Objective: Peripheral arterial disease (PAD) is associated with comorbid atherosclerosis of the coronary and carotid arteries and is a significant risk factor for stroke. However, cognitive function in PAD patients before clinically evident stroke remains poorly characterized. Here we hypothesized that, on neuropsychological testing, PAD patients would perform more poorly than healthy control subjects, and persons with mild cardiovascular disease (essential hypertension), but better than stroke patients, thus reflecting a continuum of cognitive impairment associated with increased severity of vascular disease.
Method: The cognitive performance of 38 PAD patients (mean ankle-brachial index=0.67, Fontaine Class II) was contrasted with that of 23 healthy normotensive controls, 20 essential hypertensives, and 26 anterior ischemic stroke patients on twelve neuropsychological tests.
Results: PAD patients performed significantly more poorly than hypertensives and normotensives, but better than stroke patients, on seven tests of nonverbal memory, concentration, executive function, perceptuo-motor speed, and manual dexterity. Hypertensives displayed poorer performance than normotensives on tests of nonverbal memory and manual dexterity. These findings were independent of age, education, and depression scores. Higher diastolic blood pressure and plasma glucose levels predicted poorer performance of select cognitive tests by PAD patients. Eight to 67% of PAD patients displayed impaired performance (< 5th percentile of normotensive controls) on the seven aforementioned cognitive tests.
Conclusions: PAD patients exhibit diminished performance across a variety of domains of cognitive function. Findings also suggest a continuum of cognitive impairment associated with increasingly severe manifestations of cardiovascular disease, thus emphasizing the need for enhanced preventative measures to avert functional declines.
ABI = ankle-brachial index;, ANOVA = analysis of variance;, BDI = Beck Depression Inventory;, B-VAMC = Baltimore Veterans Affairs Medical Center;, DBP = diastolic blood pressure;, HSD = honestly significant difference;, MMSE = mini-mental status examination;, PAD = peripheral arterial disease;, PVD = peripheral vascular disease;, SBP = systolic blood pressure;, WMS-R = Wechsler Memory Scale-Revised.
Peripheral arterial occlusive disease (PAD), a common form of peripheral vascular disease (PVD), results from atherosclerosis of the arteries that supply the lower extremities (ie, abdominal aorta, iliac, femoral, popliteal, tibial). PAD affects approximately 16% of adults over the age of 55, including 10% asymptomatic PAD (stage I), 5% intermittent claudication (stage II), and 1% chronic leg ischemia (stages III–IV), and is a major cause of disability among older individuals (1). Revascularization may be utilized in stage III or IV PAD (ie, necrosis or gangrene), and stage IV disease may necessitate limb amputation.
As a diffuse atherosclerotic disease, PAD is associated with comorbid atherosclerosis of the coronary and carotid arteries (2). Indeed, risk for atherosclerotic events such as myocardial infarction, PAD, and stroke clusters among individuals (3–5), and PAD is considered a significant risk factor for stroke (6). However, cognitive function in PAD patients, before clinically evident stroke, remains poorly characterized. Atherosclerosis (7–9) and many of its risk factors such as hypertension (10–12), diabetes mellitus (13, 14), hyperlipidemia (13, 15), and cigarette smoking (16, 17), have known deleterious effects on cognitive function among stroke-free persons. As all of these conditions are highly prevalent among PAD patients (2), it is likely that cognitive deficits are also concomitants of this disease.
In this regard, several early investigations utilized PVD patients as control subjects in studies of the impact of various vascular surgeries, such as carotid endarterectomy and coronary artery bypass surgery, on cognitive function (18–20). Results of these studies suggested that patients with PVD displayed mild neuropsychological dysfunction (18, 19) or showed similar cognitive function as patients with carotid disease (20). In the first study to focus on PVD patients per se, severe cognitive impairment was noted in a subset of amputees (21). Affected functions among these Stage IV patients included short-term memory, attention, concentration, orientation, and judgment. However, no control group was employed.
More recently, Phillips and colleagues contrasted the cognitive performance of amputees secondary to PVD (stage IV) with that of healthy control subjects (22). Deficits among PVD patients were found on tests of perceptuo-motor speed and executive functions. Extending on this work, these authors examined a group of amputees and nonamputees with mild to moderate claudication, as compared with healthy control subjects, and atherothrombotic stroke patients (23). Results indicated that this spectrum of PVD patients performed more poorly than healthy controls on tests of attention, psychomotor speed, executive functions, visual memory, and visuospatial ability, but not verbal memory, language, or sensory-motor function. Furthermore, the performance of the PVD patients was, in many instances, similar to that of the stroke patients, although on several tests the stroke patients did more poorly. It was also noted that measures of PVD severity and presence of ischemic heart disease were significant predictors of cognitive performance among the PVD patients, although several cardiovascular risk factors were not.
In the population-based Rotterdam study, Breteler et al. (24) found that individuals having an ankle-brachial index (ABI) < 0.90 (diagnostic of PVD) displayed poorer performance on the Mini-Mental Status Examination (MMSE) than patients with greater ABIs. The presence of PVD, as assessed by ABI, has also been associated with cognitive decline on the MMSE and a test of perceptuo-motor speed over periods of three (25) and seven (26) years, particularly among individuals having an ApoE ε4 allelle. In contrast, Rao et al. (27) noted that nonamputee PVD patients performed similarly to a group of orthopedic controls (eg, hip or knee replacement). However, little information was provided about the PVD patients or the control subjects. Interpretation of these findings is further limited given the notable prevalence of cognitive impairment among such orthopedic patients (28, 29).
The present investigation extends on prior research in several ways. First, we examine a group of milder PAD patients, all presently classified as Stage II and all nonamputees. Second, whereas prior work included control subjects with medical conditions that might also affect cognitive function, the present control subjects were screened carefully for comorbidities. Third, we include two vascular disease comparison groups - anterior ischemic stroke patients and essential hypertensives. Pronounced cognitive impairment among stroke patients is well documented (30, 31), as are the more subtle cognitive consequences of hypertension (10–12). However, the groups examined herein have never been directly compared with respect to cognitive performance. Anterior stroke patients were chosen as controls because prior research suggests that milder forms of cardiovascular disease may have a particularly potent impact on cognitive functions that are associated with adequate functioning of anterior brain regions (32). It was hypothesized that a continuum of cognitive impairment would be noted in relation to increasingly severe manifestations of cardiovascular disease - hypertension, PAD, and stroke. Fourth, as noted previously by Phillips (23), it is of interest to examine the potential influence of medically assessed cardiovascular risk factors, measured as continuous variables, on cognitive performance within PAD patients. Prior work has utilized dichotomous measures of such variables.