Impact of pulse pressure on cerebrovascular events leading to age-related cognitive decline

Abstract

Aging is a modern concept: human life expectancy has more than doubled in less than 150 yr in Western countries. Longer life span, however, reveals age-related diseases, including cerebrovascular diseases. The vascular system is a prime target of aging: the "wear and tear" of large elastic arteries exposed to a lifelong pulsatile pressure causes arterial stiffening by fragmentation of elastin fibers and replacement by stiffer collagen. This arterial stiffening increases in return the amplitude of the pulse pressure (PP), its wave penetrating deeper into the microcirculation of low-resistance, high-flow organs such as the brain. Several studies have associated peripheral arterial stiffness responsible for the sustained increase in PP, with brain microvascular diseases such as cerebral small vessel disease, cortical gray matter thinning, white matter atrophy, and cognitive dysfunction in older individuals and prematurely in hypertensive and diabetic patients. The rarefaction of white matter is also associated with middle cerebral artery pulsatility that is strongly dependent on PP and artery stiffness. PP and brain damage are likely associated, but the sequence of mechanistic events has not been established. Elevated PP promotes endothelial dysfunction that may slowly develop in parallel with the accumulation of proinflammatory senescent cells and oxidative stress, generating cerebrovascular damage and remodeling, as well as brain structural changes. Here, we review data suggesting that age-related increased peripheral artery stiffness may promote the penetration of a high PP to cerebral microvessels, likely causing functional, structural, metabolic, and hemodynamic alterations that could ultimately promote neuronal dysfunction and cognitive decline.

Keywords: cerebral arteries; endothelium; large elastic arteries; pulsatile pressure and flow.

Fig. 1.

Positioning of pulse pressure in the cerebral blood flow (CBF) autoregulation. In normal conditions, CBF is maintained constant from a pressure range of 50 to 150 mmHg; normal pulse pressure is within the “safe” zone of CBF autoregulation. Below 50 mmHg, the brain is hypoperfused; above 150 mmHg, blood vessels are passively dilated and CBF dangerously rise, favoring microbleeds or transient ischemic attacks (TIA). In hypertensive subjects, the curve of autoregulation is shifted to the right, toward higher pressures; pulse pressure is higher, toward pressure values where TIA may occur. In the context of systolic hypertension, the amplitude of the pulse pressure is dramatically increased toward pressures that do not permit CBF autoregulation and that may further induce TIA. Schematic representation was adapted from Pires et al. (84).

Fig. 2.

Schematization of the putative cellular and molecular events linking pulse pressure penetration in the cerebral microcirculation and the development of cognitive decline. Age-associated stiffening of large elastic arteries such as the aorta and carotids is due to irreversible elastin fragmentation induced by the lifelong exposure of the vascular wall to the mechanical stress inherent to the heart beat. Stiff collagen, which replaces elastin, and calcification of the vascular wall significantly reduce arterial elasticity and augment the amplitude of the pulse pressure (PP) that penetrates into the fragile low-resistance cerebral microcirculation. Arteriolar, venular, and capillary pulsatility is associated with endothelial nitric oxide synthase dysfunction and possibly endothelial senescence (p16INK4a expression), reduced cerebrovascular reactivity (CVR), and blood-brain barrier (BBB) disruption. The latter permits the infiltration of inflammatory cells and toxic molecules, leading to inflammation (through NF-κB), oxidative stress [via NADPH oxidase (NOX) activation], and ischemia. In the venules and medium-size veins, pulsatility promotes collagenosis that contributes to cerebral hypoperfusion. Altogether, this deleterious ischemic and inflammatory environment favors parenchymal damage [including white matter hyperintensity (WMH)], neurovascular uncoupling, and neuronal damage [phospho-tau and amyloid-β (Aβ) depots], ultimately leading to cognitive decline and dementia. ROS, reactive oxygen species.