This study provides a detailed assessment of relations between arterial structure and function and brain structure and function in a large community-based sample of older males and females. Primary arterial measures that were assessed included pressure and flow pulsatility and CFPWV. Brain structural measures included grey and white matter and white matter hyperintensity volumes and infarcts assessed by MRI. We also performed comprehensive quantitative cognitive testing and derived summary measures for three major cognitive domains (memory, speed and executive function). We found that higher levels of pressure and flow pulsatility and CFPWV were associated with diffuse microvascular brain lesions, including subcortical infarcts and greater white matter hyperintensity volume, and reduced scores in multiple cognitive domains. We evaluated relations between arterial stiffness and carotid flow pulsatility and showed that disproportionately higher aortic stiffness was associated with progressive impedance matching between aorta and carotids. Resulting loss of the normal impedance mismatch at this interface reduced the carotid reflection coefficient and facilitated transmission of excessive flow pulsatility into the carotid system. Our findings are consistent with the hypothesis that marked proximal aortic stiffening in older people facilitates transmission of excessive pressure and flow pulsatility into the carotid circulation where these abnormal physical forces trigger microvascular damage and remodelling that limits flow or flow reserve, leading to microvascular ischaemia, quantifiable tissue damage and reduced cognitive performance.
As in prior studies, we found relations of higher CFPWV, the current gold standard for assessing aortic stiffness, and higher central pulse pressure with increased prevalence of brain lesions and lower cognitive scores (Hanon et al., 2005
; Poels et al., 2007
; Scuteri et al., 2007
; Waldstein et al., 2008
; Elias et al., 2009
; Kearney-Schwartz et al., 2009
). Relations between memory scores and CFPWV were no longer significant after adjusting for MRI measures of brain structure, suggesting that increased CFPWV affects memory by contributing to quantifiable structural brain damage, including increased white matter hyperintensity volume and higher prevalence of subcortical infarctions. In memory models that offered CFPWV, central pulse pressure, augmentation index and flow pulsatility index together, only pulsatility index was significant, suggesting that the adverse effects of stiffness and wave reflection are mediated by transmission of excessive flow pulsatility into the cerebral circulation. Furthermore, excessive flow pulsatility is transmitted at high pulse pressure in participants with a stiff aorta, which has a multiplicative effect on the amount of pulsatile energy transmitted into and dissipated within the cerebral microvasculature. Prior studies have shown that increased aortic stiffness and excessive pressure pulsatility are associated with increased resting microvascular resistance and markedly impaired reactivity in response to ischaemic stress in the forearm (Mitchell et al., 2005
). Our observations are consistent with the hypothesis that excessive central pressure and flow pulsatility are also associated with microvascular dysfunction and damage in the brain, leading to parenchymal damage and cognitive impairment. In light of the body of literature demonstrating relations between the arterial measures that we have used and brain structure and function, future observational or interventional studies of cognitive function should consider including CFPWV, central pulse pressure and carotid pulsatility index as part of the clinical evaluation.
Higher carotid pulsatility index is often considered an indicator of increased cerebrovascular resistance. However, we have found that relations between pulsatility index, aortic stiffness and cerebrovascular function are more complex than this simple paradigm suggests. Relations between pulsatility index and pulse pressure or cerebrovascular resistance were relatively modest. In contrast, we have shown that impedance matching between aorta and carotids, as assessed by the carotid reflection coefficient, is closely related to flow pulsatility in the carotid vasculature (). Excessive pressure and flow pulsatility is associated with microvascular remodelling that increases resting resistance and limits hyperaemic reserve (Mitchell et al., 2005
). The concordant increase in flow pulsatility and cerebrovascular resistance, which limits mean flow, results in additive effects on pulsatility index. These opposite effects of aortic stiffening on pulsatile and mean flow may account for the robust associations between pulsatility index and brain measures, including cognitive function.
Wave reflection in the arterial system is often portrayed as deleterious. However, it is important to recall that wave reflection at the interface between a compliant aorta and much stiffer peripheral arteries limits transmission of excessive pulsatile energy into the periphery. We have shown that a disproportionate increase in aortic characteristic impedance as compared with carotid input impedance markedly reduces the amount of wave reflection at this proximal interface and facilitates transmission of increased pulsatility into the carotid circulation. An increase in CFPWV contributes to earlier return of the reflected wave and increased augmentation in younger people with modest elevations of CFPWV (Mitchell et al., 2010b
). However, in older people, marked stiffening of the aorta may reduce wave reflection at the interface between aorta and proximal large arteries throughout the body, similar to the reduction we have demonstrated at the interface between carotids and aorta. The resulting reductions in local and global wave reflection may contribute to the dissociation between augmentation index and measures of aortic stiffness or carotid flow pulsatility and a lack of association between augmentation index and measures of brain structure and function. Thus, in older people, the adverse effects of aortic stiffening are not captured by a measure of global wave reflection, such as augmentation index. Furthermore, loss of proximal wave reflection and increased distal transmission of flow pulsatility may play a major role in target organ damage associated with excessive aortic stiffness.
In our study, CFPWV was related to white matter hyperintensity volume, whereas CPP and pulsatility index were not. Prior studies have shown a relation between aortic PWV and white matter hyperintensity (Henskens et al., 2008
; van Elderen et al., 2010
). Increased CFPWV is associated with collagen deposition and fibrosis in the aortic wall (Najjar et al., 2005
). This raises the possibility that the association between CFPWV and white matter hyperintensity may relate, in part, to a general response to tissue injury and repair characterized by excessive fibrosis in the arterial wall and in the white matter of the brain. Alternatively, regions of the brain that are prone to develop white matter hyperintensity may be particularly susceptible to the nature of the haemodynamic insult produced by excessive waveform momentum present when pulse wave velocity is markedly elevated. White matter hyperintensities typically accumulate in regions that are supplied by directly penetrating branches of the deep cerebral circulation (Pantoni and Garcia, 1997
). These vessels differ markedly from the long, circuitous pial network that supplies the cortex and outer white matter. The latter pial vessels dampen pulsatility and decelerate the advancing waveform and hence may provide the cerebral cortex with an additional level of protection from excessive central pressure and flow pulsatility and waveform momentum.
There are limitations of our study that need to be considered. We studied an exclusively older sample with a minimum age of 69 years. In light of known non-linearities between arterial measures and age, additional studies in younger cohorts will be required in order to establish whether associations observed in our older cohort apply in younger samples. Our study employed a cross-sectional design and therefore examined associations; additional work will be required to ascertain whether these associations represent causal relations. We have demonstrated significant and variable wave reflection at the interface between aorta and carotids. Since we measured carotid pressure distal and aortic flow proximal to this interface, we may have variably overestimated aortic characteristic impedance by an average of ~6%, which is small relative to the marked increase in characteristic impedance that is seen after midlife. The strengths of our study include a large community-based sample with routine ascertainment of detailed measures of arterial and brain structure and function.
The prevalence of abnormal aortic stiffness increases dramatically with age from midlife (Mitchell et al., 2007
) and is associated with a markedly increased risk for major cardiovascular disease events (Mitchell et al., 2010a
). Aortic stiffening increases exposure of the microcirculation to abnormal physical forces and is associated with microvascular damage, remodelling and impaired reactivity. We have shown that increased aortic stiffness is associated with excessive carotid pressure and flow pulsatility, microvascular brain lesions and reduced performance in multiple cognitive domains. In light of the rapid ageing of the world population, our findings suggest that the burden of arterial stiffness-related disorders, such as cognitive impairment and dementia, may increase substantially over the next decade unless measures are identified and implemented that limit or reduce aortic stiffening with advancing age.