CoSTREAM performed and validated genetics, metabolomics, imaging and epidemiologic analyses.
The project pinpointed specific genomic regions that mediate risk to stroke or AD, elucidated the common genetic pathogenesis of the disorders and created a polygenic risk score based on genes implicated in stroke that predict AD. Our conclusion is that there is ample evidence of common genetic determinants but that the impact of genes on the co-occurrence is rather small.
NMR-based metabolomics have delivered promising metabolic markers and pathways for stroke as well as AD, and common pathways for both. In contrast to the findings on genetics, we find very strong and significant evidence that the metabolome is a key player in the co-occurrence of stroke, dementia and AD. A novel platform to assess circulating metabolites in epidemiological and clinical populations at high throughput in a cost & 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. A major finding is that vascular pathology emerges as independent risk factor from amyloid and tau. We further improved the measurement using new high field scanners. 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 stroke. A large range of vascular, social and medical risk factors have been evaluated. New findings suggest that stroke and AD risk may be reduced by targeting shared risk and protective factors. Shared protective factors can compensate for the risk factors. Linking to the imaging field, we discovered that cognitive reserve may reduce the effect of brain vascular pathologies. Moreover, we found that in a community‐dwelling population, impaired global brain perfusion increased the risk of TIA, but not of ischemic stroke. We find that amyloid positivity at PET in the general population is strongly associated to genetic and metabolic profiles.
Combining all findings, we have developed an app to predict the risk of dementia in those with and without stroke or vascular pathology.
We found that genetic predisposition to diabetes and higher HbA1c levels are associated with higher risk of strokes. We also found associations of genetically predicted insulin resistance and β-cell dysfunction with large artery and small vessel stroke that might have implications for antidiabetic treatments targeting these mechanisms. Also, we find that components of the intrinsic and common pathways of the clotting cascade, as well as other haematological traits, in the pathogenesis of cardioembolic stroke and possibly large artery stroke, but not small vessel stroke. We identified plateletcrit and factor XI as potentially tractable new targets for secondary prevention of ischaemic stroke, while factor VIII and γ' fibrinogen require further population-based studies to ascertain their aetiological roles. As to metabolic profiles, we uncovered distinct metabolic signatures associated with imaging markers of small vessel disease, cognition, and conversion to dementia that may improve the prediction of dementia in those with small vessel disease and the development new treatments.
We published >135 scientific publications and gave >75 oral and poster presentations.
