In vivo nanotracer for the detection of brain thrombi in an AD mouse model.

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is the most common cause of dementia (1). It is a multifactorial degenerative disease pathologically characterized by intracellular neurofibrillary tangles and extracellular deposition of amyloid. An early haemostatic dysregulation is also present and contributes to an increment in clot formation, leading to hypoperfusion, blood brain barrier disruption and neuronal loss (2). The detection of this prothrombotic state is of the upmost importance in diagnostic approaches to identify AD patients who would benefit from anticoagulation.AimUsing the in vivo nanotracer Thrombo‐tag (3) for the detection of brain thrombi in an AD mouse model by fast pre‐targeted positron emission tomography (PET) imaging.MethodAD animals and their wild‐type (WT) littermates were intravenously injected with the antiplatelet antibody against CD41 conjugated with transcyclooctene (TCO‐antiCD41). Twenty‐four hours later, [68Ga]core‐doped iron oxide nanoparticles (NP) functionalized with tetrazine (TZ) were intravenously administered. TCO and TZ produce a rapid in vivo reaction by means of bioorthogonal chemistry, allowing to non‐invasively evaluate platelets’ levels by PET. Two hours after [68Ga]NP‐TZ injection, a static PET study of each mouse was acquired with a scanner for small animals (nanoScan® PET/CT, Mediso, USA). Finally, biodistribution assays of different organs after the PET study were performed. All PET images were analyze by regions of interest (ROI) and voxel‐wise analyses.ResultThrombo‐tag has proven to be an effective and efficient method for neuroimaging in vivo. This PET probe allows us to accurately identify the presence and accumulation of platelets within the brain of animal models of Alzheimer’s disease. Additionally, Thrombo‐tag enables us to determine the distribution of platelets’ accumulations within various regions of the brain in comparison to WT controls.ConclusionThrombo‐tag provides a neuroimaging biomarker that could allow us to diagnose the prothrombotic state towards the personalization of anticoagulation treatment in AD patients.Funding: Carlos is the recipient of a Predoctoral Fellowship from the Fundación Española de Trombosis y Hemostasia.Bibliography: 1. Alzheimers Dement, 17, 327‐406, (2021), doi.org/10.1002/alz.123282. Cortes‐Canteli & Iadecola, Journal of the American College of Cardiology, 75, 942‐951, (2020)3. Adrover, Pellico et al., Nanoscale, 12, 22978‐22987, (2020)