Prospective cohort studies have implied associations between blood levels of troponin T, troponin I, NT-proBNP, GDF15, dementia, and cognitive function, without providing evidence favoring... Show moreProspective cohort studies have implied associations between blood levels of troponin T, troponin I, NT-proBNP, GDF15, dementia, and cognitive function, without providing evidence favoring possible causality. We aimed to assess the causal associations of these cardiac blood biomarkers with dementia and cognition using two-sample Mendelian randomization (MR). Independent genetic instruments (p < 5e−7) for troponin T and I, N-terminal pro B-type natriuretic peptide (NT-proBNP) and growth-differentiation factor 15 (GDF15) were obtained from previously-performed genome-wide association studies of predominantly European ancestry. Summary statistics for gene-outcome associations in European-ancestry participants, for the two-sample MR analyses, were obtained for general cognitive performance (n = 257,842) and dementia (n = 111,326 clinically diagnosed and “proxy” AD cases, and 677,663 controls). Two-sample MR analyses were performed using inverse variance-weighted (IWV) analyses. Sensitivity analyses to evaluate horizontal pleiotropy included weighted median estimator, MR-Egger, and MR using cis-SNPs only. Using IVW, we did not find evidence for possible causal associations between genetically influenced cardiac biomarkers with cognition and dementia. For example, per standard deviation (SD) higher cardiac blood biomarker, the odds ratio for risk of dementia was 1.06 (95%CI 0.90; 1.21) for troponin T, 0.98 (95%CI 0.72; 1.23) for troponin I, 0.97 (95%CI 0.90; 1.06) for NT-proBNP and 1.07 (95%CI 0.93; 1.21) for GDF15. Sensitivity analyses showed higher GDF15 was significantly associated with higher dementia risk and worse cognitive function. We did not find strong evidence that cardiac biomarkers causally influence dementia risk. Future research should aim at elucidating the biological pathways through which cardiac blood biomarkers associate with dementia. Show less
The aim of this thesis was to investigate cardiovascular determinants of neurocognitive functioning in old age, in particular cognitive dysfunction, depressive symptoms, and apathy. First, we found... Show moreThe aim of this thesis was to investigate cardiovascular determinants of neurocognitive functioning in old age, in particular cognitive dysfunction, depressive symptoms, and apathy. First, we found that the Geriatric Depression Scale(GDS)-3A, the apathy sub set of the GDS-15, moderately discriminates between presence and absence of apathy, and can be used in large study populations to investigate associations with apathy. Next, we demonstrated that higher levels of high sensitivity cardiac troponin T (hs-cTnT), a clinical cardiac biomarker, are related to accelerated cognitive decline, but not to apathy or depression.In the next chapters, we tested the hypothesis that in those older persons with more vascular brain damage, a lower rather than a higher blood pressure is related to worse neurocognitive function. Indeed, we found that only in those older persons with worse daily functioning and those with more cerebral small vessel disease, lower blood pressure was related to more symptoms of apathy. This pattern was not observed for depression or cognitive function.In conclusion, we found that cardiovascular risk factors are important for neurocognitive functioning in older persons. Moreover, we found that specific cardiovascular determinants, such as blood pressure and hs-cTnT, have different associations with apathy than with depression and cognitive function. Show less
