Abstract

The role of carotid stenosis on cognition remains to be determined. To study whether people with stenosis of the carotid artery have increased cognitive impairments, we studied 53 patients with moderate or severe carotid stenosis (with no symptoms of stroke or dementia) and 53 controls. We describe which cognitive functions were impaired in the patients and whether there were differences based on the side, the severity of the stenosis or the presence of neurological symptoms. Using the Repeatable Battery for the Assessment of Neuropsychological Status, we found that the patients with carotid stenosis had lower cognitive performances in attention, verbal memory, visuospatial capacity and verbal fluency. Patients with lesser degrees of stenosis than healthy control patients had better scores in learning and memory. The results from this study suggest that patients with severe carotid stenosis have a lower cognitive status than healthy control patients, which is associated with the degree of total carotid stenosis.

Introduction

Approximately 15 million people worldwide suffer from strokes each year. Vascular risk factors are the primary cause of strokes (Goldstein et al., 2006), and severe stenosis of internal carotid arteries cause from 20% to 30% of cerebrovascular accidents (Timsit et al., 1992). Although chronic cerebral ischemia and cerebrovascular accidents are known to cause cognitive impairments (Korczyn & Vakhapova, 2007), the relationship between carotid artery stenosis and cognitive function is less clear.

Notions of a possible role of carotid stenosis in the pathogenesis of cognitive impairment arose from epidemiological studies in the mid-90s, including the cross-sectional study “Etude sur le vieillissement arteriel” (EVA; Auperin et al., 1996), the Artherosclerosis Risk Communities (ARIC) study (Cerhan et al., 1998), and the Tromso study (Mathiesen et al., 2004). In the EVA study (Auperin et al., 1996), a cohort of 1,200 people over 60 years was evaluated. The authors observed an association between the presence of carotid plaques and attention difficulties with reduced performance on the Mini-Mental State Examination (MMSE) and a relationship between carotid wall thickness and cognitive performance. This later finding was also reported in the ARIC study (Cerhan et al., 1998) which described an inverse association between carotid wall thickness and memory and digit symbol task performances. Subsequently, the epidemiological study Tromso (Mathiesen et al., 2004) of a subgroup of patients (n = 189) with carotid stenosis >35% and no symptomatology found an inverse relation between the degree of stenosis and the Grooved Peboard Test (Matthews & Klove, 1964) and Trail Making Test (Reitan, 1958) scores. These studies provided valuable data on the relationship between carotid stenosis and cognitive impairment and generated hypotheses for future investigation.

Thromboendarterectomy (TEA) has become the surgical procedure used to prevent the occurrence of cerebrovascular events in patients with symptomatic (Goldstein et al., 2006; Sacco et al., 2006; Sztriha et al., 2004) and asymptomatic (Mohammed & Anand, 2005; Rothwell et al., 2003) carotid stenosis. Studies on whether there are cognitive impairments in patients with carotid stenosis scheduled for surgery have not been conclusive. Most of the previous studies evaluated the cognitive differences produced as a result of endarterectomy, without considering the basal cognitive state of the patients in detail. Several studies have investigated the cognitive status before the intervention but these studies were conducted on relatively small cohorts of mainly symptomatic patients with transient ischemic attack (TIA; Goldstein et al., 2006; Sacco et al., 2006; Sztriha et al., 2004) or patients who were asymptomatic (Mohammed & Anand, 2005; Rothwell et al., 2003). Some authors found that before TEA, there was a worse performance in executive functions and visuospatial–constructional capabilities (Martinić-Popović, Lovrencić-Huzjan, & Demarin, 2009), visual motor attention (Heyer et al., 2002), visual memory, attention, and visual motor functions, compared with healthy individuals (Hamster & Diener, 1984; Heyer et al., 2002; Mathiesen et al., 2004). In contrast, other studies comparing patients who had suffered a TIA with a control group (Boeke, 1981) found no cognitive differences between the groups (Iddon, Sahakian, & Kirkpatrick, 1997; Van den Burg et al., 1985). The results are divergent from one another due to methodological variability between the studies (De Rango et al., 2008). The conflicting results are attributable to differences in several methodological issues (lack of statistical power, type of neuropsychological test, type of statistical analyses, follow-up schedule, inclusion/absence of a control group), clinical and demographic variables (age, presence of diabetes, difference in symptomatology), and the variety of tests used to assess cognition in each study.

The need for TEA is determined by the degree of carotid stenosis together with the presence of neurological symptoms. Despite the importance of the severity of the obstruction in medical decision-making, the relationship between cognition and the progression of the disorder over time remains unclear. Knopman and colleagues (2001), in their longitudinal study, found an association between carotid artery wall thickness and cognitive scores after 6 years of follow-up. However, more recent studies have shown mixed results. In a study by Bossema and colleagues (2006), patients with severe bilateral stenosis, as pointed out by Knopman and colleagues (2001), showed poorer cognitive performance than patients with milder stenosis (Bossema et al., 2006; Knopman et al., 2001; Martinić-Popović et al., 2009). However, in a study by Landgraff, Whitney, Rubinstein, and Yonas (2010), no differences were found when patients were divided according to severity or the presence of stenosis in one or two carotids. The four studies differed in the inclusion and exclusion criteria used; therefore, it is difficult to get conclusive data on whether the severity of stenosis affects cognition.

Similarly, in studies that have assessed the importance of the presence of neurological symptoms in preoperative cognitive performance, the results have not been conclusive. Some authors have reported cognitive differences according to the neurological symptoms of the patients (Brand, Bossema, Ommen Mv, Moll, & Ackerstaff, 2004; Heyer et al., 2002; Rao, Jackson, & Howard, 1999), whereas other studies have reported no such relationship (Bo et al., 2006; Bossema et al., 2006; Fearn et al., 2003; Heyer et al., 2006; Mononen, Lepojärvi, & Kallanranta, 1990; Soinne et al., 2009). This discrepancy is likely due to the limited information provided by the authors on the characteristics of the stroke patients.

Several studies have aimed to find the specific effects of laterality on cognitive functions after TEA, based on the assumption that the restoration of blood supply to the brain is more beneficial to the functions mediated by the ipsilateral hemisphere on the side of the operation rather than on the contralateral side. The results of these studies, however, have shown great variability. Whereas some studies reported ipsilateral cognitive effects (Hemmingsen et al., 1986; Mononen et al., 1990), others reported contralateral effects (Bornstein, Benoit, & Trites, 1981; De Leo et al., 1987), mixed effects (Bornstein, Benoit, & Trites, 1981; De Leo et al., 1987; Greiffenstein, Brinkman, Jacobs, & Braun, 1988; Lind et al., 1993), or no specific effects (Antonelli Incalzi et al., 1997; Boeke, 1981; Bossema et al., 2007; Casey, Ferguson, Kimura, & Hachinski, 1989; Van den Burg et al., 1985). These studies, however, were focused on the effect of improved postoperative blood flow, leaving the question of whether there are cognitive differences prior to intervention unanswered.

The aim of the current study was to determine whether patients with severe stenosis of the carotid artery but without significant cerebrovascular symptoms (stroke) and without dementia, who would undergo TEA, have worse cognitive functioning than healthy participants. Thus, we selected a sample of patients with severe carotid stenosis without dementia and matched them one by one according to age, sex, and education with a sample of healthy control participants with no dementia and no vascular risk factors. The main objective was to describe which cognitive functions were impaired and whether there were cognitive differences based on the severity of the stenosis, the side that was to be operated on right internal carotid artery (RICA) or left internal carotid artery (LICA), the presence of neurological symptoms (TIA), and the role played by vascular risk factors. Our hypothesis was that patients with a high degree of carotid stenosis, who have not yet been operated on, would have worse cognitive functioning than healthy participants.

Methods

Participants

One hundred and six participants, including 53 patients with carotid stenosis and 53 healthy controls, were recruited to participate in this cross-sectional study. All 53 patients had carotid stenosis in one or both carotid arteries. The patients were assessed by the Doppler ultrasound of the carotid bifurcation and magnetic resonance angiography of the supraaortic branches (TSA). Patients were recruited among those eligible for TEA in the “Hospital Universitari Mutua Terrassa” in Terrassa, Spain, between September 2004 and December 2008. The degree of stenosis was defined as mild (0%–50%), moderate (50%–70%), and severe (>70%) according to the criteria of the European Carotid Surgery Trial (ECST) by performing an angiography prior to surgery. All patients underwent a brain-imaging test (computed tomography [CT] and/or magnetic resonance imaging [MRI]). Patients who had suffered a stroke were excluded from the study. The patients were classified according to medical records as having had a TIA, non-hemispheric symptoms (dizzy spells, vertigo, or other symptoms typical of vertebro-basilar ischemia) or no symptoms at all. The stenosis was asymptomatic in 11 patients and symptomatic in 42; symptoms involved one episode of TIA in 20 participants and non-hemispheric symptoms in 22. The control group consisted of 53 healthy participants who were recruited among the companions of the patients in the Memory Unit of Hospital Universitari Mutua Terrassa. Each patient was paired with a healthy control participant of the same age, sex, education, and handedness (all were right-handed) to minimize the possible influence of the above-mentioned factors on cognition.

The exclusion criteria for both groups were as follows: severe sensory deficits (vision and hearing) and the current presence of psychiatric pathology according to Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition. Text revised criteria (American Psychiatric Association, 2000). To exclude the degree of cognitive impairment in dementia, we used the MMSE (Folstein, Folstein, & McHugh, 1975) with a cutoff score of 24. In the patient group, we excluded those who had suffered a stroke by conducting a neuroimaging test (CT and/or MRI). The presence or the absence of the following vascular risk factors was recorded via clinical interview: hypertension, dyslipidemia and diabetes mellitus. Interviews performed in the control group ruled out cerebrovascular disease or any other neurological, psychiatric, or metabolic disease and confirmed the absence of the vascular risk factors mentioned above that may influence cognitive function.

To analyze whether there were cognitive differences based on the severity of the stenosis, the patient group was subdivided into three groups. To make this subdivision, the type of stenosis in both carotid arteries was taken into account and classified as moderate stenosis (when one of the carotids had a moderate stenosis and the other a mild stenosis), high stenosis (presenting moderate stenosis in one carotid and severe stenosis in the other), or severe stenosis (when both carotids had severe stenosis). To examine the cognitive differences within the patient group according to the side that would be operated on, the group was divided into RICA and LICA. To study the cognitive differences of the group of patients according to the presence or the absence of neurological symptoms (TIA), the group of patients was subdivided into two groups, depending on whether they were asymptomatic or symptomatic.

The research protocol was performed in accordance with the Review Board and Ethics Committee (CEIC) of the Hospital Universitari Mutua Terrassa. The participants were asked to authorize the use of general information recorded in the data collection workbook (CRD), which excluded their personal information.

Neuropsychological assessment

The patients were assessed 1 week before TEA in the neurology unit. At the beginning of the session, all patients and healthy controls were informed about the nature of the study and the type of assessment they would be given. The battery of neuropsychological tests was administered by an experienced neuropsychologist (LCH) and a research psychologist (NCM) trained to carry out the assessment and correction of these tests. The examiners were blinded to the status of the participants.

The cognitive assessment was performed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), created in 1993 by Christopher Randolph (Randolph, Tierney, Mohr, & Chase, 1998) and adapted for Spanish-speaking population (Muntal et al., 2011). The RBANS is a brief, individually administered screening test battery measuring several cognitive domains. It consists of 12 subtests, which yield five index scores—Immediate Memory (composed of List Learning and Story Memory subtests), Visuospatial–Constructional (composed of Figure Copy and Line Orientation subtests), Language (composed of the Picture Naming and Semantic Fluency subtests), Attention (composed of Digit Span and Coding subtests), and Delayed Memory (composed of List Recall, List Recognition, Story Recall, and Figure Recall subtests).

The item scores are raw scores recorded during the test of RBANS. The domain scores are converted from the item scores using conversion tables in the RBANS manual. The total score is converted from the sum of index scores using the appropriate table in the RBANS manual. For additional details, refer to the RBANS manual (Randolph, 1998).

Statistical analysis

Quantitative variables are expressed as the mean (M) and standard deviation (SD) or median and range. To begin testing the primary aims of the paper, the inferential analysis was made using the Student's t-test for quantitative variables. When the qualitative variable had more than two categories, one-way analysis of variance with Sheffé's contrast was used to compare scores from the groups on the five indices and 12 subtests of the RBANS. We developed a multiple linear regression model using the Enter method to analyze the relationship between the total score of the RBANS scale and the five indices as the dependents variables and the predictors (age, education, sex, vascular risk factors, degree of stenosis, neurological symptoms) as the independent variables. We performed a χ2 tests to investigate the possible association between stenosis (moderate, high, and severe) and vascular risk factors. For all tests, by the Bonferroni correction for multiple analyzes, we calculated an initial p-value of .009 to maintain statistical significance at .05. Statistical analysis of the data was performed using SPSS version 17. Additionally, we calculated the effect size (Cohen, 1988) to measure the magnitude of the differences found. The following cutoff (Aharon-Peretz et al., 2003) scores were applied: 1.10 to <1.45, very large effect; 0.75 to <1.10, large effect; 0.40 to <0.75, medium effect; 0.15 to <0.40, small effect.

To provide information about the level of impairment in the patient group, we calculated the percentage of participants whose performance fell 1 SD (represent the lower end of normal), 1.5 SD (Mild Cognitive Impairment; Petersen et al., 2001), and 2 SD (clearly fall into the impaired range) below the control group.

Results

The study consisted of 106 participants: Fifty-three patients with carotid stenosis awaiting surgery by endarterectomy and 53 healthy participants, matched one-to-one based on age, sex, education, and handedness (Table 1). The MMSE used as an inclusion criteria to exclude cognitive impairment in the degree of dementia showed significant differences between the patients group (M: 27.73, SD: 1.88) and the control group (M: 28.60 SD: 1.37). The results were within the normal range for both groups, but the control group scored significantly better than the group of patients. The clinical characteristics of the group of patients with stenosis are listed in Table 2.

Table 1.

Characteristics of the 106 participants at time of enrollment

 Patients (n = 53) Controls (n = 53) p-value 
Age (M [SD]) 70.25 (9.12) 70.70 (9.26)  
Men 39 (73%) 39 (73%)  
Women 14 (27%) 14 (27%)  
Educational level 6.62 (4.05) 6.89 (3.84)  
Handedness 
 Right-handedness 53 (100%) 53 (100%)  
MMSE 27.73 (1.88) 28.60 (1.37) .008 
 Patients (n = 53) Controls (n = 53) p-value 
Age (M [SD]) 70.25 (9.12) 70.70 (9.26)  
Men 39 (73%) 39 (73%)  
Women 14 (27%) 14 (27%)  
Educational level 6.62 (4.05) 6.89 (3.84)  
Handedness 
 Right-handedness 53 (100%) 53 (100%)  
MMSE 27.73 (1.88) 28.60 (1.37) .008 

Notes: Age is in years. Education level is in years. M = mean; SD = standard deviation; MMSE = Mini-Mental State Examination.

Table 2.

Clinical characteristics of patients with carotid stenosis

 Patients (n = 53) 
Side scheduled for surgery 
 RICA 25 (47.2%) 
 LICA 28 (52.8%) 
Symptoms 
 Asymptomatic 33 (62.3%) 
 Symptomatic 20 (37.7%) 
Right-sided stenosis severity 
 Mild 9 (17.0%) 
 Moderate 11 (20.8%) 
 Severe 33 (62.3%) 
Left stenosis severity 
 Mild 5 (9.4%) 
 Moderate 10 (18.9%) 
 Severe 38 (71.7%) 
Total stenosis severity 
 Moderate 14 (26.4%) 
 High 21 (39.6%) 
 Severe 18 (34.0%) 
Vascular risk factors 
 Hypertension 38 (71.5%) 
 Diabetes Mellitus 22 (41.5%) 
 Dyslipemia 23 (43.4%) 
 Patients (n = 53) 
Side scheduled for surgery 
 RICA 25 (47.2%) 
 LICA 28 (52.8%) 
Symptoms 
 Asymptomatic 33 (62.3%) 
 Symptomatic 20 (37.7%) 
Right-sided stenosis severity 
 Mild 9 (17.0%) 
 Moderate 11 (20.8%) 
 Severe 33 (62.3%) 
Left stenosis severity 
 Mild 5 (9.4%) 
 Moderate 10 (18.9%) 
 Severe 38 (71.7%) 
Total stenosis severity 
 Moderate 14 (26.4%) 
 High 21 (39.6%) 
 Severe 18 (34.0%) 
Vascular risk factors 
 Hypertension 38 (71.5%) 
 Diabetes Mellitus 22 (41.5%) 
 Dyslipemia 23 (43.4%) 

Notes: RICA = Right Internal Carotid Artery; LICA = Left Internal Carotid Artery; Asymptomatic = no hemispheric symptoms or no symptoms at all; Symptomatic = TIA. Mild stenosis severity (0%–50%), moderate stenosis severity (50%–70%), and severe stenosis severity (+70%); total stenosis in both carotid: Moderate (mild and moderate stenosis), high (moderate and severe stenosis), and severe (severe and severe stenosis).

Neuropsychological assessment with RBANS revealed that patients with carotid stenosis achieved a lower RBANS performance in the raw scores for List Learning (Immediate Recall), Figure Copy and Line Orientation (Visuospatial–Constructional), Semantic Fluency (Language), and Coding (attention and speed of information processing scores). The five indices of the tests, the sum of these values, and the total scale score also showed significant differences. In all of these cases, the patients had a lower performance than the control group (Table 3). The most significant differences between the groups was found in the Visuospatial–Constructional index (d = 0.94, p < .001).

Table 3.

RBANS descriptive data for patients and controls

Domain Subtest Range Patients (n = 53) Controls (n = 53) p-value d-value 
IM  40–152 75.43 (14.48) 86.77 (11.63) .000 0.87 
 List Learning 0–40 19.68 (5.21) 23.91 (4.59) .000 0.87 
 Story Memory 0–24 11.75 (4.19) 12.91 (3.52) .129 0.30 
VC  50–136 101.98 (19.03) 116.35 (10.68) .000 0.94 
 Figure Copy 0–20 18.47 (2.29) 19.68 (0.77) .001 0.72 
 Line Orientation 0–20 15.83 (3.12) 17.60 (1.89) .001 0.69 
LA  40–137 91.11 (10.57) 95.64 (5.92) .008 0.53 
 Picture Naming 0–10 9.75 (0.55) 9.89 (0.32) .135 0.31 
 Semantic Fluency 0–40 15.26 (5.35) 16.96 (3.15) .050 0.39 
AT  40–154 68.98 (16.96) 76.32 (16.12) .004 0.45 
 Digit Span 0–16 7.51 (1.87) 8.04 (2.17) .184 0.26 
 Coding 0–89 21.53 (12.40) 26.94 (11.60) .025 0.45 
DM  40–137 80.49 (19.34) 89.11 (13.78) .010 0.52 
 List Recall 0–10 2.94 (2.54) 3.77 (2.39) .087 0.34 
 List Recognition 0–20 16.92 (2.18) 17.55 (2.24) .150 0.29 
 Story Recall 0–12 5.58 (3.64) 6.64 (2.29) .077 0.35 
 Figure Recall 0–20 12.09 (5.08) 13.47 (3.87) .120 0.31 
SI  200–800 416.00 (59.96) 464.20 (37.78) .000 0.97 
TS  40–160 78.71 (14.62) 90.00 (9.46) .000 0.92 
Domain Subtest Range Patients (n = 53) Controls (n = 53) p-value d-value 
IM  40–152 75.43 (14.48) 86.77 (11.63) .000 0.87 
 List Learning 0–40 19.68 (5.21) 23.91 (4.59) .000 0.87 
 Story Memory 0–24 11.75 (4.19) 12.91 (3.52) .129 0.30 
VC  50–136 101.98 (19.03) 116.35 (10.68) .000 0.94 
 Figure Copy 0–20 18.47 (2.29) 19.68 (0.77) .001 0.72 
 Line Orientation 0–20 15.83 (3.12) 17.60 (1.89) .001 0.69 
LA  40–137 91.11 (10.57) 95.64 (5.92) .008 0.53 
 Picture Naming 0–10 9.75 (0.55) 9.89 (0.32) .135 0.31 
 Semantic Fluency 0–40 15.26 (5.35) 16.96 (3.15) .050 0.39 
AT  40–154 68.98 (16.96) 76.32 (16.12) .004 0.45 
 Digit Span 0–16 7.51 (1.87) 8.04 (2.17) .184 0.26 
 Coding 0–89 21.53 (12.40) 26.94 (11.60) .025 0.45 
DM  40–137 80.49 (19.34) 89.11 (13.78) .010 0.52 
 List Recall 0–10 2.94 (2.54) 3.77 (2.39) .087 0.34 
 List Recognition 0–20 16.92 (2.18) 17.55 (2.24) .150 0.29 
 Story Recall 0–12 5.58 (3.64) 6.64 (2.29) .077 0.35 
 Figure Recall 0–20 12.09 (5.08) 13.47 (3.87) .120 0.31 
SI  200–800 416.00 (59.96) 464.20 (37.78) .000 0.97 
TS  40–160 78.71 (14.62) 90.00 (9.46) .000 0.92 

Notes: AT = Attention; DM = Delayed Memory; IM = Immediate Memory; LA = Language; SI = Sum of indices; TS = Total Scale; VC = Visuospatial–constructive. RBANS scores are raw scores. Data are expressed as means (M) and standard deviation (SD).

In a second analysis, the group of patients with carotid stenosis (irrespective of the side of operation) was divided according to the degree of total stenosis presented in both carotid arteries. No differences regarding age, sex, and education were reported when performing this analysis. Significant differences were observed when comparing patients according to the level of stenosis: Poorer RBANS performance was observed in List Learning and List Recall tasks in patients with severe stenosis in comparison with patients with mild stenosis (Table 4).

Table 4.

RBANS descriptive data for patients according to the severity of stenosis

Domain Subtest Moderate stenosis (n = 21) High stenosis (n = 14) Severe stenosis (n = 18) p-value 
IM  81.42 (13.37) 75.04 (15.56) 71.22 (13.10) .140 
 List Learning 22.57 (4.87) 19.33 (4.12) 17.83 (5.86) .033 
 Story Memory 12.64 (3.65) 12.33 (4.23) 10.39 (4.42) .234 
VC  108.21 (18.09) 98.09 (19.19) 101.66 (19.32) .310 
 Figure Copy 19.21 (1.05) 18.24 (2.46) 18.17 (2.72) .374 
 Line Orientation 15.71 (4.17) 15.71 (2.72) 16.06 (2.77) .934 
LA  95.07 (11.19) 90.76 (7.99) 88.44 (12.26) .212 
 Picture Naming 10.00 (0.00) 9.71 (0.56) 9.61 (0.69) .128 
 Semantic Fluency 17.07 (5.91) 15.29 (4.26) 13.83 (5,88) .240 
AT  70.28 (18.61) 68.33 (17.47) 62.83 (15.04) .427 
 Digit Span 7.57 (2.06) 7.90 (2.09) 7.00 (1.37) .327 
 Coding 23.00 (12.14) 23.37 (13.03) 18.06 (11.89) .402 
DM  89.57 (21.41) 80,04 (16.53) 73.94 (18.93) .073 
 List Recall 4.43 (2.92) 2.62 (2.26) 2.17 (2.14) .030 
 List Recognition 17.71 (2.23) 16.86 (2.17) 16.39 (2,09) .234 
 Story Recall 6.86 (3.54) 5.52 (2.92) 4.67 (4.31) .243 
 Figure Recall 12.57 (5.86) 12.81 (4.85) 10.89 (4.75) .469 
SI  444.57 (57.65) 412.28 (59.92) 398.11 (56.60) .086 
TE  85.50 (14.62) 77.38 (14.52) 75.00 (13.70) .113 
Domain Subtest Moderate stenosis (n = 21) High stenosis (n = 14) Severe stenosis (n = 18) p-value 
IM  81.42 (13.37) 75.04 (15.56) 71.22 (13.10) .140 
 List Learning 22.57 (4.87) 19.33 (4.12) 17.83 (5.86) .033 
 Story Memory 12.64 (3.65) 12.33 (4.23) 10.39 (4.42) .234 
VC  108.21 (18.09) 98.09 (19.19) 101.66 (19.32) .310 
 Figure Copy 19.21 (1.05) 18.24 (2.46) 18.17 (2.72) .374 
 Line Orientation 15.71 (4.17) 15.71 (2.72) 16.06 (2.77) .934 
LA  95.07 (11.19) 90.76 (7.99) 88.44 (12.26) .212 
 Picture Naming 10.00 (0.00) 9.71 (0.56) 9.61 (0.69) .128 
 Semantic Fluency 17.07 (5.91) 15.29 (4.26) 13.83 (5,88) .240 
AT  70.28 (18.61) 68.33 (17.47) 62.83 (15.04) .427 
 Digit Span 7.57 (2.06) 7.90 (2.09) 7.00 (1.37) .327 
 Coding 23.00 (12.14) 23.37 (13.03) 18.06 (11.89) .402 
DM  89.57 (21.41) 80,04 (16.53) 73.94 (18.93) .073 
 List Recall 4.43 (2.92) 2.62 (2.26) 2.17 (2.14) .030 
 List Recognition 17.71 (2.23) 16.86 (2.17) 16.39 (2,09) .234 
 Story Recall 6.86 (3.54) 5.52 (2.92) 4.67 (4.31) .243 
 Figure Recall 12.57 (5.86) 12.81 (4.85) 10.89 (4.75) .469 
SI  444.57 (57.65) 412.28 (59.92) 398.11 (56.60) .086 
TE  85.50 (14.62) 77.38 (14.52) 75.00 (13.70) .113 

Notes: AT = Attention; DM = Delayed Memory; IM = Immediate Memory; LA = Language; SI = Sum of indices; TS = Total Scale; VC = Visuospatial–constructive. RBANS scores are raw scores. Data are expressed as means (M) and standard deviation (SD). Total stenosis in both carotid: Moderate (mild and moderate stenosis), high (moderate and severe stenosis), and severe (severe and severe stenosis).

When the TEA patient group was divided into the RICA (47.2%) and LICA (52.8%) groups by the degree of stenosis in each carotid and the presence of neurological symptoms, no differences in the variables of age, sex, and education were observed between groups. Also, no significant differences were observed on RBANS performance (Table 5).

Table 5.

RBANS descriptive data for RICA, LICA, and Controls

Domain Subtest RICA (n = 25) LICA (n = 28) Controls (n = 53) RICA versus LICA
 
RICA versus Controls
 
LICA versus Controls
 
p-value d-value p-value d-value p-value d-value 
IM  77.52 (14.26) 73.57 (14.68) 86.77 (11.63) .327 0.28 .003 0.75 .000 1.05 
 List Learning 20.64 (4.85) 18.82 (5.46) 23.91 (4.59) .208 0.36 .005 0.71 .000 1.05 
 Story Memory 12.12 (4.11) 11.43 (4.31) 12.91 (3.52) .554 0.17 .387 0.22 .101 0.39 
VC  104.40 (19.36) 99.82 (18.81) 116.35 (10.68) .387 0.24 .007 0.86 .000 1.2 
 Figure Copy 18.80 (2.12) 18.18 (2.43) 19.68 (0.77) .329 0.28 .055 0.66 .003 0.98 
 Line Orientation 15.92 (3.45) 15.75 (2.86) 17.60 (1.89) .845 0.05 .029 0.68 .004 0.83 
LA  93.44 (13.72) 89.03 (6.20) 95.64 (5.92) .150 0.43 .448 0.24 .000 1.7 
 Picture Naming 9.72 (0.61) 9.79 (0.49) 9.89 (0.32) .669 0.13 .210 0.40 .337 0.26 
 Semantic Fluency 16.76 (6.43) 13.93 (3.80) 16.96 (3.15) .054 0.55 .883 0.01 .000 0.91 
AT  68.04 (19.40) 66.03 (14.74) 76.32 (16.12) .672 0.12 .051 0.49 .006 0.67 
 Digit Span 7.60 (2.00) 7.43 (1.79) 8.04 (2.17) .743 0.09 .398 0.21 .208 0.3 
 Coding 24.00 (13.90) 19.68 (11.04) 26.94 (11.60) .231 0.35 .356 0.24 .008 0.64 
DM  82.36 (20.45) 78.82 (18.50) 89.11 (13.78) .511 0.19 .143 0.42 .006 0.67 
 List Recall 2.52 (2.55) 3.32 (2.52) 3.77 (2.39) .256 0.32 .038 0.52 .431 0.19 
 List Recognition 17.16 (2.11) 16.71 (2.25) 17.55 (2.24) .463 0.21 .471 0.18 .117 0.38 
 Story Recall 5.08 (3.06) 6.04 (4.08) 6.64 (2.29) .345 0.27 .014 0.62 .472 0.2 
 Figure Recall 12.84 (4.81) 11.43 (5.30) 13.47 (3.87) .317 0.28 .537 0.15 .051 0.47 
SI  425.76 (67.38) 407.28 (52.18) 464.20 (37.78) ,267 0.31 .012 0.79 .000 1.33 
TS  80.72 (16.90) 76.92 (12.27) 90.00 (9.46) .360 0.26 .015 0.76 .000 1.26 
Domain Subtest RICA (n = 25) LICA (n = 28) Controls (n = 53) RICA versus LICA
 
RICA versus Controls
 
LICA versus Controls
 
p-value d-value p-value d-value p-value d-value 
IM  77.52 (14.26) 73.57 (14.68) 86.77 (11.63) .327 0.28 .003 0.75 .000 1.05 
 List Learning 20.64 (4.85) 18.82 (5.46) 23.91 (4.59) .208 0.36 .005 0.71 .000 1.05 
 Story Memory 12.12 (4.11) 11.43 (4.31) 12.91 (3.52) .554 0.17 .387 0.22 .101 0.39 
VC  104.40 (19.36) 99.82 (18.81) 116.35 (10.68) .387 0.24 .007 0.86 .000 1.2 
 Figure Copy 18.80 (2.12) 18.18 (2.43) 19.68 (0.77) .329 0.28 .055 0.66 .003 0.98 
 Line Orientation 15.92 (3.45) 15.75 (2.86) 17.60 (1.89) .845 0.05 .029 0.68 .004 0.83 
LA  93.44 (13.72) 89.03 (6.20) 95.64 (5.92) .150 0.43 .448 0.24 .000 1.7 
 Picture Naming 9.72 (0.61) 9.79 (0.49) 9.89 (0.32) .669 0.13 .210 0.40 .337 0.26 
 Semantic Fluency 16.76 (6.43) 13.93 (3.80) 16.96 (3.15) .054 0.55 .883 0.01 .000 0.91 
AT  68.04 (19.40) 66.03 (14.74) 76.32 (16.12) .672 0.12 .051 0.49 .006 0.67 
 Digit Span 7.60 (2.00) 7.43 (1.79) 8.04 (2.17) .743 0.09 .398 0.21 .208 0.3 
 Coding 24.00 (13.90) 19.68 (11.04) 26.94 (11.60) .231 0.35 .356 0.24 .008 0.64 
DM  82.36 (20.45) 78.82 (18.50) 89.11 (13.78) .511 0.19 .143 0.42 .006 0.67 
 List Recall 2.52 (2.55) 3.32 (2.52) 3.77 (2.39) .256 0.32 .038 0.52 .431 0.19 
 List Recognition 17.16 (2.11) 16.71 (2.25) 17.55 (2.24) .463 0.21 .471 0.18 .117 0.38 
 Story Recall 5.08 (3.06) 6.04 (4.08) 6.64 (2.29) .345 0.27 .014 0.62 .472 0.2 
 Figure Recall 12.84 (4.81) 11.43 (5.30) 13.47 (3.87) .317 0.28 .537 0.15 .051 0.47 
SI  425.76 (67.38) 407.28 (52.18) 464.20 (37.78) ,267 0.31 .012 0.79 .000 1.33 
TS  80.72 (16.90) 76.92 (12.27) 90.00 (9.46) .360 0.26 .015 0.76 .000 1.26 

Notes: RICA = Right Internal Carotid Artery; LICA = Left Internal Carotid Artery; AT = Attention; DM = Delayed Memory; IM = Immediate Memory; LA = Language; SI = Sum of indices; TS = Total Scale; VC = Visuospatial–constructive. RBANS scores are raw scores. Data are expressed as means (M) and standard deviation (SD).

However, when comparing the performance of each of the subgroups with the control group, there were indeed significant differences. When comparing the right carotid stenosis in the patients (RICA) group with healthy participants, the patients showed greater deficits in immediate and delayed memory (List Learning and Story Recall) and Line Orientation, for the Immediate Memory index, Visuospatial–Constructional index, sum of indices, and the Total Scale score (Table 5). Of the significant differences between patient groups, the greatest effect was on the Visuospatial–Constructional index (d = 0.86, p = .007). In contrast, when comparing the control group with the left carotid stenosis (LICA) group, we found that the latter showed lower scores in a greater number of areas: List Learning, Figure Copy, Line Orientation, Semantic Fluency, Coding, and all the indices that make up the scale (Immediate Memory, Visuospatial–Constructional, Language, Attention, and Delayed Recall) as well as the sum of the indices and the Total Scale (Table 5). The largest effect was seen for the sum of the indices (d = 1.33, p < .001).

When preoperative scores (left- and right-sided patients separated) were compared with the mean of the control group, the comparisons revealed that 40% of the RICA group performed 1.5 SD below the mean. The Visuospatial–Constructional index and the Immediate Memory index had the highest percentage of participants with scores <1.5 SD below the mean for the RICA group (32%). On the other hand in the LICA group, 42.9% of the participants performed 1.5 SD below the mean of the control group, and 53.6% performed 1 SD below the mean. The Visuospatial–Constructional index had the highest percentage of participants with scores <1.5 SD below the mean for the LICA group (Table 6).

Table 6.

Percentage of RICA and LICA patients below the control group

 SD IM (%) VC (%) LA (%) AT (%) DM (%) TS (%) 
RICA 32 44 28 44 32 52 
 1.5 32 32 20 24 24 40 
 20 28 16 24 32 
LICA 39.3 60 42.9 46.4 39.3 53.6 
 1.5 39.3 50 35.7 10.7 17.9 42.9 
 25 50 14.3 10.7 23.2 
 SD IM (%) VC (%) LA (%) AT (%) DM (%) TS (%) 
RICA 32 44 28 44 32 52 
 1.5 32 32 20 24 24 40 
 20 28 16 24 32 
LICA 39.3 60 42.9 46.4 39.3 53.6 
 1.5 39.3 50 35.7 10.7 17.9 42.9 
 25 50 14.3 10.7 23.2 

Notes: RICA = Right Internal Carotid Artery; LICA = Left Internal Carotid Artery; AT = Attention; DM = Delayed Memory; IM = Immediate Memory; LA = Language; TS = Total Scale; VC = Visuospatial–constructive. SD = standard deviation; data are expressed as percentages below the normative data.

No significant differences in age, sex, or education were found when comparing symptomatic and asymptomatic patients. Similarly, when comparing neuropsychological test scores, no significant differences in RBANS performance were found between the groups (Table 7). We also did not observe differences on RBANS performance when comparing patients with non-hemispheric symptoms with TIA patients, patients with non-hemispheric symptoms with asymptomatic patients, or TIA patients with asymptomatic patients.

Table 7.

RBANS descriptive data for asymptomatic and symptomatic patients

Domain Subtest Asymptomatic (n = 33) Symptomatic (n = 20) p-value d-value 
IM  74.39 (13.64) 77.15 (15.98) .507 0.19 
 List Learning 19.55 (4.65) 19.90 (6.15) .813 0.07 
 Story Memory 11.33 (4.26) 12.45 (4.09) .353 0.27 
VC  104.15 (19.38) 98.40 (18.35) .291 0.31 
 Figure Copy 18.67 (2.11) 18.15 (2.58) .432 0.23 
 Line Orientation 16.12 (3.25) 15.35 (2.90) .389 0.25 
LA  90.66 (8.72) 91.85 (13.30) .697 0.11 
 Picture Naming 9.82 (0.46) 9.65 (0.67) .332 0.32 
 Semantic Fluency 14.67 (4.82) 16.25 (6.12) .301 0.30 
AT  70.33 (16.76) 61.45 (16.18) .064 0.55 
 Digit Span 7.73 (1.73) 7.15 (2.08) .282 0.32 
 Coding 22.72 (13.58) 19.29 (9.78) .316 0.28 
DM  77.54 (18.50) 83.35 (20.17) .156 0.31 
 List Recall 2.76 (2.15) 3.25 (3.12) .539 0.20 
 List Recognition 16.55 (2.22) 17.55 (2.01) .105 0.48 
 Story Recall 5.27 (4.04) 6.10 (2.86) .428 0.23 
 Figure Recall 11.91 (5.35) 12.40 (4.70) .737 0.10 
SI  417.09 (61.51) 414.20 (58.85) .867 0.05 
TS  79.24 (14.95) 77.85 (14.39) .740 0.10 
Domain Subtest Asymptomatic (n = 33) Symptomatic (n = 20) p-value d-value 
IM  74.39 (13.64) 77.15 (15.98) .507 0.19 
 List Learning 19.55 (4.65) 19.90 (6.15) .813 0.07 
 Story Memory 11.33 (4.26) 12.45 (4.09) .353 0.27 
VC  104.15 (19.38) 98.40 (18.35) .291 0.31 
 Figure Copy 18.67 (2.11) 18.15 (2.58) .432 0.23 
 Line Orientation 16.12 (3.25) 15.35 (2.90) .389 0.25 
LA  90.66 (8.72) 91.85 (13.30) .697 0.11 
 Picture Naming 9.82 (0.46) 9.65 (0.67) .332 0.32 
 Semantic Fluency 14.67 (4.82) 16.25 (6.12) .301 0.30 
AT  70.33 (16.76) 61.45 (16.18) .064 0.55 
 Digit Span 7.73 (1.73) 7.15 (2.08) .282 0.32 
 Coding 22.72 (13.58) 19.29 (9.78) .316 0.28 
DM  77.54 (18.50) 83.35 (20.17) .156 0.31 
 List Recall 2.76 (2.15) 3.25 (3.12) .539 0.20 
 List Recognition 16.55 (2.22) 17.55 (2.01) .105 0.48 
 Story Recall 5.27 (4.04) 6.10 (2.86) .428 0.23 
 Figure Recall 11.91 (5.35) 12.40 (4.70) .737 0.10 
SI  417.09 (61.51) 414.20 (58.85) .867 0.05 
TS  79.24 (14.95) 77.85 (14.39) .740 0.10 

Notes: Asymptomatic = no hemispheric symptoms or no symptoms at all; Symptomatic = transient ischemic attack (TIA); AT = Attention; DM = Delayed Memory; IM = Immediate; Memory; LA = Language; SI = Sum of indices; TS = Total Scale; VC = Visuospatial constructive. RBANS scores are raw scores. Data are expressed as means (M) and standard deviation (SD).

In a subsequent analysis, no demographic differences among the subgroups of patients with carotid stenosis were found when considering the effect of the vascular risk factors on RBANS performance. There was indeed a poorer performance in picture naming in patients with hypertension (M: 9.66, SD: 0.62; d = 0.65, p = .002) compared with those without hypertension (M: 10, SD: 0.00) and a reduced Story Recall in patients with dyslipidemia (M: 10.26; SD: 4.46; d = 0.67, p = .022) compared with non-dyslipidemic individuals (M: 12.26, SD: 3.65). However, there were no significant differences in cognition between patients with diabetes mellitus and those without this pathology. When a χ2-test was performed to investigate the possible association between stenosis (moderate, high, and severe) and vascular risk factors, no significant results were obtained.

Finally, in the multiple linear regression analysis applied to study, the relationship between the dependent variables (RBANS Total Scale and the five indices) and the hypothesized predictors or adjustment variables (age, education, sex, vascular risk factors, degree of stenosis, or neurological symptoms), only education reached statistical significance (r = .588, p < .01).

Discussion

The results of our study support the idea that patients with carotid stenosis, who are candidates for TEA and have no evidence of severe neurological damage, show a greater risk for cognitive impairment compared with healthy individuals with no vascular risk factors or cognitive impairments. In the carotid stenosis patient group to whom we administered a battery of neuropsychometric tests, we found that the affected cognitive areas were attention and speed of information processing, verbal memory, verbal fluency, and visuospatial–constructional function. These findings are in line with previous studies that found deficits before surgery in verbal and visual memory (Aharon-Peretz et al., 2003; Bossema, Brand, Moll, Ackerstaff, & van Doornen, 2005; Gaunt et al., 1994; Hamster & Diener, 1984), attention (Aharon-Peretz et al., 2003; Bossema et al., 2005, 2006; Gaunt et al., 1994; Hamster & Diener, 1984), executive function (Aharon-Peretz et al., 2003; Bossema et al., 2005, 2006, 2007; Heyer et al., 2002), psychomotor skills (Bossema et al., 2005; Gaunt et al., 1994; Hamster & Diener, 1984; Heyer et al., 2002), and motor function and visuospatial function (Bossema, Brand, Moll, Ackerstaff, & van Doornen, 2007; Gaunt et al., 1994; Heyer et al., 2002).

In contrast to these results, no cognitive differences between patients with carotid stenosis and control participants were found in other studies (Aleksic et al., 2006; Heyer et al., 2008). The results of these studies may differ from ours due to the fact that there were no healthy individuals used as controls in their studies. The study by Aleksic and colleagues (2006) was conducted in patients with peripheral vascular disease, and the study by Heyer and colleagues (2008) used patients with coronary heart disease. A high degree of carotid disease in both of these types of patients have been demonstrated by several studies (Cheng, Wu, Ting, Lau, & Wong, 1999; Cinà, Safar, Maggisano, Bailey, & Clase, 2002; House et al., 1999; Pilcher, Danaher, & Khaw, 2000; Van den Burg et al., 1985), making these groups not ideal to be used as controls to assess the existing cognitive differences in samples of patients with carotid stenosis. Other studies (Iddon et al., 1997; Kishikawa et al., 2003) that found no preoperative differences between healthy control participants and carotid stenosis patients were carried out using only patients with unilateral, but not bilateral, stenosis, which contrasts with our sample consisting mainly of patients with stenosis in both carotid arteries. If we consider that these patients had no contralateral carotid stenosis, we could ascribe the results to vascular compensatory mechanisms. Because this has not been confirmed, one way to address this would be to conduct an arteriographic study in both carotids to provide as much useful information about the stenosis and the degree of obstruction as possible. It is important to note that most of the studies on cognition and carotid stenosis have focused on the effect that the surgical operation has on cognitive performance, and their description of cognition before the operation is indirect and simplistic. One of the contributions of our study is that it aimed to investigate the cognitive status of stenosis patients, candidates to TEA, before the operation.

Regarding the importance of the degree of stenosis, we have found that cognitive impairment is related to the severity of the stenosis; similar to a study by Bossema and colleagues (2006), a worse performance was observed for list learning and recalling in patients with a severe degree of stenosis (+70%). In connection with this finding, there are previous studies that refer to the importance of stenosis severity in the cognitive outcome after surgery. These papers claim to find a greater cognitive improvement in memory tasks in patients with a high degree of stenosis (Jacobs, Ganji, Shirley, Morrell, & Brinkman, 1983; Owens et al., 1980). However, another study (Diener, Hamster, & Seboldt, 1984) performed in the same decade found no such relationship. The relation between stenosis severity and cognition is complex. In our study, we expected to observe a greater level of deterioration in many cognitive areas in patients with severe stenosis. However, only verbal mnesic function, short and long term, was affected by severe stenosis. As in the studies using different control groups, the methodological differences in sample selection may be the cause of the heterogeneity of the results. Having a larger and more homogeneous sample while controlling for confounding factors (contralateral stenosis, neurological symptoms, and vascular risk factors) might have provided more consistent results.

We expected the degree of cognitive impairment to be greater in patients with neurological symptoms (TIA), but these differences were not revealed in the results, and the cognitive state of the two groups of patients was similar to what was previously found (Bo et al., 2006; Fearn et al., 2003; Hamster & Diener, 1984; Heyer et al., 2006; Mononen et al., 1990; Soinne et al., 2009). Moreover, in a study of a subgroup of patients with reticular pathology, Bossema and colleagues (2006) found that patients with hemispheric pathology and asymptomatic patients, including patients who had previously undergone carotid surgery, had cognitive differences, but only in 3 of the 17 subtests studied (digit span, visual recognition, and verbal fluency). Thus, the authors concluded that these results did not support the distinction of subclinical groups according to symptoms (stroke) (Bossema et al., 2006). We should also note that in Bossema's study, the subgroup of asymptomatic patients had better cognitive scores in some of the subtests than the healthy control participants. As discussed in our introduction, this study provides the groundwork for further investigations, as there is another group of studies that did find preoperative cognitive differences, depending on the presence of neurological disease (Brand et al., 2004; Heyer et al., 2002; Pearson, Maddern, & Fitridge, 2003; Rao et al., 1999). It is possible that the data overlooked in these studies, that is, the territory impaired, neurological sequel present, the time span between the onset of symptoms and cognitive assessment among others, could help explain the variability in these findings. Therefore, the best approach would be to carry out a comprehensive study of asymptomatic and symptomatic patients with minor symptoms (TIA and non-hemispheric symptoms) and include patients with stroke in a second phase because of its greater complexity. Regarding the relevance of neurological symptomatology, our findings confirm the importance of regular assessment of the cognitive status of patients with carotid stenosis, as the presence or the absence of neurological symptomatology (AIT) did not influence cognitive performance.

In analyzing the importance of laterality in cognition, the neuropsychological data we obtained showed no significant differences between the RICA and LICA groups, consistent with previous works (Antonelli Incalzi et al., 1997; Bo et al., 2006; Bossema et al., 2006). Also consistent with the literature, we found greater impairment in the subsample of LICA patients compared with the control group especially when the cutoff is set to 1 SD (Desmond, Moroney, Sano, & Stern, 2002; Lin et al., 2003; Román et al., 1993). Therefore, our current study, which assesses preoperative cognitive functions and the differences between the RICA and LICA groups (in contrast to most studies which have focused on its effects after CEA), provides relevant data on the effect of carotid stenosis on cognition. Information on the degree of stenosis and neurological symptomatology, combined with data on cognitive performance on the affected side, could improve our understanding on the influence of left carotid stenosis on pre-surgery stroke risk (Rothwell, Slattery, & Warlow, 1997).

According to the literature, a possible cause of cognitive impairment in patients with stenosis may be the presence of silent infarcts, white matter lesions (De Groot et al., 2002; Gunning-Dixon & Raz, 2000; Mungas et al., 2002; Sabri et al., 1999), or arteriosclerotic narrowing or blockage in the vertebrobasilar arterial network (Dull et al., 1982). These factors were not evaluated in our study, and therefore, their relationship with the deterioration remains to be demonstrated. However, we omitted patients with cerebrovascular lesions of large caliber. Other authors who studied cognitive impairment in patients with carotid stenosis also considered the possibility that blood redistribution, which according to Vriens and colleagues (2001) takes place in the circle of Willis, may be acting even before surgery by improving and compensating for the difference in blood velocity between stenotic and non-stenotic carotids.

The role played by vascular risk factors in cognitive impairment has been acknowledged (Biessels & Kappelle, 2005 for review; Qiu, Winblad, & Fratiglioni, 2005; Whitmer, Sidney, Selby, Johnston, & Yaffe, 2005). These factors' association with stroke and carotid stenosis complicates matters further (Biessels, Staekenborg, Brunner, Brayne, & Scheltens, 2006; Whitmer et al., 2005). Regarding the set of vascular risk factors evaluated in our study, we encountered major difficulties in the learning capacity of the group of patients with dyslipidemia. These results are consistent with a study by the Teunissen group (Teunissen et al., 2003) that showed a negative relationship between precursor levels of cholesterol and memory tests. The group of patients in the sample with hypertension performed the most poorly in picture naming. This finding has not been specifically described in previous studies but has been implied in those describing the presence of a non-amnesic type of cognitive impairment (Obisesan et al., 2008; Reitz, Tang, Manly, Mayeux, & Luchsinger, 2007; van den Berg, Kloppenborg, Kessels, Kappelle, & Biessels, 2009). Unlike other vascular risk factors, diabetic patients with carotid disease did not show any difference in cognitive performance compared with non-diabetic individuals. These results differ from those obtained in studies that specifically analyzed diabetic participants without carotid disease (Bruehl et al., 2007; Kumar, Anstey, Cherbuin, Wen, & Sachdev, 2008; Van den Berg et al., 2009). In general, our data support that some vascular risk factors play a role in the cognition of patients with carotid stenosis. This contribution awaits further investigation with a larger control population.

This study presents some limitations. First, one of the major limitations of our study is the sample size; with a larger size, different subgroups of patients could have been obtained (symptomatic, asymptomatic, or non-hemispheric symptoms), allowing for a better analysis of the differences between them. It would have also been helpful to explore whether patients without clinical symptoms suffered greater cognitive impairments than healthy participants with the same characteristics. Second, to improve the quality of the data found, we should have performed a carotid study on the participants in the control group and used MRI and/or diffusion tensor imaging to provide structural data on their brain state. The patient group had indeed undergone a brain-imaging test, but the data collected were minimal and only used to rule out stroke. The study could have been improved by analyzing these images thoroughly and extracting data to complement the quality of the results. Third, the control group was matched with the experimental group on demographic variables (sex, age, education, and handedness) but it was not matched by vascular risk factors (number of risk factors and time of exposure) and it would have been better to do it to explore the relationship between them. Finally, a cognitive assessment should be made on executive functions. In contrast, the neuropsychological battery used (for its brevity and simplicity of use) is a good tool to be used by other centers, which would allow for meaningful comparisons between working groups, and hence, improving the cognitive characterization of patients with carotid stenosis.

The number of people with carotid disease will continue to increase over time due to increased life expectancy. The group of patients with symptomatic or asymptomatic carotid stenosis should be given clearer information on how carotid stenosis affects their cognition and to what extent a surgery operation would improve their cognitive status and their quality of life.

In summary, the present data indicate that patients with severe carotid stenosis have a low pre-surgical cognitive status compared with a healthy population with the same sociodemographic characteristics, and that cognition is associated with the degree of carotid stenosis and vascular risk factors. Information on the cognitive status of stenosis patients may help to improve their treatment.

Funding

This study was supported by a grant from the Fundación Mutua Madrileña (http://www.fundacionmutua.es) Project: “Endarterectomia de la estenosis de carótida y cambios neuropsicológicos” ref 2724 February.

Conflict of Interest

None declared.

Acknowledgments

The authors thank Salvador Quintana for statistical consultation. We also thank Silvia Zaragoza for helpful support, Noemi Calzado for her rigorous assessment of participants, the Vascular Surgeons department and the research administration's team for the assistance in the study.

References

Aharon-Peretz
J.
Tomer
R.
Gabrieli
I.
Aharonov
D.
Nitecki
S.
Hoffman
A.
Cognitive performance following endarterectomy in asymptomatic severe carotid stenosis
European Journal of Neurology: The Official Journal of the European Federation of Neurological Societies
 , 
2003
, vol. 
10
 
5
(pg. 
525
-
528
)
Aleksic
M.
Huff
W.
Hoppmann
B.
Heckenkamp
J.
Pukrop
R.
Brunkwall
J.
Cognitive function remains unchanged after endarterectomy of unilateral internal carotid artery stenosis under local anaesthesia
European Journal of Vascular and Endovascular Surgery: The Official Journal of the European Society for Vascular Surgery
 , 
2006
, vol. 
31
 
6
(pg. 
616
-
621
)
American Psychiatric Association
Diagnostic and statistical manual of mental disorders (4th ed., text rev.)
 , 
2000
Washington, DC
Author
Antonelli Incalzi
R.
Gemma
A.
Landi
F.
Pagano
F.
Capparella
O.
Snider
F.
, et al.  . 
Neuropsychologic effects of carotid endarterectomy
Journal of Clinical and Experimental Neuropsychology
 , 
1997
, vol. 
19
 
6
(pg. 
785
-
794
)
Auperin
A.
Berr
C.
Bonithon-Kopp
C.
Touboul
P.-J.
Ruelland
I.
Ducimetiere
P.
, et al.  . 
Ultrasonographic assessment of carotid wall characteristics and cognitive functions in a community sample of 59- to 71-year-olds
Stroke
 , 
1996
, vol. 
27
 
8
(pg. 
1290
-
1295
)
Biessels
G. J.
Kappelle
L. J.
Utrecht Diabetic Encephalopathy Study Group. Increased risk of Alzheimer's disease in Type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology?
Biochemical Society Transactions
 , 
2005
, vol. 
33
 
Pt 5
(pg. 
1041
-
1044
)
Biessels
G. J.
Staekenborg
S.
Brunner
E.
Brayne
C.
Scheltens
P.
Risk of dementia in diabetes mellitus: A systematic review
Lancet Neurology
 , 
2006
, vol. 
5
 
1
(pg. 
64
-
74
)
Bo
M.
Massaia
M.
Speme
S.
Cappa
G.
Strumia
K.
Cerrato
P.
, et al.  . 
Risk of cognitive decline in older patients after carotid endarterectomy: An observational study
Journal of the American Geriatrics Society
 , 
2006
, vol. 
54
 
6
(pg. 
932
-
936
)
Boeke
S.
The effect of carotid endarterectomy on mental functioning
Clinical Neurology and Neurosurgery
 , 
1981
, vol. 
83
 
4
(pg. 
209
-
217
)
Bornstein
R. A.
Benoit
B. G.
Trites
R. L.
Neuropsychological changes following carotid endarterectomy
The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques
 , 
1981
, vol. 
8
 
2
(pg. 
127
-
132
)
Bossema
E.
Brand
N.
Moll
F.
Ackerstaff
R.
van Doornen
L.
Testing the laterality hypothesis after left or right carotid endarterectomy: No ipsilateral effects on neuropsychological functioning
Journal of Clinical and Experimental Neuropsychology
 , 
2007
, vol. 
29
 
5
(pg. 
505
-
513
)
Bossema
E. R.
Brand
N.
Moll
F. L.
Ackerstaff
R. G. A.
de Haan
E. H. F.
van Doornen
L. J. P.
Cognitive functions in carotid artery disease before endarterectomy
Journal of Clinical and Experimental Neuropsychology
 , 
2006
, vol. 
28
 
3
(pg. 
357
-
369
)
Bossema
E. R.
Brand
N.
Moll
F. L.
Ackerstaff
R. G. A.
van Doornen
L. J. P.
Does carotid endarterectomy improve cognitive functioning?
Journal of Vascular Surgery: Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
 , 
2005
, vol. 
41
 
5
(pg. 
775
-
781
discussion 781
Brand
N.
Bossema
E. R.
van Ommen Mv
M.
Moll
F. L.
Ackerstaff
R. G. A.
Left or right carotid endarterectomy in patients with atherosclerotic disease: Ipsilateral effects on cognition?
Brain and Cognition
 , 
2004
, vol. 
54
 
2
(pg. 
117
-
123
)
Bruehl
H.
Rueger
M.
Dziobek
I.
Sweat
V.
Tirsi
A.
Javier
E.
, et al.  . 
Hypothalamic-pituitary-adrenal axis dysregulation and memory impairments in type 2 diabetes
The Journal of Clinical Endocrinology and Metabolism
 , 
2007
, vol. 
92
 
7
(pg. 
2439
-
2445
)
Casey
J. E.
Ferguson
G. G.
Kimura
D.
Hachinski
V. C.
Neuropsychological improvement versus practice effect following unilateral carotid endarterectomy in patients without stroke
Journal of Clinical and Experimental Neuropsychology
 , 
1989
, vol. 
11
 
4
(pg. 
461
-
470
)
Cerhan
J. R.
Folsom
A. R.
Mortimer
J. A.
Shahar
E.
Knopman
D. S.
McGovern
P. G.
, et al.  . 
Correlates of cognitive function in middle-aged adults. Atherosclerosis Risk in Communities (ARIC) Study Investigators
Gerontology
 , 
1998
, vol. 
44
 
2
(pg. 
95
-
105
)
Cheng
S. W.
Wu
L. L.
Ting
A. C.
Lau
H.
Wong
J.
Screening for asymptomatic carotid stenosis in patients with peripheral vascular disease: A prospective study and risk factor analysis
Cardiovascular Surgery (London, England)
 , 
1999
, vol. 
7
 
3
(pg. 
303
-
309
)
Cinà
C. S.
Safar
H. A.
Maggisano
R.
Bailey
R.
Clase
C. M.
Prevalence and progression of internal carotid artery stenosis in patients with peripheral arterial occlusive disease
Journal of Vascular Surgery: Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
 , 
2002
, vol. 
36
 
1
(pg. 
75
-
82
)
Cohen
J.
Statistical power analysis for the behavioral sciences : Jacob Cohen
 , 
1988
2nd ed.
Hillsdale, NJ
Lawrence Erlbaum
 
9. printing. ed.
De Groot
J. C.
De Leeuw
F.-E.
Oudkerk
M.
Van Gijn
J.
Hofman
A.
Jolles
J.
, et al.  . 
Periventricular cerebral white matter lesions predict rate of cognitive decline
Annals of Neurology
 , 
2002
, vol. 
52
 
3
(pg. 
335
-
341
)
De Leo
D.
Serraiotto
L.
Pellegrini
C.
Magni
G.
Franceschi
L.
Deriu
G. P.
Outcome from carotid endarterectomy. Neuropsychological performances, depressive symptoms and quality of life: 8-month followup
International Journal of Psychiatry in Medicine
 , 
1987
, vol. 
17
 
4
(pg. 
317
-
325
)
De Rango
P.
Caso
V.
Leys
D.
Paciaroni
M.
Lenti
M.
Cao
P.
The role of carotid artery stenting and carotid endarterectomy in cognitive performance: A systematic review
Stroke: A Journal of Cerebral Circulation
 , 
2008
, vol. 
39
 
11
(pg. 
3116
-
3127
)
Desmond
D. W.
Moroney
J. T.
Sano
M.
Stern
Y.
Incidence of dementia after ischemic stroke: Results of a longitudinal study
Stroke: A Journal of Cerebral Circulation
 , 
2002
, vol. 
33
 
9
(pg. 
2254
-
2260
)
Diener
H. C.
Hamster
W.
Seboldt
H.
Neuropsychological functions after carotid endarterectomy
European Archives of Psychiatry and Neurological Sciences
 , 
1984
, vol. 
234
 
1
(pg. 
74
-
77
)
Dull
R. A.
Brown
G. G.
Adams
K. M.
Shatz
M. W.
Diaz
F. G.
Ausman
J. I.
Preoperative neurobehavioral impairment in cerebral revascularization candidates
Journal of Clinical Neuropsychology
 , 
1982
, vol. 
4
 
2
(pg. 
151
-
165
)
Fearn
S. J.
Hutchinson
S.
Riding
G.
Hill-Wilson
G.
Wesnes
K.
McCollum
C. N.
Carotid endarterectomy improves cognitive function in patients with exhausted cerebrovascular reserve
European Journal of Vascular and Endovascular Surgery: The Official Journal of the European Society for Vascular Surgery
 , 
2003
, vol. 
26
 
5
(pg. 
529
-
536
)
Folstein
M. F.
Folstein
S. E.
McHugh
P. R.
«Mini-mental state». A practical method for grading the cognitive state of patients for the clinician
Journal of Psychiatric Research
 , 
1975
, vol. 
12
 
3
(pg. 
189
-
198
)
Gaunt
M. E.
Martin
P. J.
Smith
J. L.
Rimmer
T.
Cherryman
G.
Ratliff
D. A.
, et al.  . 
Clinical relevance of intraoperative embolization detected by transcranial Doppler ultrasonography during carotid endarterectomy: A prospective study of 100 patients
The British Journal of Surgery
 , 
1994
, vol. 
81
 
10
(pg. 
1435
-
1439
)
Goldstein
L. B.
Adams
R.
Alberts
M. J.
Appel
L. J.
Brass
L. M.
Bushnell
C. D.
, et al.  . 
Primary prevention of ischemic stroke: A guideline from the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline
Stroke: A Journal of Cerebral Circulation
 , 
2006
, vol. 
37
 
6
(pg. 
1583
-
1633
)
Greiffenstein
M. F.
Brinkman
S.
Jacobs
L.
Braun
P.
Neuropsychological improvement following endarterectomy as a function of outcome measure and reconstructed vessel
Cortex: A Journal Devoted to the Study of the Nervous System and Behavior
 , 
1988
, vol. 
24
 
2
(pg. 
223
-
230
)
Gunning-Dixon
F. M.
Raz
N.
The cognitive correlates of white matter abnormalities in normal aging: A quantitative review
Neuropsychology
 , 
2000
, vol. 
14
 
2
(pg. 
224
-
232
)
Hamster
W.
Diener
H. C.
Neuropsychological changes associated with stenoses or occlusions of the carotid arteries. A comparative psychometric study
European Archives of Psychiatry and Neurological Sciences
 , 
1984
, vol. 
234
 
1
(pg. 
69
-
73
)
Hemmingsen
R.
Mejsholm
B.
Vorstrup
S.
Lester
J.
Engell
H. C.
Boysen
G.
Carotid surgery, cognitive function, and cerebral blood flow in patients with transient ischemic attacks
Annals of Neurology
 , 
1986
, vol. 
20
 
1
(pg. 
13
-
19
)
Heyer
E. J.
DeLaPaz
R.
Halazun
H. J.
Rampersad
A.
Sciacca
R.
Zurica
J.
, et al.  . 
Neuropsychological dysfunction in the absence of structural evidence for cerebral ischemia after uncomplicated carotid endarterectomy
Neurosurgery
 , 
2006
, vol. 
58
 
3
(pg. 
474
-
480
discussion 474–480
Heyer
E. J.
Gold
M. I.
Kirby
E. W.
Zurica
J.
Mitchell
E.
Halazun
H. J.
, et al.  . 
A study of cognitive dysfunction in patients having carotid endarterectomy performed with regional anesthesia
Anesthesia and Analgesia
 , 
2008
, vol. 
107
 
2
(pg. 
636
-
642
)
Heyer
E. J.
Sharma
R.
Rampersad
A.
Winfree
C. J.
Mack
W. J.
Solomon
R. A.
, et al.  . 
A controlled prospective study of neuropsychological dysfunction following carotid endarterectomy
Archives of Neurology
 , 
2002
, vol. 
59
 
2
(pg. 
217
-
222
)
House
A. K.
Bell
R.
House
J.
Mastaglia
F.
Kumar
A.
D'Antuono
M.
Asymptomatic carotid artery stenosis associated with peripheral vascular disease: A prospective study
Cardiovascular Surgery (London, England)
 , 
1999
, vol. 
7
 
1
(pg. 
44
-
49
)
Iddon
J. L.
Sahakian
B. J.
Kirkpatrick
P. J.
Uncomplicated carotid endarterectomy is not associated with neuropsychological impairment
Pharmacology, Biochemistry, and Behavior
 , 
1997
, vol. 
56
 
4
(pg. 
781
-
787
)
Jacobs
L. A.
Ganji
S.
Shirley
J. G.
Morrell
R. M.
Brinkman
S. D.
Cognitive improvement after extracranial reconstruction for the low flow—endangered brain
Surgery
 , 
1983
, vol. 
93
 
5
(pg. 
683
-
687
)
Kishikawa
K.
Kamouchi
M.
Okada
Y.
Inoue
T.
Ibayashi
S.
Iida
M.
Effects of carotid endarterectomy on cerebral blood flow and neuropsychological test performance in patients with high-grade carotid stenosis
Journal of the Neurological Sciences
 , 
2003
, vol. 
213
 
1–2
(pg. 
19
-
24
)
Knopman
D.
Boland
L. L.
Mosley
T.
Howard
G.
Liao
D.
Szklo
M.
, et al.  . 
Cardiovascular risk factors and cognitive decline in middle-aged adults
Neurology
 , 
2001
, vol. 
56
 
1
(pg. 
42
-
48
)
Korczyn
A. D.
Vakhapova
V.
The prevention of the dementia epidemic
Journal of the Neurological Sciences
 , 
2007
, vol. 
257
 
1–2
(pg. 
2
-
4
)
Kumar
R.
Anstey
K. J.
Cherbuin
N.
Wen
W.
Sachdev
P. S.
Association of type 2 diabetes with depression, brain atrophy, and reduced fine motor speed in a 60- to 64-year-old community sample
The American Journal of Geriatric Psychiatry: Official Journal of the American Association for Geriatric Psychiatry
 , 
2008
, vol. 
16
 
12
(pg. 
989
-
998
)
Landgraff
N. C.
Whitney
S. L.
Rubinstein
E. N.
Yonas
H.
Cognitive and physical performance in patients with asymptomatic carotid artery disease
Journal of Neurology
 , 
2010
, vol. 
257
 
6
(pg. 
982
-
991
)
Lin
J.-H.
Lin
R.-T.
Tai
C.-T.
Hsieh
C.-L.
Hsiao
S.-F.
Liu
C.-K.
Prediction of poststroke dementia
Neurology
 , 
2003
, vol. 
61
 
3
(pg. 
343
-
348
)
Lind
C.
Wimmer
A.
Magometschnigg
H.
Ehrmann
L.
Havelec
L.
Reichenauer
M.
, et al.  . 
Effects of carotid endarterectomy on various neuropsychologic parameters. A neuropsychologic longitudinal study
Langenbecks Archiv Für Chirurgie
 , 
1993
, vol. 
378
 
6
(pg. 
345
-
352
)
Martinić-Popović
I.
Lovrencić-Huzjan
A.
Demarin
V.
Assessment of subtle cognitive impairment in stroke-free patients with carotid disease
Acta Clinica Croatica
 , 
2009
, vol. 
48
 
3
(pg. 
231
-
240
)
Mathiesen
E. B.
Waterloo
K.
Joakimsen
O.
Bakke
S. J.
Jacobsen
E. A.
Bønaa
K. H.
Reduced neuropsychological test performance in asymptomatic carotid stenosis: The Tromsø Study
Neurology
 , 
2004
, vol. 
62
 
5
(pg. 
695
-
701
)
Matthews
C. G.
Klove
H.
Instruction manual for the adult neuropsychology test battery
1964
Madison, Wisconsin
University of Wisconsin Medical School
Mohammed
N.
Anand
S. S.
Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomized controlled trial. MRC asymptomatic carotid surgery trial (ACST) collaborative group
Vascular Medicine
 , 
2005
, vol. 
10
 
1
(pg. 
77
-
78
)
Mononen
H.
Lepojärvi
M.
Kallanranta
T.
Early neuropsychological outcome after carotid endarterectomy
European Neurology
 , 
1990
, vol. 
30
 
6
(pg. 
328
-
333
)
Mungas
D.
Reed
B. R.
Jagust
W. J.
DeCarli
C.
Mack
W. J.
Kramer
J. H.
, et al.  . 
Volumetric MRI predicts rate of cognitive decline related to AD and cerebrovascular disease
Neurology
 , 
2002
, vol. 
59
 
6
(pg. 
867
-
873
)
Muntal Encinas
S.
Gramunt-Fombuena
N.
Badenes Guia
D.
Casas Hernanz
L.
Aguilar Barbera
M.
Spanish translation and adaptation of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Form A in a pilot sample
Neurologia, [Epub ahead of print Sep 7]
 , 
2011
Obisesan
T. O.
Obisesan
O. A.
Martins
S.
Alamgir
L.
Bond
V.
Maxwell
C.
, et al.  . 
High blood pressure, hypertension, and high pulse pressure are associated with poorer cognitive function in persons aged 60 and older: The Third National Health and Nutrition Examination Survey
Journal of the American Geriatrics Society
 , 
2008
, vol. 
56
 
3
(pg. 
501
-
509
)
Owens
M.
Pressman
M.
Edwards
A. E.
Tourtellotte
W.
Rose
J. G.
Stern
D.
, et al.  . 
The effect of small infarcts and carotid endarterectomy on postoperative psychologic test performance
Journal of Surgical Research
 , 
1980
, vol. 
28
 
3
(pg. 
209
-
216
)
Pearson
S.
Maddern
G.
Fitridge
R.
Cognitive performance in patients after carotid endarterectomy
Journal of Vascular Surgery: Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
 , 
2003
, vol. 
38
 
6
(pg. 
1248
-
1252
discussion 1252–1253
Petersen
R. C.
Doody
R.
Kurz
A.
Mohs
R. C.
Morris
J. C.
Rabins
P. V.
, et al.  . 
Current concepts in mild cognitive impairment
Archives of Neurology
 , 
2001
, vol. 
58
 
12
(pg. 
1985
-
1992
)
Pilcher
J. M.
Danaher
J.
Khaw
K. T.
The prevalence of asymptomatic carotid artery disease in patients with peripheral vascular disease
Clinical Radiology
 , 
2000
, vol. 
55
 
1
(pg. 
56
-
61
)
Qiu
C.
Winblad
B.
Fratiglioni
L.
The age-dependent relation of blood pressure to cognitive function and dementia
Lancet Neurology
 , 
2005
, vol. 
4
 
8
(pg. 
487
-
499
)
Randolph
C.
Tierney
M. C.
Mohr
E.
Chase
T. N.
The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): Preliminary clinical validity
Journal of Clinical and Experimental Neuropsychology
 , 
1998
, vol. 
20
 
3
(pg. 
310
-
319
)
Rao
R.
Jackson
S.
Howard
R.
Neuropsychological impairment in stroke, carotid stenosis, and peripheral vascular disease, a comparison with healthy community residents
Stroke: A Journal of Cerebral Circulation
 , 
1999
, vol. 
30
 
10
(pg. 
2167
-
2173
)
Reitz
C.
Tang
M.-X.
Manly
J.
Mayeux
R.
Luchsinger
J. A.
Hypertension and the risk of mild cognitive impairment
Archives of Neurology
 , 
2007
, vol. 
64
 
12
(pg. 
1734
-
1740
)
Reitan
R. M.
Validity of the Trail Making Test as an indication of organic brain damage
Perceptual and Motor Skills
 , 
1958
, vol. 
8
 (pg. 
271
-
276
)
Román
G. C.
Tatemichi
T. K.
Erkinjuntti
T.
Cummings
J. L.
Masdeu
J. C.
Garcia
J. H.
, et al.  . 
Vascular dementia: Diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop
Neurology
 , 
1993
, vol. 
43
 
2
(pg. 
250
-
260
)
Rothwell
P. M.
Eliasziw
M.
Gutnikov
S. A.
Fox
A. J.
Taylor
D. W.
Mayberg
M. R.
, et al.  . 
Analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis
Lancet
 , 
2003
, vol. 
361
 
9352
(pg. 
107
-
116
)
Rothwell
P. M.
Slattery
J.
Warlow
C. P.
Clinical and angiographic predictors of stroke and death from carotid endarterectomy: Systematic review
Br Med J
 , 
1997
, vol. 
315
 pg. 
157
 
Sabri
O.
Ringelstein
E. B.
Hellwig
D.
Schneider
R.
Schreckenberger
M.
Kaiser
H. J.
, et al.  . 
Neuropsychological impairment correlates with hypoperfusion and hypometabolism but not with severity of white matter lesions on MRI in patients with cerebral microangiopathy
Stroke: A Journal of Cerebral Circulation
 , 
1999
, vol. 
30
 
3
(pg. 
556
-
566
)
Sacco
R. L.
Adams
R.
Albers
G.
Alberts
M. J.
Benavente
O.
Furie
K.
, et al.  . 
Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: A statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: Co-sponsored by the Council on Cardiovascular Radiology and Intervention: The American Academy of Neurology affirms the value of this guideline
Circulation
 , 
2006
, vol. 
113
 
10
(pg. 
e409
-
e449
)
Soinne
L.
Helenius
J.
Tikkala
I.
Saimanen
E.
Salonen
O.
Hietanen
M.
, et al.  . 
The effect of severe carotid occlusive disease and its surgical treatment on cognitive functions of the brain
Brain and Cognition
 , 
2009
, vol. 
69
 
2
(pg. 
353
-
359
)
Sztriha
L. K.
Vörös
E.
Sas
K.
Szentgyörgyi
R.
Pócsik
A.
Barzó
P.
, et al.  . 
Favorable early outcome of carotid artery stenting without protection devices
Stroke: A Journal of Cerebral Circulation
 , 
2004
, vol. 
35
 
12
(pg. 
2862
-
2866
)
Teunissen
C. E.
De Vente
J.
von Bergmann
K.
Bosma
H.
van Boxtel
M. P. J.
De Bruijn
C.
, et al.  . 
Serum cholesterol, precursors and metabolites and cognitive performance in an aging population
Neurobiology of Aging
 , 
2003
, vol. 
24
 
1
(pg. 
147
-
155
)
Timsit
S. G.
Sacco
R. L.
Mohr
J. P.
Foulkes
M. A.
Tatemichi
T. K.
Wolf
P. A.
, et al.  . 
Early clinical differentiation of cerebral infarction from severe atherosclerotic stenosis and cardioembolism
Stroke: A Journal of Cerebral Circulation
 , 
1992
, vol. 
23
 
4
(pg. 
486
-
491
)
van den Berg
E.
Kloppenborg
R. P.
Kessels
R. P. C.
Kappelle
L. J.
Biessels
G. J.
Type 2 diabetes mellitus, hypertension, dyslipidemia and obesity: A systematic comparison of their impact on cognition
Biochimica Et Biophysica Acta
 , 
2009
, vol. 
1792
 
5
(pg. 
470
-
481
)
van den Burg
W.
Saan
R. J.
Van Zomeren
A. H.
Boontje
A. H.
Haaxma
R.
Wichmann
T. E.
Carotid endarterectomy: Does it improve cognitive or motor functioning?
Psychological Medicine
 , 
1985
, vol. 
15
 
2
(pg. 
341
-
346
)
Vriens
E. M.
Wieneke
G. H.
Hillen
B.
Eikelboom
B. C.
Van Huffelen
A. C.
Visser
G. H.
Flow redistribution in the major cerebral arteries after carotid endarterectomy: A study with transcranial Doppler scan
Journal of Vascular Surgery: Official Publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter
 , 
2001
, vol. 
33
 
1
(pg. 
139
-
147
)
Whitmer
R. A.
Sidney
S.
Selby
J.
Johnston
S. C.
Yaffe
K.
Midlife cardiovascular risk factors and risk of dementia in late life
Neurology
 , 
2005
, vol. 
64
 
2
(pg. 
277
-
281
)