Project Summary Our prior studies suggest that stiffening within the aortic arch (as quantified by aortic arch PWV measured by MRI) disrupts coupling in the aortic-brain system and consequently increases hemodynamic pulsatility transmitted to the brain. This project will test the hypothesis that aortic arch stiffness contributes to age- related brain insults beyond its influence on central pulse pressure by disrupting healthy aorta-brain system dynamics. We are proposing a systems approach, synergistically combining advanced MRI, fluid dynamics, and mathematical modeling to understand the basic physics and physiology underlying aorta-brain hemodynamics. We will test our hypothesis with three specific aims: 1.) Study the mechanisms whereby aortic arch stiffness impacts the hemodynamics of pulsatile energy transmission to the brain. 2.) Define a systems model based on the intrinsic frequency (IF) method to describe the healthy aorta-brain system vs. the system perturbed by aortic arch stiffness. 3). Use mechanistic approaches to understand the impact of disrupted aorta- brain coupling on brain health and cognitive function. We will use cardiovascular MRI techniques to directly assess key vascular properties of the system guiding pulsatile wave transmission in the aortic-brain system including assessment of aortic arch stiffness as well as downstream cerebrovascular resistance and compliance. We will prospectively study 150 non-demented elders from a deeply phenotyped cohort from a concurrent Brain Aging Study at Huntington Medical Research Institutes (HMRI). Brain vascular function will be richly characterized using a combination of imaging techniques and biomarker analysis from bloodwork and cerebrospinal fluid. Our MRI vascular assessments include automated quantification of white matter hyperintensity (WMH) volume as well as cerebrovascular reactivity. Brain integrity and risk for neurodegenerative disease will be assessed with CSF beta-amyloid (Aβ) measurements and a comprehensive neuropsychological battery which includes indices of global function, memory, and executive function. Arterial function will be characterized using MRI measures of blood flow in the aorta and carotid artery combined with arterial tonometry for quantification of the pulsatile hemodynamic energy transmission to the brain, wave reflection analysis, and evaluation of vascular compliance and resistance. Vascular function data will determine physiologic parameters for an in-vitro LV-aortic simulator (that includes cerebral vasculature) and computational fluid dynamics models which will also direct mathematical systems analysis of the aorta-brain system using intrinsic frequency (IF) method. These studies are designed to enhance understanding of how aortic stiffening leads to dementia. Our long-term goal is to develop non-invasive, inexpensive, and easy-to-use measures of brain vascular health that can be used to identify, predict, and quantify risk of vascular brain damage.