Peripheral Arterial Disease and Cognitive Function: Understanding the Connection

At the cellular level, it is unclear how PAD can have an effect on cognitive impairment. The neuropathology of cognitive impairment includes an accumulation of brain lesions and damage to the integrity of white matter, which can lead to cognitive decline. White matter hyperintensities are areas of increased signal when viewed with T2-weighted magnetic resonance imaging (MRI) and are a manifestation of ischemic damage in the brain. A study demonstrated that patients with intermittent claudication had a high prevalence of silent brain infarction and white matter lesions compared with those without intermittent claudication. A similar study demonstrated a mouse model of cerebral small vessel disease and vascular cognitive impairment through inducing chronic cerebral hypoperfusion by bilateral common carotid artery stenosis. This led to the development and testing of a new type of cognitive function testing: the trail making test and part recall test, which can be done on mice and can be useful for future studies in animal models.

Stepwise multiple regression analyses will be undertaken using the Stata Statistical Software to evaluate the relationships between leg function as an independent variable and cognitive impairment, controlling for potential confounding variables. The regression model will be done in two parts so that cognitive impairment will first be the dependent variable, and then global cognitive function will be the dependent variable. Finally, study findings are compared with those in other studies. This meta-analysis of observational studies indicates that individuals with PAD seem to have a higher risk of cognitive impairment compared to those without PAD. The findings may add understanding to the association between PAD and cognitive impairment and guide future studies on this topic for PAD patients.

Imaging studies have shown that those with cerebral vascular disease have a higher degree of cognitive impairment compared with those without PAD. Also, the association between PAD and cerebral vascular disease is more widely recognized. Meta-analysis of the six studies showed that individuals with PAD had double the risk of transient ischemic attack or stroke than those without PAD. This was ascertained by cerebral vascular events occurring in 14.5% 11 years among those with PAD and only 8.7% among those without PAD, with an adjusted relative risk of 2.27.

Peripheral arterial disease (PAD) is a common age-related circulatory disorder that occurs when the blood vessels and arteries in the legs become narrowed or blocked by fatty deposits. In fact, 4-12% of the adult population 55 years and older have PAD, and the percentage increases to 15-20% in individuals over the age of 70. This percentage is even higher in those with coronary artery disease: 65% of women and 70% of men. The manifestation of PAD in the lower extremities results in functional impairment as well as physical disability, a decrease in quality of life, and, late in the disease, limb loss.

Overview of Peripheral Arterial Disease (PAD)

The symptoms of PAD vary, and often people mistake intermittent claudication for aging. This is dangerous because PAD is a sign of widespread systematic damage, which can pose more serious health risks.

PAD also takes place when plaque builds up in the large arteries of the legs. This can lead to severe pain when walking, and in serious cases, it can lead to foot or leg amputation.

Renal artery disease occurs when plaque builds up in the renal arteries, and these arteries carry blood to the kidneys. This can lead to high blood pressure and, in severe cases, kidney failure.

Carotid artery disease is when plaque builds up in the arteries on each side of your neck, and these arteries carry blood to the head. This is a high-risk area because where plaque occurs, it can cause a stroke by stopping blood flow to the brain.

Peripheral artery disease (PAD) is a condition that occurs when there is a buildup of plaque in the arteries that carry blood to the head, organs, and limbs. Plaque is made up of fat, cholesterol, calcium, fibrous tissue, and other substances in the blood. When plaque buildup occurs, it is because of atherosclerosis in which the arteries are narrowed and blood flow has decreased, and such plaque can run over years or have multiple buildup sites.

Overview of Cognitive Function

Specifically, patients with PAD often exhibit an abnormal gait and have difficulties with motor function, which are thought to be due to intermittent claudication. It is also suggested that the risk factors for PAD, such as smoking, diabetes, and hypertension, are associated with greater cognitive decline. In order to further understand this important topic, it is critical that there is a review of the cognitive assessment tools, as well as the constraints and findings of the various studies that have been completed. This will enable us to investigate whether it is merely a coincidence that many patients with cognitive decline have comorbid PAD or whether there is a plausible connection between the two.

In recent years, there has been a growing concern in the study of cognitive functioning in the patient population that has peripheral arterial disease (PAD). This has led to the interesting question of whether or not there is a connection between cognitive function and PAD. It is suggested that cognitive impairment in the elderly is associated with an increased risk for disability, dementia, and death. Additionally, cognitive function and the disorders associated with it may be influenced by systemic and cerebrovascular atherosclerotic processes.

Cognition is defined as the process of thought that includes the aspects of awareness, perception, thinking, reasoning, and judgment. It is the process of the mind that enables one to be aware of the world and their experiences, to think, and to enable the best possible judgment. However, it does not incorporate any form of motor or sensory function. There is no one specific area of the brain that is solely responsible for cognition, but it involves certain areas of the brain working together to bring about an activity. Any abnormality of the structure of the brain can cause a disturbance in the process of cognition. This can often be seen in patients with dementia or delirium.

The Link Between Peripheral Arterial Disease and Cognitive Function

Our interest in the relationship between PAD and cognitive function grew out of observations in patients with functional impairment due to leg symptoms that suggested involvement of cognitive function. For example, in qualitative studies of patients with PAD, pain and reduced ambulatory function were shown to negatively impact independence and the ability to perform instrumental activities of daily living. Furthermore, functional impairment in PAD has been associated with symptoms of depression and anxiety, though the reasons for this are not entirely clear. Given these anecdotal observations in the PAD population, we sought to determine if PAD is associated with objectively measured cognitive impairment. Because functional impairment in PAD has been attributed to ischemic damage to muscle, it is important to determine if any observed cognitive impairment in PAD patients is the result of ischemic damage to the brain. This work has potential clinical implications, as if cognitive impairment is a consequence of PAD, it would provide further rationale for aggressive treatment of PAD to prevent ischemic damage to the brain.

If lower extremity peripheral arterial disease (PAD) is underdiagnosed and undertreated, then cognitive decline may be one of the unrecognized consequences. This concept is at the heart of our effort to understand the relationship between PAD and cognitive function. To set the stage for a discussion regarding the link between PAD and cognitive function, it is helpful to first consider the relationship between systemic atherosclerotic vascular disease and cognitive function. This topic has been most thoroughly studied in the context of stroke, and more recent attention has turned to cognitive decline as a potential consequence of cardiovascular risk factors and diseases in the absence of stroke. Data from the Framingham study, as well as other cohort studies, clearly demonstrate an association between various cardiovascular risk factors, particularly hypertension and diabetes, and diseases and cognitive decline and increased risk of dementia.

Impact of PAD on Cognitive Function

Unfortunately, the exact means by which (PAD) affects cognitive function are not yet understood. It was hypothesized that cerebral ischemia was the cause, with several indications of small, usually sub-clinical, strokes being linked to non-focal cognitive deficit. This theory may, however, be insufficient to explain the cognitive impairment experienced by PAD sufferers. Cognitive deficit related to PAD has also been measured using the (MMSE). An observation of 669 patients by Newman et al. identified a 71.2% incidence of cognitive impairment when using the MMSE. Results from this study showed that the odds of cognitive impairment significantly increased with the severity of PAD. These results remained significant even after adjustment for age, education, and comorbid factors known to affect cognitive function. This led Newman et al. to conclude that there was a strong independent relationship between PAD and cognitive impairment. A possible common pathway for general cardiovascular disease and cognitive impairment has been explained by associative factors such as hypertension resulting in cerebral small vessel disease. White matter lesion (WML) formation as a result of ischemic damage to the cerebral cortex has been identified as a probable cause of cognitive impairment in the elderly. In a community-based study of 199 people, WML burden was associated with a 2.7 relative risk of cognitive decline over 4 years. WML presence and extent in PAD populations have been studied using MRI with results consistently showing a higher prevalence and extent of WML in PAD groups compared to controls. This has led to the hypothesis that chronic cerebral ischemia as a result of diffuse atherosclerosis will lead to WML formation, ultimately resulting in cognitive impairment. This is the strongest evidence yet for an underlying mechanism responsible for the cognitive impairment experienced by PAD sufferers.

Mechanisms Connecting PAD and Cognitive Decline

Research on potential mechanisms for the link between PAD and cognitive dysfunction is burgeoning, and there are several plausible biological pathways, including shared risk factors, cerebral emboli from atherosclerosis and micro-emboli, chronic brain hypoperfusion, white matter changes, and inflammation. Shared risk factors such as age, hypertension, and diabetes have been found to predict both cognitive decline and incident PAD. However, adjusting for these risk factors does not completely attenuate the relationship between PAD and cognitive impairment. Although it is known that peripheral atherosclerosis is associated with cerebral infarcts and clinically covert strokes detected by MRI, a recent study on PAD patients found no association between measures of atherosclerosis and the burden of cerebral ischemic lesions. This suggests that cerebral emboli may not be a significant cause of cognitive decline in PAD. Alternatively, rather than large cerebral emboli, micro-emboli thrown from disrupted atherosclerotic plaques may cause subtle cognitive deficits by occluding small cerebral vessels. However, a direct relationship to cognitive impairment has not been proven. Changes to the cerebral vasculature in terms of chronic brain hypoperfusion may also be a cause of cognitive impairment in PAD. Studies on chronic brain hypoperfusion in animal models have shown cognitive impairment that is reversible with correction of cerebral blood flow. Similar to PAD patients, these animals develop cognitive impairment without any major stroke or dementia syndrome, suggesting pathological changes also observed in humans with white matter changes and silent infarction. White matter changes identified by MRI are more frequent in patients with cardiovascular disease, and PAD has been found to be independently associated with progressive white matter change and incident white matter lesions. White matter lesions disrupt conduction between neurons, and their cognitive correlates are deficits in executive function, information processing, and psychomotor abilities that are similar to those observed in PAD patients. A recent study by our research group also found that lower extremity function is associated with white matter integrity, and this relationship was mediated by inflammatory markers, suggesting that inflammation may also play a role in white matter changes seen in PAD patients. Finally, inflammation has been proposed as a potential mechanism connecting PAD and cognitive impairment. Inflammatory markers such as C-reactive protein and interleukin-6 are elevated in PAD patients, and elevated levels have been found to be associated with cognitive impairment in the general population. Although at this point in time, the link between inflammation, PAD, and cognitive impairment requires further investigation. Though these mechanisms are plausible, at present, the precise pathophysiological processes for cognitive decline in PAD remain an enigma.

Discussion 2-2: Mechanisms Connecting PAD and Cognitive Decline

Factors Influencing the Connection

We recognize from the start that the association between PAD and cognitive dysfunction increases with advancing age. This was very elegantly shown in a recent study, with an analysis of the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik Study), which is a part of the larger Reykjavik Study. This particular study was performed on a subset of 576 subjects recruited from a random sample of surviving AGES-Reykjavik cohort members. Cases of cognitive impairment were identified using a telephone-based screening of the whole cohort with specific questions and then further evaluated by an extensive neuropsychological testing battery and a clinical assessment. This generated a sample of 70 cases of cognitive impairment and 506 normal controls. The analysis was well done with very good adjustment for potential confounding factors. The subjects with PAD were identified by both clinical examination and an ankle-brachial index (ABI) ≤ 0.9. The main analysis was done on the sample aged 64-71 years due to a small number of cases of cognitive impairment in the older groups. In this age group, the subjects with PAD were at higher risk of cognitive impairment or decline compared with those without PAD. A separate analysis of ABI ≤ 0.9 and clinical PAD comparisons to the normal controls also showed increased risk of cognitive impairment or decline. These associations of PAD with cognitive dysfunction were persistent after extensive adjustments for potential confounders including cardiovascular disease and several health and lifestyle factors. In other subgroups of the sample, there weren’t consistent associations between PAD and cognitive impairment or decline, possibly due to small numbers of cases, a healthy survivor effect, or misclassification of PAD. This study makes a significant contribution to understanding the association between PAD and cognitive dysfunction while adjusting for potential confounders, particularly showing that the increased risk of cognitive impairment or decline with PAD may occur specifically in early old age. The editors of AJM commented that surely this cohort will be followed up, and we are eager for more research to confirm and extend these findings because cognitive function data in PAD patients is sparse and difficult to interpret.

Age and the Association between PAD and Cognitive Function

Given the well-known association between aging and cognitive decline, it is important to consider that elderly patients with PAD may have accumulated multiple comorbidities known to contribute to cognitive impairment. As age is an unmodifiable factor, the prevention and treatment of PAD in the elderly will continue to be an important public health issue. Yet the potential benefits of PAD treatment on cognitive function in this group may be offset by disability and cognitive impairment resulting from other competing conditions. This is an important area for future research, particularly in an era of increasing life expectancy and limited healthcare resources.

It has been widely accepted that older age is associated with decreased cognitive function and is a prominent risk factor for the development of cognitive impairment and dementia. In fact, the prevalence of cognitive impairment increases two to threefold every 5 years in those aged over 65. This knowledge has been supported by recent evidence, which suggests that a stronger association exists between PAD and cognitive impairment in younger patients, despite there being a higher prevalence of cognitive impairment in older patients with PAD. This was demonstrated by McDermott et al. using data from the Walking and Leg Circulation Study, where patients with and without PAD, aged 55 years and older, were compared on global and domain-specific cognitive function. In studies such as this, the interaction of age and its influence on the association between PAD and cognitive impairment has not been taken into account.

Vascular Risk Factors and Cognitive Decline

The relationship between dyslipidaemia and cognitive function is more complex. While some studies have suggested that high total cholesterol in midlife is a risk factor for late-life Alzheimer’s disease and cognitive decline, there is evidence to support the ‘cholesterol-lowering’ paradox observed in some clinical trials. High total cholesterol and midlife and late-life LDL cholesterol were shown to be associated with a decreased risk of Alzheimer’s disease and cognitive decline in a cohort of elderly Japanese-American men. It is speculated that the statin and non-statin lipid lowering effects of cholesterol on cognition may differ and that the potential adverse effects of the lipids may be offset by their impact on the incidence of cerebrovascular events.

Similar to the effects of hypertension, the impact of diabetes on cognitive function is well documented. Diabetes increases the risk of both vascular dementia and Alzheimer’s disease and has been shown to accelerate cognitive decline. In an analysis of the Canadian Study of Health and Aging, diabetes was associated with a 1.5-2 fold increased risk of onset and progression of cognitive impairment. Poor glycemic control has also been associated with an increased risk of cognitive impairment and dementia in a study of Type 2 diabetics aged 55-80.

A vast amount of data from epidemiological studies, clinic-based research, and large studies like the Cardiovascular Health Cognition Study and the Women’s Health and Ageing Study have established the strong relationship between vascular risk factors and cognitive impairment. Hypertension, a potent risk factor for both stroke and cognitive impairment, has been consistently associated with cognitive decline. A six-year, longitudinal study of 13,000 participants 60 years and above, reported increased cognitive decline and a higher risk of Alzheimer’s disease in individuals with high diastolic blood pressure. Conversely, a study examining the effects of blood pressure lowering on cognitive function found that a reduction in blood pressure was associated with a decreased risk of cognitive impairment and dementia.

Other Potential Contributing Factors

Others have suggested that there are systemic effects of atherosclerosis that impact on the brain and cognitive function independently of strokes and cerebral vascular disease. A potential mechanism is the burden of chronic inflammation due to atherosclerosis. Inflammatory mediators such as interleukin-6 and C-reactive protein have been linked with atherosclerosis and are negative predictors of cognitive function in older adults. Inflammatory mechanisms may also be implicated in various psychiatric conditions seen in patients with cerebrovascular disease. High homocysteine levels are another systemic effect of atherosclerosis that may be a factor in cognitive impairment, given that homocysteine has been linked with poorer general health status of the brain in the elderly and found to increase the risk of dementia and Alzheimer’s disease. He et al in 2007 suggested that there was a strong link between low ankle-brachial pressure index, a PAD diagnostic tool, and homocysteine levels. High homocysteine levels have been linked to cardiovascular disease, and low ABPI is an indicator of significant PAD. Though no studies to date have directly linked high homocysteine level and cognitive impairment in patients with PAD, it remains an interesting area for further research.

Our review of the literature identified several other potential factors, some of which relate to youth of age. Our review did not uncover a consistent association between cardiovascular risk factors, such as smoking or high cholesterol, with cognitive impairment. When individual small- and large-vessel ischemic strokes have been investigated, they do not appear to increase the risk of vascular dementia, suggesting that cumulative cerebral ischemia may be the critical factor, not helping in elucidating the connection between cardiovascular disease and cognitive impairment. Considering that many individuals with PAD will suffer at some stage from intermittent claudication and PAD is a strong risk factor for stopping physical activity, it is interesting to note that only a few studies have directly compared peripheral arterial disease with cognitive function. One such study suggested that participants with intermittent claudication had an increased risk of cognitive impairment compared to those without; however, no significance level was provided. Another possibility is that there is an indirect link between PAD and cognitive function related to the functional limitations and lifestyle changes resulting from PAD. Clearly, more research in this area is warranted.

Implications and Future Directions

Overall, the goal of the research is to identify methods of preventing cognitive decline and impairment in patients with PAD, as these can have profound effects on quality of life and the ability to carry out everyday tasks.

Also, research is being conducted to identify the mechanisms by which PAD affects brain function. The goal is to find if there are specific processes that occur when blood flow to the brain is compromised and clarify whether the cerebral effects of PAD may be due to other risk factors, coexisting conditions, or simply a manifestation of the extent of peripheral disease. By determining the mechanisms and the precise cause of cognitive impairments in PAD patients, there is potential to develop treatments that can prevent or reverse these. These treatments could be anything that improves blood flow to the brain or specific therapies targeted at the identified areas of cognitive function that are affected.

In light of the preliminary findings that suggest that patients with PAD may be at a greater risk for cognitive decline or impairment, further research will be conducted to gain a more comprehensive understanding of this theory and determine exactly what aspects of cognitive function are affected. Studies are being designed to look at specific areas of cognitive function such as memory, learning, language abilities, and complex problem solving. By identifying exactly what areas of cognitive function are affected by PAD, patients can be screened more precisely for impairments in these areas. This will not only help to detect cognitive impairments more accurately, but it will also help to identify those at greatest risk for developing cognitive deficits and provide clear areas of cognitive function to target in efforts to prevent further decline.

Clinical Considerations for Patients with PAD

With the growing awareness of the significance of cognitive status to the patient’s overall quality of life, this review suggests that it is equally important to maintain functional status and quality of life in treating patients with PAD, in addition to preventing cardiovascular events. Improvement of cognitive function can be considered an additional therapeutic goal, and there may be patients with PAD who would stand to benefit from treatment targeting the prevention of further cognitive decline.

The identification of cognitive impairment in patients with PAD may be difficult, as some of the features associated with cognitive decline may also reflect apathy and decreased physical activity caused by leg ischemia. Health professionals need to be aware of this possible association. In instances of unexplained cognitive decline in an elderly patient with known PAD, further investigations into the patient’s cognitive status may be warranted.

In the meantime, while there is a demand for more specific research on vascular dementia, it is important that we do not overlook the significance of recognizing the association of PAD with cognitive decline. This is now a significant consideration for public health. PAD is a common disease affecting older people, and the findings from this review may have significant implications for the care of elderly patients with cognitive impairment.

Research Opportunities for Further Understanding the Connection

This is an area of acute paucity, and the opportunity for research is extensive. While there is no evidence to suggest that early revascularization has a beneficial effect on cognitive function, several commentaries have championed this idea. It has been suggested that, in view of animal data showing a vast improvement in cerebral and cognitive function following revascularization, patients with cognitive impairment and significant carotid disease should be considered for early carotid endarterectomy. This remains highly provocative, and this group would need careful selection to avoid the risk of perioperative stroke. Randomized control trials (RCTs) have heralded the highest standard of medical evidence in several areas of treating vascular causes of cognitive impairment. An RCT looking at supervised exercise and cognitive function in PAD patients would not only be interesting but also have the potential to lead to a safe, simple treatment method for these patients who often have multiple co-morbidities and difficulty taking part in rigorous exercise. Finally, another observational data suggests that control of inflammatory markers may improve cognitive function in dementia patients. A systematic review of available data looking at treatments to control inflammation and their effect on cognitive function in vascular patients could aid the design of more specific treatments in the future.

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