Is it time to utilize measurement of arterial stiffness to identify and reduce the risk of cognitive impairment?

Vascular factors have become increasingly recognized to be associated with cognitive impairment and dementia. Dissecting out the relative contribution of hypertension and the interrelated factor of vascular stiffness is of considerable importance because of the increasing prevalence of cognitive impairment and dementia as our population ages and the limited therapeutic options once dementia has developed. The data from Muela and colleauges1 contend that “higher arterial stiffness is related to cognitive impairment at different levels of hypertension.” Furthermore, two different but related measures of arterial stiffness, specifically pulse wave velocity (PWV) and augmentation index, as well as structural properties of the carotid artery—its intimal medial thickness—are associated with lower cognitive performances.1 Cognitive function was been assessed using the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment, and a neuropsychological evaluation battery. Higher PWV significantly correlated with poorer cognitive performance in all cognitive domains, with statistical differences in global cognitive function, episodic memory, visuospatial abilities, attention, and processing speed.1 The study builds on a well-defined and usually consistent base of knowledge that links arterial stiffness to impairment in cognitive function and dementia.2 Although there are some studies that do not demonstrate a strong relationship,3 it is useful to consider a few of the previous investigations as a background. Scuteri and colleagues4 studied a small number of individuals referred for memory impairment, excluding those with clinical or radiologic evidence of stroke, and found that PWV, normalized for mean blood pressure (BP), was inversely correlated with the MMSE after controlling for other factors such as education, cardiovascular disease, cardiovascular risk factors, and medications. Furthermore, increased arterial stiffness was greater in persons with cortical atrophy than in patients with subcortical microvascular lesions or controls.4 Kearney-Schwartz and colleagues5 conducted a cross-sectional evaluation of 198 individuals, mean age 69 years, with subjective memory complaints but excluded those with severe hypertension or dementia. PWV (carotid femoral PWV) was significantly and independently associated with memory impairment in men, after adjustment for cardiovascular risk factors.5 Arterial stiffness (as assessed by augmentation index), as well as increased carotid intima-media thickness, was associated with increased severity of white matter lesions on brain magnetic resonance imaging.5 Triantafyllidi and colleagues6 found that impaired cognitive function was associated with increased large artery stiffness in patients with newly diagnosed, untreated hypertension. In multivariate analysis weighted for age, arterial stiffness was the only predictor for MMSE score in a population after adjustment for body mass index, office systolic and diastolic BP and pulse pressure, 24-hour mean systolic and diastolic BP, urine albumin, sex, and atherosclerotic risk factors (smoking, cholesterol, and triglycerides).6 In the Framingham offspring cohort of 1101 participants, with a mean age of 69 years, aortic stiffness assessed by carotid femoral PWV, after adjustment for age and sex, predicted an increased risk of mild cognitive impairment, all-cause dementia, and Alzheimer disease.7 Vascular stiffness correlates with significant brain changes on computed tomography or magnetic resonance imaging.2 Increased arterial stiffness is associated with relatively smaller total brain and cortical gray matter volumes.8 In young healthy adults, increased aortic stiffness as measured by PWV is associated with brain magnetic resonance imaging findings of lower regional fractional anisotropy in areas such as the corpus callosum and the corona radiate, as well as lower grey matter density in the thalamus—areas associated with cognition, suggesting that greater aortic stiffness produces vascular brain injury.9 The ability of vascular stiffness to induce target organ changes independent of the effect of BP is not unique to the brain but occurs in the heart and the kidney.10, 11 There are a number of fundamental mechanisms that can explain the relationship of arterial stiffness and memory impairment. O'Rourke and Safar11 theorized that the high blood flow and low resistance in the brain “exposes small arterial vessels to the high-pressure fluctuations” thereby producing microvascular damage.11 Magnetic resonance imaging studies have expanded this concept by demonstrating the associations between aortic stiffness and cerebral microvascular remodeling and microvascular parenchymal damage.12 These data suggest that increased vascular stiffness, independent of the level of BP, produces cerebral vascular damage, impairing cerebral blood flow with resulting damage to the brain that leads to cerebral atrophy. A similar logic would apply to the ability of increased arterial stiffness to induce cerebral microbleeds, which, in turn, damage brain structure and function.13 Loss of brain mass when it involves areas of the brain involved in memory inevitably leads to loss of cognitive function. To the extent that β-amyloid plaque deposits in the brain are involved in the development of cognitive impairment and dementia, it is noteworthy that arterial stiffness is strongly associated with the progressive deposition of β-amyloid plaques in the brain in persons assessed by positron emission tomography.14 These plaques may also originate from cerebral damage induced by microbleeding13 from cerebral vessels damaged by increased aortic vascular stiffness. Yet another potential mechanism is that the increased small vessel pulse pressure, from increased arterial stiffness, may impair cerebrospinal fluid flow and impede clearance of β-amyloid.15 The study by Muela and colleagues indicates the depth of the cognitive impairment that can be attributed to vascular stiffness. Impairment in language, processing speed, and visuospatial ability can be profound, even after considering other factors.1 While this kind of observation study does not have the same power of persuasion as prospective cohort studies or clinical trials with a randomized intervention, it nevertheless adds another piece of evidence to the case that it may now be appropriate to utilize measurement of arterial stiffness to identify individuals at high risk for accelerated cognitive decline. It should also be a stimulus for new clinical trials focusing on arterial stiffness to determine whether our current pharmacological and nonpharmacological treatment of patients lowers arterial stiffness and will reduce the development of cognitive impairment.

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