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Common mechanisms and pathways in Stroke and Alzheimer's disease.

Periodic Reporting for period 2 - CoSTREAM (Common mechanisms and pathways in Stroke and Alzheimer's disease.)

Reporting period: 2017-06-01 to 2018-11-30

Stroke and Alzheimer’s (AD) are on the rise and often co-occur in the same patient. One in four patients develops dementia within 10 years of suffering from a stroke, with a substantial proportion developing AD. Similarly, many elderly patients with AD suffer from co-morbid cardiovascular disease and stroke. Risk factors of stroke are seen often in patients with AD. Also stroke risk factors such as diabetes, high blood pressure and cholesterol levels, and obesity co-occur in AD. Both diseases have long been considered “partners in crime”, with overlapping mechanisms causing the diseases. It is important to find out the connection between the origins of these two disorders.

The CoSTREAM project (Common mechanisms and pathways in Stroke and AD) aims to address the major gaps in our understanding of the relationship between these diseases. Current model systems are focused on each disease separately while the interplay between the two has remained an area unexplored in the prevention and treatment of patients.

The 5-year project uses a multidisciplinary approach that incorporates new analytical strategies and emerging technologies in the fields of genetics, metabolomics, brain imaging and clinical prediction. The main objectives are to
• identify joint genetic and environmental pathways
• discover metabolic pathways that explain the occurrence of AD in stroke patients
• understand how genetic, environmental and metabolic pathways relate to structural and functional alterations in the brain, as seen through medical imaging using MRI and PET
• discover compensatory mechanisms protecting against both stroke and AD
• determine predictive accuracy of metabolic and imaging markers for stroke and AD
• develop new directions for therapeutic interventions based on the metabolic, as well as imaging markers
• develop a model system of the neurovascular unit for high-throughput research on both underlying pathways and possibly therapeutics
• use genetic data to evaluate potential therapeutic approaches which target processes shared between stroke and AD
In the second period from month 19 to 36, CoSTREAM validated and expanded on the genetics, metabolomics and biomedical imaging analyses from the first period. In addition, epidemiologic analyses have been performed.

The project has been able to pinpoint specific genomic regions that mediate risk to stroke or Alzheimer’s disease (AD), and elucidated the common genetic pathogenesis of the disorders and created a polygenic risk score based on genes implicated in stroke that predicts AD.

NMR-based metabolomics have delivered promising metabolic markers and pathways for stroke as well as AD, and also common pathways for both. A novel platform to assess circulating metabolites in epidemiological and clinical populations at high-throughput in a cost and time efficient way has been established.

CoSTREAM has successfully analysed MRI data from multiple sites using automated tractography and found consistent relationships between tract measures, age, and memory ability across sites. Metabolic changes have also been shown to be associated with neurodegeneration and vascular brain pathology.

Multiple risk factors, including demographic factors, vascular risk factors and cardiovascular diseases have been related to incident AD and incident stroke. Evidence that loneliness is associated with increased risk of cognitive decline and dementia rather than a result of dementia or depression was found.

Multiple protective factors, including lifestyle factors, social network, leisure time activity have been identified for AD and incident stroke. In addition, it was also found that leisure time activity can compensate the harmful effect of diabetes on cognitive decline and also improves the protective effect of Nordic prudent Dietary Pattern on cognitive function. Higher education is associated with a lower risk of dementia after stroke or TIA, particularly in men, which might be explained by a higher cognitive reserve.

For AD, we found evidence that a specific pathway risk score interacts with smoking history. A recent risk score developed in the USA for genetic stratification was validated using an EU population cohort. A novel deep-learning-based frame work to clinically validate CoSTREAM findings was also validated.

Furthermore, we provided evidence that antihypertensives and statins might reduce the incidence of dementia. Using Mendelian Randomization, we benchmarked the protective effect of education on AD and found suggestive evidence confirming the association of smoking, 25-hydroxyvitamin D concentrations and coffee consumption. Higher homocysteine levels and lower folate levels are associated with increased risk of small vessel stroke. We also found evidence that a genetic variant in PDE3A influences endothelial function in early life and leads to subsequent increased risk of ischaemic stroke. We have been able to develop a cutting-edge prototype of a neurovascular unit on a chip that can be used for translational research.

So far, the project has published more than 40 major scientific publication and gave over 40 oral and poster presentations.
CoSTREAM is improving our understanding of the common mechanisms of stroke and AD. The project uses a multidisciplinary approach, combining genetics, metabolomics, epidemiology, biomedical imaging and biotechnology to investigate knowledge gaps in the co-morbidity of both diseases and identify specific pathways triggering AD in stroke patients.

This is the first time a consortium combines unique clinical, epidemiological, genetic and metabolic research with state-of-the art pre-clinical genetic, metabolomics and imaging data to understand the co-occurrence of stroke and AD. Working in a multidisciplinary framework in which discovery, replication and validation can be achieved in close collaboration with other consortia, the project will be able to achieve breakthroughs in the most cost- and time efficient way.

This will result in novel biomarkers that are related to specific pathways underlying the co-occurrence of both diseases. These may also open the opportunity for treatment monitoring, improving the chances of success and enabling effective precision medicine and prevention targeting specific pathways. CoSTREAM will, for the first time, provide an easy-to-use prediction toolbox combining genomic, metabolomic, imaging and epidemiological data on both risk increasing and protective factors to accurately identify persons at highest risk of stroke, AD, or both.

The ambition of CoSTREAM is that stroke patients will undergo comprehensive AD risk modelling based only on a blood sample and a brain scan and that through CoSTREAM the opportunity to prevent progression of vascular and AD pathology will be seized.
The major barrier in the development of novel evidence-based treatment is the lack of animal or cellular models. To overcome this obstacle CoSTREAM develops a model for the neurovascular unit that can be used for mechanistic and therapeutic research. Together, activities in CoSTREAM will result in early identification of persons at risk, strategies for optimal prevention, and important insights into effective therapies. This will lead to significant health benefits at an individual and societal level, informed directions for therapy development, and coordinated therapeutic management aimed at reducing co-morbidity.
CoSTREAM schematic overview