Work Packages

CoSTREAM is a 5-year research programme that consists of three phases: aetiology, pathways, and translation. Together these form the basis for seven interrelated Work Packages. An essential feature will be joint work across Work Packages that will thereby ensure smooth transition across the three phases

Genetics
Work Package 1

CoSTREAM's first Work Package aims to identify shared genetic factors common to stroke and Alzheimer's disease to identify mechanisms and pathways common to both diseases and to link these with metabolic, imaging, and clinical findings. It will determine the genetic overlap between stroke and Alzehimer's disease as well as their subtypes and provide an estimate of the genetic correlation between the two. Furthermore, this Work Package will pinpoint specific genes or genomic regions that mediate risk to stroke or stroke subtypes, relevant MRI markers and Alzheimer's disease.

Metabolomics
Work Package 2

This Work Package aims to explore a wide range of metabolites to discover novel pathways underlying the co-occurrence of stroke and Alzheimer's disease with the ultimate goals to identify persons with a potentially modifiable metabolic aetiology. Work Package 2 will apply untargeted metabolomics to genes that relate to both stroke and AD to fully cover the physicochemical and biochemical metabolite space. In a complementary approach, we will use targeted, biology-driven metabolomics addressing metabolites of selected genes and their role in the pathway. Metabolites identified through these two approaches can then be correlated to established and new imaging data from Work Package 3 and be used in a Mendelian Randomization setting to test their causal association with stroke and Alzheimer's disease in Work Package 6.

Brain Imaging
Work Package 3

The third Work Package will use novel imaging markers to study pathophysiological mechanisms common to both stroke and Alzheimer's disease, including novel PET ligands and ultra-high field MR imaging. The specific aims are to image the earliest molecular brain changes in stroke and Alzheimer's disease, study brain connectivity and perfusion changes as contributors to cognitive impairment in stroke and Alzheimer's disease and study the relationship of genetic, metabolic, and molecular features with downstream effects in stroke and AD.

Compensatory Mechanisms
Work Package 4

Work Package 4 aims to investigate the compensatory effect of healthy behaviours and lifestyles against the deleterious effects of pathological mechanisms and pathways identified in the Work Packages 1 to 3. Using imaging-markers from Work Package 3 and metabolites from Work Package 2, we investigate to what extent they explain the variation in occurrence of stroke and Alzheimer's disease and how much of the unexplained variation is due to putative compensatory mechanisms. We aim to elucidate potential compensatory mechanisms that lower the risk of the co-occurrence of stroke and Alzheimer's disease.

Clinical Prediction
Work Package 5

The project's fifth Work Package aims to integrate of results from the four previous Work Packages by assessing the joint predictive value and clinical utility of genetic, metabolomic, imaging, and compensatory factors for stroke and Alzheimer's disease. Genetic, metabolomic, imaging, and compensatory mechanisms from Work Package 1 to 4 and markers thereof will be validated in independent studies for their association with stroke and Alzheimer's disease. A joint risk score for stroke and Alzheimer's diseasebased on abovementioned biomarkers will then be developed. Based on biomarkers that are validated, a clinical prediction rule will be constructed that provides individual prediction estimates for stroke only, Alzheimer's diseaseonly, and the combined outcomes ‘stroke or Alzheimer's disease’ and ‘stroke and Alzheimer's disease’.

Therapeutics
Work Package 6

This Work Package aims to exploit -omics databases to develop novel directions and analytical approaches to inform novel pathophysiological based treatments for stroke and Alzheimer's disease, and in particular to identify therapeutic synergies and approaches that provide more than the sum of individual strategies to prevent stroke or Alzheimer's disease. This approach will be combined with a novel organ-on-a-chip approach to model the neurovascular system and allow evaluation of different novel therapeutic approaches.

Project management, dissemination and exploitation
Work Package 7

The horizontal Work Package 7 will be focussed on the coordination and the management of the entire project. It will ensure the necessary legal, financial and day to day activities. As Project Coordinator, Erasmus MC will handle all communication within the consortium and liaise with the European Commission. This Work Package is also tasked with the establishment governance procedures, including the implementation of feedback from a Scientific Advisory Board with experts in the fields of genomics, metabolomics, brain imaging, and public health, and patient representatives. Work Package 7 will ensure the quality and timeliness of project progress and results.

In addition, this Work Package will also develop and pursue the overall external project communication activities, as well as dissemination activities to raise awareness of the project’s new innovative tools. Work Package 7 will disseminate project results and demonstrate the benefits to scientists, health care professionals, stakeholder groups and the general public.