Subclinical Carotid Artery Atherosclerosis and Cognitive Function: A Mini-Review

Carotid artery atherosclerosis, the result of a multitude of vascular risk factors, is a promising marker for use in risk stratification. Recent evidence suggests that carotid artery atherosclerosis affects cognitive function and is an independent risk factor for the development of cognitive impairment. Both atherosclerosis and cognitive impairment develop over a prolonged period (years), and due to the aging population, markers to identify persons at risk are needed. Carotid artery atherosclerosis can easily be visualized using non-invasive ultrasound, potentially enabling early and intensified risk factor management to preserve cognitive function or delay further decline. However, the burden of atherosclerosis and temporal exposure required to pose a risk of cognitive impairment is unclear. This mini-review aims to explore the available evidence on the association between carotid atherosclerosis and cognition, and furthermore identify the remaining gaps in knowledge.


INTRODUCTION
The prevention of cognitive impairment is one of the most significant challenges of our time with up to 10 million new cases each year (1). The consequences of underlying vascular risk factors such as hypertension increase the risk of both atherosclerosis and cognitive impairment. Monitoring and treating vascular risk factors mid-life is a promising strategy to prevent dementia later in life (2). Furthermore, the burden of atherosclerosis correlates to the underlying burden of vascular risk factors (3) and can be viewed as a surrogate marker of total vascular risk.
Vascular risk factors including atherosclerosis seem to contribute not only to vascular cognitive impairment, but also in the pathophysiology of Alzheimers disease (4). It has been proposed that there may be a convergence of mechanisms in vascular and neurodegenerative processes that cause impairments of cognition. These mechanisms are not yet fully elucidated, but most likely mediated through small vessel disease, endothelial dysfunction, silent ischemia, and reduced cerebral blood flow, which precedes neurodegeneration and amyloid accumulation (5).
Atherosclerosis represents a systemic multifactorial and inflammatory disease affecting the vascular bed (6). It develops gradually over years, first as a thickening of the vessel wall's innermost layer -the intima (7), this can either abate or progress into an atherosclerotic plaque and a vascular stenosis (8). Several studies have shown an independent association between atherosclerosis and increased risk of cognitive impairment (9,10). Predilection sites for atherosclerosis are large and medium-sized arteries as well as areas where laminar blood flow is disturbed.
The carotid artery is ideally placed for ultrasound examination and assessment of atherosclerosis. Different types of angiography examinations are available but either demand more resources or are associated with radiation exposure, leaving ultrasound best suited for screening purposes. Atherosclerosis in the carotid arteries correlates with the presence of atherosclerosis in other vessels (11). Definitions of subclinical atherosclerotic disease in various studies include increased intima-media thickness (IMT), atherosclerotic plaques, and asymptomatic stenosis. Assessment of subclinical carotid artery atherosclerosis holds promise as a marker to identify persons at risk and those who may benefit from intensified risk factor management to prevent further progression of atherosclerosis and cognitive decline.
Symptomatic atherosclerosis in pre-and intra-cerebral vessels increases the risk of brain damage with an associated increased risk of cognitive impairment (12). However, the link between subclinical atherosclerosis (meaning nearly or completely asymptomatic) and cognitive function in stroke-free subjects is not as clear, the available evidence is mainly from large population-based cohort studies.
In this mini-review, focusing on subclinical atherosclerosis located in the carotid arteries, we aim to explore the currently available evidence on the association between carotid atherosclerosis and cognition. Furthermore, evaluate any potential progressive relationships, and identify the remaining gaps in knowledge.

SUBCLINICAL CAROTID ATHEROSCLEROSIS AND COGNITION
Several large population studies have assessed the association between atherosclerosis and cognitive function, 20,000 with cross sectional design and 50,000 with a longitudinal design with long term follow-up (up 20 years) between initial assessment of atherosclerosis and outcome, i.e., worsening in cognitive performance or dementia (13). The studies included in our mini-review are described in detail in Table 1.
Four studies found an association between greater IMT and reduced performance in some specific cognitive domains (14,16,18,22). The majority of studies included subjects with more advanced atherosclerosis, i.e., plaque, plaque burden, and stenosis (14-16, 20, 21), supporting the notion of an inverse association between increasing atherosclerotic burden and cognitive function.
The location of the IMT measurement may be of importance. In the Framingham study, greater IMT in the internal carotid artery was associated with impaired cognitive function. However, no such association was found when assessing the common carotid intima-media thickness (ccIMT) and cognitive impairment (32).

DISCUSSION
There is a significant association between different subclinical atherosclerosis measures and cognition in large population studies, both in studies with cross-sectional design and in longitudinal studies showing progressive changes over time.
The current evidence suggests a stronger association between cognitive impairment and more pronounced subclinical atherosclerosis. In the Cardiovascular Health Study and the Framingham study, asymptomatic ≥50% carotid artery stenosis (conventionally defined as significant atherosclerosis) predicted poorer cognitive performance (10,32). Both studies failed to find an association between ccIMT and cognition.
Some studies reported no association between continuous measures of IMT and cognitive function, while as a dichotomized variables were significant (35). While increased IMT may represent non-atherosclerotic age-associated changes in the vessel wall, vessel wall tension, or an adaptive response to changes in flow, it is believed that IMT in the upper reference range is less likely to reflect these non-atherosclerotic processes.
Whether the location of atherosclerosis is relevant is still unclear. In the Framingham study, they found that IMT in the internal carotid artery (ICA), in contrast to ccIMT, was more associated with cognitive impairment (32). Atherosclerosis develops earlier in vessel bifurcations and origins such as the carotid bulb and proximal ICA which could explain associations between IMT and cognitive impairment in ICA, but not common carotid artery. However, atherosclerosis (including increased IMT) in other locations than the carotid arteries have also been associated with reduced cognition, supporting the hypothesis that atherosclerosis is a systemic disease of the vascular bed (36).
The exact pathophysiological mechanisms of atherosclerosisinduced cognitive impairment have not yet been identified. Population-based studies do not have the ideal design to illicit an answer and mechanisms may include cerebral changes resulting from silent embolization, inflammation or hypoperfusion (2,37,38). Increased arterial stiffness leads to increased pulsewave velocity,pulsatile pressure and flow in the small vessels (2,39), and a potential failure in the blood-brain barrier. Since the pathological mechanisms remain unknown, the possibility of reverse causality or that atherosclerosis and cognitive impairment develop in parallel cannot with certainty   be excluded. A major limitation of the available evidence is the absence of a universal understanding of how to define and assess subclinical atherosclerosis. Measurement of increased IMT, which is thought to represent the first structural change in the atherosclerotic process, is affected by the exact timing of measurement (varies throughout a cardiac cycle), the location of measurement, and the software algorithm used. Carotid plaques which are more strongly associated with traditional cardiovascular risk factors (3) and proven to be a better predictor of a future cardiovascular event, are highly age-dependent, with a lower prevalence in younger populations (3). Plaque detection rate is also affected by the resolution of the ultrasound devices.
As most of the studies were conducted in the '90s with older ultrasound devices, an underestimation of plaque occurrence is likely. Furthermore, the definition of plaque is not consistent between the different studies.
As with the assessment of atherosclerosis, evaluation and definition of cognitive impairment lack standardization. The use of different cognitive test batteries, and the definition of cognitive impairment across studies makes it difficult to draw clear conclusions. There are conflicting findings regarding which cognitive domains that are most vulnerable to atherosclerotic carotid disease. In general, vascular cognitive impairment is typically characterized by reduced speed of information processing, complex attention, and frontal-executive functioning (40). However, it seems likely that vascular disease contributes to the cascade of neurodegeneration (2), also affecting other cognitive domains.

FUTURE PERSPECTIVES
Despite associations between atherosclerosis and cognitive function seen in many populations, the amount of atherosclerosis required to pose a risk of cognitive impairment is unclear and is likely both age and person dependent.
Ultrasound of the carotid arteries is a cheap and noninvasive and technique to quantify atherosclerotic burden. Future studies should use standardized imaging protocols, standard definitions of atherosclerosis, and predefined outcome measures. Whether subclinical atherosclerosis poses different risk at different ages and whether different locations, and or intensifying risk factor management can contribute to halting further cognitive impairment needs further exploration.

CONCLUSION
Subclinical carotid artery atherosclerosis provides additional information about vascular risk factors burden in realtion to cognitive performance. More research is needed to address whether the assessment of carotid artery atherosclerosis could be used to identify people at increased risk of cognitive impairment and justify intensified risk factor management.

AUTHOR CONTRIBUTIONS
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.