anti-amyloid monoclonal antibody (mAb) that binds plaque amyloid [ 4 ], while a subset of patients developed Amyloid related Imaging abnormalities (ARIA) with mostly transient and asymptomatic vasogenic edema and/or microhemorrhages [ 5 , 6 , 7 ]. Although controversial, the aducanumab clinical trials demonstrated that higher antibody exposure was associated with better biomarker changes and clinical outcomes [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Acute Effects of Focused Ultrasound-Induced Blood-Brain Barrier Opening on Anti-Pyroglu3 Abeta Antibody Delivery and Immune Responses

et al. 2022

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Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and hyperphosphorylated tau in the brain. Currently, therapeutic agents targeting amyloid appear promising for AD, however, delivery to the CNS is limited due to the blood-brain-barrier (BBB). Focused ultrasound (FUS) is a method to induce a temporary opening of the BBB to enhance the delivery of therapeutic agents to the CNS. In this study, we evaluated the acute effects of FUS and whether the use of FUS-induced BBB opening enhances the delivery of 07/2a mAb, an anti-pyroglutamate-3 Aβ antibody, in aged 24 mo-old APP/PS1dE9 transgenic mice. FUS was performed either unilaterally or bilaterally with mAb infusion and the short-term effect was analyzed 4 h and 72 h post-treatment. Quantitative analysis by ELISA showed a 5–6-fold increase in 07/2a mAb levels in the brain at both time points and an increased brain-to-blood ratio of the antibody. Immunohistochemistry demonstrated an increase in IgG2a mAb detection particularly in the cortex, enhanced immunoreactivity of resident Iba1+ and phagocytic CD68+ microglial cells, and a transient increase in the infiltration of Ly6G+ immune cells. Cerebral microbleeds were not altered in the unilaterally or bilaterally sonicated hemispheres. Overall, this study shows the potential of FUS therapy for the enhanced delivery of CNS therapeutics.

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“…31 The presence of pretreatment hemosiderin products most consistent with CAA, lobar microhemorrhages and superficial siderosis, is a serious imaging risk factor predictive of ARIA with the use of anti-amyloid mAb therapies, particularly in APOE-e4 carriers. 39,40 Due to the increased risk of adverse events in homozygous APOE-e4 carriers, APOE-e4 testing could be considered before drug initiation and could be used to help determine the frequency of safety monitoring examinations in future, updated treatment guidelines.…”

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confidence: 99%

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

Cogswell¹,

Barakos

Barkhof

et al. 2022

AJNR Am J Neuroradiol

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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.

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Detection and Management of Amyloid-Related Imaging Abnormalities in Patients with Alzheimer’s Disease Treated with Anti-Amyloid Beta Therapy

Cited by 54 publications

References 0 publications

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

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

Acute Effects of Focused Ultrasound-Induced Blood-Brain Barrier Opening on Anti-Pyroglu3 Abeta Antibody Delivery and Immune Responses

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

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