Arterial Stiffening with Age Correlates with Structural Damage to the Brain
Today's open access research paper is a reminder of one of the more direct mechanistic links between vascular aging and brain aging. Blood vessels stiffen with age, becoming progressively worse at the necessary task of contracting and relaxing in response to circumstances. This is in part due to cross-linking in the extracellular matrix, in which advanced glycation end-products (AGEs) such as glucosepane form persistent bonds that collectively alter tissue properties. This has the effect of reducing elasticity in tissues such as blood vessel walls, skin, and others. Dysfunction also occurs in the layer of smooth muscle surrounding blood vessels, driven by numerous forms of age-related damage, such as accumulation of senescent cells, mitochondrial dysfunction, and so forth.
Stiffening of blood vessels produces the raised blood pressure of hypertension as a side-effect. Blood pressure is controlled by feedback mechanisms that malfunction in an environment in which blood vessels no longer contract and relax as well as they should, biasing the system towards raised blood pressure. That raised blood pressure is more than delicate tissues can withstand. Small blood vessels rupture more frequently, and even without that breakage, pressure damage can occur to nearby tissues, particularly the blood-brain barrier. In the brain this produces tiny regions of destruction, effectively minuscule and unnoticed strokes that break neural structures. Over time this incremental damage adds up to cause meaningful levels of cognitive decline.
Aortic stiffness is closely linked with cardiovascular diseases (CVDs), but recent studies suggest that it is also a risk factor for cognitive decline and dementia. However, the brain changes underlying this risk are unclear. We examined whether aortic stiffening during a 4-year follow-up in mid-to-late life was associated with brain structure and cognition in the Whitehall II Imaging Sub-study.
In this study, we show that an increased rate of arterial stiffening is associated with lower white matter (WM) microstructural integrity and cerebral blood flow (CBF) in older age. Furthermore, these associations were present in diffuse brain areas, suggesting that exposure to excess pulsatility may result in a widespread damaging effect on the fragile cerebral microstructure. Cognitive function at follow-up related more closely with baseline arterial stiffness rather than rate of arterial stiffening. Taken together, these findings suggest that although faster rates of arterial stiffening in the transition to old age may negatively impact brain structure and function, long-term exposure to higher levels of arterial stiffness prior to this point may be the most important determinant for future cognitive ability.
While aortic stiffening has predominantly been studied in the context of CVD, recent evidence suggests that large artery dysfunction may also play a role in dementia. Indeed, patients with Alzheimer's disease and vascular dementia reportedly have higher levels of aortic stiffness relative to cognitively healthy adults. Aortic stiffening is a hallmark of vascular ageing and may lead to a heightened state of oxidative and inflammatory damage within the cerebral tissues due to an increased penetrance of excess pulsatility into the fragile microcirculation of the brain. These changes have been shown to disrupt endothelial cell function and the blood brain barrier in animal models and have also been hypothesised to compromise cerebral perfusion and ultimately lead to amyloid deposition, neurodegeneration, and cognitive impairment. While previous studies have related cross-sectional measures of arterial stiffness to cognition, this is the first study, to our knowledge, to publish associations between progressive increases in aortic stiffening over a 4-year period and cerebral and cognitive outcomes in later life.
Our findings suggest two things. First - and in agreement with previous studies linking modifiable risk factors to later adverse outcomes - early prevention strategies to reduce life-term exposure to risk factors may be required to in order to offer maximal benefits to later-life cognition, particularly in relation to domains such as semantic fluency and verbal learning. Second, novel to this study is our observation of additional relationships between faster rates of arterial stiffening during this period of life and the presence of pathological differences in WM structure and cerebral perfusion observed in the following years. We show for the first time that interventions to reduce or prevent the rapid increases in arterial pulsatility in mid-to-late life may reduce detrimental changes in WM integrity and blood flow, which have previously been linked to cognitive function, and may therefore also offer additional (albeit possibly more modest) benefits to cognitive ability in older age.