CoSTREAM's first Work Package aimed 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 determined the genetic overlap between stroke and Alzehimer's disease as well as their subtypes and provided an estimate of the genetic correlation between the two. Furthermore, this Work Package pinpointed specific genes or genomic regions that mediate risk to stroke or stroke subtypes, relevant MRI markers and Alzheimer's disease.
This Work Package explored 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 applied 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 used 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.
The third Work Package used 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 aim was 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.
Work Package 4 aimed 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 investigated 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 aimed to elucidate potential compensatory mechanisms that lower the risk of the co-occurrence of stroke and Alzheimer's disease.
The project's fifth Work Package aimed 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 were validated in independent studies for their association with stroke and Alzheimer's disease. A joint risk score for stroke and Alzheimer's disease based on the abovementioned biomarkers was then be developed. Based on biomarkers that are validated, a clinical prediction rule was constructed that provides individual prediction estimates for stroke only, Alzheimer's disease only, and the combined outcomes ‘stroke or Alzheimer's disease’ and ‘stroke and Alzheimer's disease’.
This Work Package aimed 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 was combined with a novel organ-on-a-chip approach to model the neurovascular system and allow evaluation of different novel therapeutic approaches.
The horizontal Work Package 7 focussed on the coordination and the management of the entire project. It ensured the necessary legal, financial and day to day activities. As Project Coordinator, Erasmus MC handled all communication within the consortium and liaise with the European Commission. This Work Package was 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 ensured the quality and timeliness of project progress and results.
In addition, this Work Package also developed and pursued the overall external project communication activities, as well as dissemination activities to raise awareness of the project’s new innovative tools. Work Package 7 disseminated project results and demonstrated the benefits to scientists, health care professionals, stakeholder groups and the general public.
This project has received funding from the European Union‘s Horizon 2020 research and innovation programme under grant agreement No 667375
Copyright CoSTREAM 2016
