In silico exploration of amyloid‐related imaging abnormalities in the gantenerumab open‐label extension trials using a semi‐mechanistic model

Aldea, Roxana; Grimm, Hans Peter; Gieschke, Ronald; Hofmann, Carsten; Lott, Dominik; Bullain, Szófia S.; Delmar, Paul; Klein, Gregory; Lyons, Marco; Piazza, Fabrizio; Carare, Roxana O.; Mazer, Norman A.

doi:10.1002/trc2.12306

Cited by 8 publications

(9 citation statements)

References 41 publications

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“…This is in keeping with the hypothesis that immunotherapy-induced ARIA-E are iatrogenic manifestations of the spontaneously occurring ARIA-E of CAA-ri and point to CSF testing for anti-Aβ (auto)antibodies as a promising diagnostic, prognostic, and response to treatment biomarker of ARIA-E. 2,10,12,47,48 Further research to validate the utility of the biomarker is needed to reduce current heterogeneity in the interpretation of trials' results and improve the detection, therapeutic management, and monitoring of ARIA-E side events. 8,49,50 In this context, our results are of paramount importance for expediting the design of future confirmatory studies, e.g., (1) the need of testing patients within the first month from ARIA-E diagnosis, as the rate of microglial activation may change very quickly; (2) the importance of carefully considering preexisting CAA in addition to the Aβ plaque burden; (3) the potential of CSF testing for anti-Aβ (auto)antibodies; and (4) the urgent need of randomized clinical trials to confirm the effectiveness of corticosteroids in the prevention of ARIA-E. 1 Filling these knowledge gaps is of paramount importance if we consider that current guidelines suggest an empirical cutoff value of 5 microhemorrhages for patient enrollment in clinical trials and that no data exist on primary prevention with mAbs in patients with CAA. If the ARIA Paradox is true, it is possible that patients with CAA, but no AD copathology, have a reduced risk of ARIA-E.…”

Section: Discussionmentioning

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: 99%

“…Further research to validate the utility of the biomarker is needed to reduce current heterogeneity in the interpretation of trials' results and improve the detection, therapeutic management, and monitoring of ARIA-E side events. 8, 49, 50…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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“…The aforementioned ARIA mechanisms were recently translated into the first semi‐mechanistic, in the silico model of ARIA‐E, the vascular wall disturbance (VWD) model 22 . The VWD model hypothesized that high local rates of Aβ removal (parenchymal or vascular) can trigger the ARIA‐E onset, as long as they are not counterbalanced by the rate of an intrinsic vascular repair process.…”

Section: Aging Aria and Caa‐related Inflammationmentioning

confidence: 99%

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

Kelly,

Brown,

Michalik

et al. 2023

Alzheimer's & Dementia

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This editorial summarizes advances from the Clearance of Interstitial Fluid and Cerebrospinal Fluid (CLIC) group, within the Vascular Professional Interest Area (PIA) of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART). The overarching objectives of the CLIC group are to: (1) understand the age‐related physiology changes that underlie impaired clearance of interstitial fluid (ISF) and cerebrospinal fluid (CSF) (CLIC); (2) understand the cellular and molecular mechanisms underlying intramural periarterial drainage (IPAD) in the brain; (3) establish novel diagnostic tests for Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA), retinal amyloid vasculopathy, amyloid‐related imaging abnormalities (ARIA) of spontaneous and iatrogenic CAA‐related inflammation (CAA‐ri), and vasomotion; and (4) establish novel therapies that facilitate IPAD to eliminate amyloid β (Aβ) from the aging brain and retina, to prevent or reduce AD and CAA pathology and ARIA side events associated with AD immunotherapy.

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“… 12 Similarly, a semimechanistic pharmacokinetics (PK)–pharmacodynamics (PD) model has been developed for gantenerumab‐mediated ARIA‐E adverse effects. 13 Both models do not generalize to other antibodies.…”

Section: Introductionmentioning

confidence: 99%

“…A time‐to‐event phenomenological exposure–response model for ARIA‐E has been developed specifically for aducanumab based on clinical data 12 . Similarly, a semimechanistic pharmacokinetics (PK)–pharmacodynamics (PD) model has been developed for gantenerumab‐mediated ARIA‐E adverse effects 13 . Both models do not generalize to other antibodies.…”

Section: Introductionmentioning

confidence: 99%

A combined physiologically‐based pharmacokinetic and quantitative systems pharmacology model for modeling amyloid aggregation in Alzheimer's disease

Geerts¹,

Walker²,

Rose³

et al. 2023

CPT Pharmacom & Syst Pharma

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Antibody-mediated removal of aggregated βamyloid (Aβ) is the current, most clinically advanced potential disease-modifying treatment approach for Alzheimer's disease. We describe a quantitative systems pharmacology (QSP) approach of the dynamics of Aβ monomers, oligomers, protofibrils, and plaque using a detailed microscopic model of Aβ 40 and Aβ 42 aggregation and clearance of aggregated Aβ by activated microglia cells, which is enhanced by the interaction of antibody-bound Aβ. The model allows for the prediction of Aβ positron emission tomography (PET) imaging load as measured by a standardized uptake value ratio. A physiology-based pharmacokinetic model is seamlessly integrated to describe target exposure of monoclonal antibodies and simulate dynamics of cerebrospinal fluid (CSF) and plasma biomarkers, including CSF Aβ 42 and plasma Aβ 42 /Aβ 40 ratio biomarkers. Apolipoprotein E genotype is implemented as a difference in microglia clearance. By incorporating antibody-bound, plaque-mediated macrophage activation in the perivascular compartment, the model also predicts the incidence of amyloid-related imaging abnormalities with edema (ARIA-E). The QSP platform is calibrated with pharmacological and clinical information on aducanumab, bapineuzumab, crenezumab, gantenerumab, lecanemab, and solanezumab, predicting adequately the change in PET imaging measured amyloid load and the changes in the plasma Aβ 42 /Aβ 40 ratio while slightly overestimating the change in CSF Aβ 42 . ARIA-E is well predicted for all antibodies except bapineuzumab. This QSP model could support the clinical trial design of different amyloid-modulating interventions, define optimal titration and maintenance schedules, and provide a first step to understand the variability of biomarker response in clinical practice.

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In silico exploration of amyloid‐related imaging abnormalities in the gantenerumab open‐label extension trials using a semi‐mechanistic model

Cited by 8 publications

References 41 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

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

A combined physiologically‐based pharmacokinetic and quantitative systems pharmacology model for modeling amyloid aggregation in Alzheimer's disease

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