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Published on: January 28, 2014
Biomarkers
Nicolás Lamanna-Rama1,2, Marta Casquero-Veiga2,3, Carlos Ceron2
1Consejo Superior de Investigaciones Científicas - Centro Internacional de Neurociencia Cajal (CSIC - CINC), Alcalá de Henares, Madrid, Spain.
Insights
Alzheimer's disease (AD) involves fibrin accumulation in brain vessels, contributing to neurodegeneration. The BioClotAD project develops fibrin-binding probes for early detection and potential treatment with anticoagulants.
Area of Science:
- Neuroscience
- Biomarker Development
- Medical Imaging
Background:
- Alzheimer's disease (AD) is the most common dementia, characterized by complex neuropathology.
- A prothrombotic state, leading to fibrin accumulation in cerebral vessels, is implicated in AD pathogenesis.
- Fibrin deposition exacerbates hypoperfusion, neurodegeneration, and blood-brain barrier disruption in a subset of AD patients.
Purpose of the Study:
- To develop novel imaging biomarkers for non-invasively detecting the pro-coagulant state in AD.
- To utilize fibrin-binding probes (FBPs) for identifying cerebral fibrin accumulation.
- To establish early detection methods for identifying AD patients who may benefit from anticoagulant therapies.
Main Methods:
- The BioClotAD project employs in vitro, ex vivo, and in vivo assays across multiple European sites.
- Fibrin-binding probes (FBPs) are tested for in vivo detection of cerebral occlusions via nuclear imaging.
- FBPs coupled with a transferrin receptor antibody (FBP-TfR) are developed to enhance blood-brain barrier penetration for optical and nuclear imaging, with validation in human AD brain samples.
Main Results:
- Feasible neuroimaging strategies were developed to detect and localize fibrin accumulation in vivo in AD models.
- The study identified specific regional distributions of cerebral fibrin deposition.
- These findings lay the groundwork for future clinical trials investigating neuroimaging of fibrin in AD.
Conclusions:
- The developed neuroimaging biomarkers enable early detection of the pro-thrombotic state in AD.
- This early detection opens opportunities for personalized anticoagulant therapies to potentially delay disease progression.
- The BioClotAD project paves the way for advancing diagnostic and therapeutic approaches in Alzheimer's disease.
Background:
Alzheimer's disease (AD) is the most common form of dementia[1]. Despite the advances in the understanding of its main neuropathological hallmarks, a significant gap remains in comprehending this multifactorial neurodegenerative disorder. Contributing factors to AD include chronic vascular dysregulation and a prothrombotic milieu, promoting fibrin accumulation in brain vessels[2]. Fibrin, the main protein component of blood clots, is significantly increased in 60% of AD-patients' brains[3]. Furthermore, its strong interaction with amyloid-β promotes the production of degradation-resistant clots[2]. This prothrombotic milieu intensifies hypoperfusion, neurodegeneration and blood-brain barrier (BBB) disruption[4], but not in all patients. Early detection could help identify patients which might benefit from anticoagulant therapies[5]. The BioClotAD Project aims to develop an imaging biomarker based on a fibrin binding probe (FBP)[6] to non-invasively identify AD's pro-coagulant state.
Method:
BioClotAD involves four partners in three European countries with complementary expertise, using extensive in vitro, ex vivoand in vivo assays, including AD animal models and human AD brain samples. Our project is based on three blocks: 1) Testing the FBP to in vivo detect the cerebral occlusions by nuclear imaging. 2) Detecting fibrin deposits inside the brain parenchyma with FBP coupled to a transferrin receptor antibody (FBP-TfR) to facilitate BBB crossing[7]. FBP-TfR will be labelled for optical and nuclear imaging. 3) Validating the most promising FBP probes in frozen brain samples of AD patients by autoradiography or fluorescence microscopy.
Result:
BioClotAD provides feasible neuroimaging strategies to in vivo detect the fibrin cerebral accumulation of AD models and identify the specific regional distribution in the brain. Our project will set the basis for future clinical trials on neuroimaging of the cerebral fibrin accumulation in AD.
Conclusion:
BioClotAD neuroimaging biomarkers will allow the early detection of the pro-thrombotic state in AD, opening a window of opportunity to delay the disease progression by personalized anticoagulant therapies. References 1. Alzheimer's Association. 2021. https://www.alz.org/media/documents/alzheimers-facts-and-figures.pdf. 2. Cortes-Canteli et al. 2020. https://doi.org/10.1016/j.jacc.2019.10.062 3. Cortes-Canteli, et al. 2015. https://doi.org/10.1016/j.neurobiolaging.2014.10.030 4. Cortes-Canteli, et al. 2012. https://doi.org/10.3233/JAD-2012-120820 5. Cortes-Canteli, et al. 2019. https://doi.org/10.1016/j.jacc.2019.07.081 6. Oliveira, Caravan. 2017. https://doi.org/10.1039/c7dt02634j 7. Sehlin, et al. 2019. https://doi.org/10.1007/s00259-019-04426-0.
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