Overall plan of work

With this truly multicenter, multidisciplinary project, we aim to improve our understanding of the influence of hemodynamic changes on cognitive functioning in the elderly. This project could lead to new tools to assess relevant components of the hemodynamic status in individual patients. Such tools, combined with new pathophysiological insights that we expect to acquire in this project, could lead to innovative, personalized therapeutic options to improve or stabilize declining cognition in an aging population.

The starting point is the foundation of a national, interdisciplinary network to study the contribution of hemodynamic changes to VCI. Such a network has been identified in recent recommendations by the AHA/ASA and by NIH as a prerequisite to advance the understanding of VCI and AD

[1, 50]. The proposed network hosts excellent research groups with complementary expertise that allows for high quality interdisciplinary and translational research.

Our target population is elderly patients presenting with VCI visiting a memory clinic, patients with symptomatic COD and patients with clinically manifest HF. The choice for these three populations is based on dysfunction of different components of the heart-brain axis. In all three populations, we will study the association between hemodynamic status and cognitive performance in a cross-sectional and a longitudinal study design. The work-up in these three cohorts will be identical, which allows us to study the separate contribution of the different components of the heart-brain axis with respect to the pathogenesis of VCI. The longitudinal design will allow assessment of the prognostic value of the hemodynamic status for further cognitive decline in the future.
All patients will be extensively phenotyped using identical, comprehensive protocols. These protocols comprise an extensive MRI protocol providing information on the structure and function of heart, aorta, cerebropetal arteries, cerebral microvasculature, and brain, a recently developed and validated neuropsychological protocol, and a comprehensive set of relevant biomarkers. The acquired data will be stored and analyzed centrally and algorithms will be defined for identifying hemodynamic parameters, other biomarkers, and combinations thereof that are associated with cognitive impairment and that predict development of cognitive decline.

The primary aims in each of the three clinical populations are identical: 1) to assess the relationship between cardiovascular function/structure and cerebral perfusion and 2) to determine the relation between cerebral perfusion and cognition. Therefore, in each of the three populations we will assess heart function, vascular structure and function, cerebral perfusion, brain MRI abnormalities, and cognition in a standardized fashion. Addressing the role of co-morbidities and medication use will be a key target in both the clinical work-up and the analyses. Uniform diagnostic criteria for cognitive impairment, HF, and COD will be used in all three populations to be able to compare data across these populations. The presence of cognitive impairment will be based on performance on a comprehensive neuropsychological test battery.

For the diagnosis of HF, standard MRI of the heart will be used in addition to assessment of signs and symptoms to objectively determine structure and function of both the left and the right ventricle; N-terminal prohormone brain natriuretic peptide (NT-proBNP) levels will be used as suggested by the guidelines [51]; heart rate and blood pressure will be assessed; and a standard 12-lead electrocardiogram will be obtained in all patients. These records will be assessed by an expert committee of HF cardiologists, who will decide whether a patient has HF.

The presence of COD will be based on an MR-angiography study. With a sample size of 175 patients in each patient cohort we will be able to detect associations in which the determinant explains 5% or more of the variance in the dependent variable (i.e., the equivalent of a correlation coefficient of 0.2 or more with alpha 0.05, power 90%), taking up to 10 to 20 relevant co-variates (such as confounders, medication, and co-morbidities) into account. Assuming that the dropout rate will not exceed 25% over two years, we will have 80% power to detect associations of the same strength at follow-up. We argue that variables that explain less than 5% in our primary dependent variables (i.e., cerebral perfusion and cognition) should not be regarded as key determinants and that therefore the selected sample size is sufficient to detect clinically significant associations.

Using an epidemiological approach, we will assess the relationship between hemodynamic status and subclinical cognitive impairment in the elderly population of the large Rotterdam Study. These relationships will be studied using a cross-sectional as well as a longitudinal study design. Apart from adding information regarding the hemodynamic factors associated with subclinical cognitive impairment, the associations found will generate new hypotheses that can, subsequently, be tested in our patient populations and in our animal models.

Due to their observational nature, the clinical and epidemiological studies will provide evidence for the relation between hemodynamic status and cognitive performance in the elderly by demonstrating associa- tions. The extensive phenotyping in general, and the extensive parameters reflecting different aspects of the hemodynamic status in particular, as well as the use of relevant biomarkers will enable us to develop a mechanistic model for the observed associations.