Project: Cerebral amyloid angiopathy and vascular dementia

Acronym	SNOWBALL (Reference Number: 170)
Duration	01/04/2016 - 31/03/2019
Project Topic	There is increasing evidence that ischemic stroke aggravates dementia resulting in a “snowball” effect. In the case of cerebral amyloid angiopathy (CAA) patients do not only establish dementia but also microbleeds, lobar hermorrhages and ischemic stroke. We hypothesize that the intimate interactions between amyloid deposition, inflammatory response, blood-brain-barrier (BBB) disturbances and ischemia contribute to ongoing neurodegeneration. We will study the influence of ischemic stroke on amyloid pathology and vice versa by evaluating the key players of the neurovascular unit, e.g. BBB. Hereby in-vitro models and amyloid transgenic mouse models will be employed and analyzed by imaging techniques for neuronal networks, reorganization and BBB transporter functions following induction of ischemic stroke. Through a multidisciplinary cross-disease analysis combining pharmacologic biotechnologists, radiopharmacologists, BBB-, imaging-, biomarker- and Alzheimer experts and stroke expertise we will offer a novel perception of neurodegeneration. This will be undertaken by exploiting the excellent ongoing collaboration between partners of an FP7 project funded by the European Union. Research questions that will be addressed are 1) Are BBB changes a consequence of Aβ deposition in the cerebral vasculature? 2) Does perfusion, neuronal network changes or vascular Aβ deposition occur before the development of cerebral amyloid plaques? 3) Will existing amyloid deposition alter pathophysiological reaction to stroke? 4) Will ischemia influences amyloid deposition in the long-term? 5) Are there biomarkers identifying BBB disturbances or amyloid transportation proteins? 6) Could these biomarkers be used in the clinical situation? The project will focus on dynamic shifts in endothelial ABC transporter patterns using CAA models that are exposed to transient MCAO. Tight junction expression levels as well as mediators of Aβ endocytosis will be correlated to relevant signaling pathways like oxidative stress, hypoxia and inflammation. Advanced imaging techniques will be applied. Moreover, we propose to identify new biomarkers and molecular pathways through the use of the TgCRND8 and APP23 APP-transgenic mice line as an experimental model of cerebral β-amyloidosis and will verify these findings in a clinical multi-center study of CAA patients with stroke using MRI, PET and CSF analysis in the acute and chronic phase. Comments regarding modifications to the pre-proposal: · According to the reviewers suggestions we described the co-ordination towards results in more detail in the section “timeplan” and “deliverables” and used the increased volume of this “full proposal” to describe tasks and collaborative efforts in more detail. · We focus on the biomarker issue in more detail in the Workpackage 3 and 4 (reviewer 2) · According to the reviewer recommendation we added RNA seq. (WP5) for the evaluation of pathways and biomarker analysis and of course will a professional statistician be included in the consortium. A house-hold statistician from partner 1 (university of Heidelberg) and for the clinical study the “Coordinating Centre for Clinical Trials - Heidelberg” · To increase the impact of our study we will validate our experimental findings in CAA patients in a clinical two-center study WP6 (reviewer 1). · Because of a minor financial support for our Spanish partner we decided to do the clinical study with CAA patients only in two centers (Heidelberg and Homburg). This is also being easier for ethical issues and availability of PET imaging. Financial support for this pilot study will be given by the local universities and the manufacturer of Aß PET tracer.
Network	JPco-fuND
Call	Neurodegenerative diseases: risk and protective factors, longitudinal cohort approaches and advanced experimental models

Project partner

Number	Name	Role	Country
1	University of Heidelberg	Coordinator	Germany
2	Universite D´Artois	Partner	France
3	University Medical Center Utrecht	Partner	Netherlands
4	Saarland University	Partner	Germany
5	HOSPITAL UNIVERSITARI VALL D'HEBRON	Partner	Spain