From the Society for Vascular Surgery

Asymptomatic carotid stenosis is associated with

cognitive impairment
Brajesh K. Lal, MD,a,b Moira C. Dux, PhD,c Siddhartha Sikdar, PhD,d Carly Goldstein, BA,a,b
Amir A. Khan, PhD,a,d John Yokemick, BA, RVT,a and Limin Zhao, MBBS, RVT,a,b Baltimore, Md; and Fairfax, Va

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d
Assess a patient with carotid stenosis and cognitive impairment.
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ABSTRACT
Background: Cerebrovascular risk factors (eg, hypertension, coronary artery disease) and stroke can lead to vascular
cognitive impairment. The Asymptomatic Carotid Stenosis and Cognitive Function study evaluated the isolated impact
of asymptomatic carotid stenosis (no prior ipsilateral or contralateral stroke or transient ischemic attack) on cognitive
function. Cerebrovascular hemodynamic and carotid plaque characteristics were analyzed to elucidate potential
mechanisms affecting cognition.
Methods: There were 82 patients with $50% asymptomatic carotid stenosis and 62 controls without stenosis but
matched for vascular comorbidities who underwent neurologic, National Institutes of Health Stroke Scale, and
comprehensive neuropsychological examination. Overall cognitive function and five domain-specific scores were
computed. Duplex ultrasound with Doppler waveform and B-mode imaging defined the degree of stenosis, least luminal
diameter, plaque area, and plaque gray-scale median. Breath-holding index (BHI) and microembolization were

From the Department of Vascular Surgery, University of Maryland School of
Medicine,a and the Vascular Serviceb and Neuropsychology Section,c Veter-
ans Affairs Medical Center, Baltimore; and the Department of Bioengineering,
George Mason University, Fairfax.d
This study was funded by Veterans Affairs Merit Award CX000407 to B.K.L. B.K.L.
is also funded by the National Institute of Neurological Disorders and Stroke
and the National Institute on Aging, National Institutes of Health. S.S. is
funded by the National Institute of Arthritis and Musculoskeletal and Skin
Diseases, National Institutes of Health.
Clinical Trial registration: NCT01353196.
Author conflict of interest: none.
Presented at the late-breaking clinical trials session of the 2016 Vascular Annual
Meeting of the Society for Vascular Surgery, National Harbor, Md, June
8-11, 2016.
Correspondence: Brajesh K. Lal, MD, University of Maryland Medical Center, 22 S
Greene St, S10B00, Baltimore, MD 21201 (e-mail: blal@som.umaryland.edu).
The editors and reviewers of this article have no relevant financial relationships to
disclose per the JVS policy that requires reviewers to decline review of any
manuscript for which they may have a conflict of interest.
0741-5214
Copyright Ó 2017 by the Society for Vascular Surgery. Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.jvs.2017.04.038

1083
1084 Lal et al Journal of Vascular Surgery
October 2017

measured using transcranial Doppler. We assessed cognitive differences between stenosis patients and control patients
and of stenosis patients with low vs high BHI and correlated cognitive function with microembolic counts and plaque
characteristics.
Results: Stenosis and control patients did not differ in vascular risk factors, education, estimated intelligence, or
depressive symptoms. Stenosis patients had worse composite cognitive scores (P ¼ .02; Cohen’s d ¼ 0.43) and domain-
specific scores for learning/memory (P ¼ .02; d ¼ 0.42) and motor/processing speed (P ¼ .01; d ¼ 0.65), whereas scores for
executive function were numerically lower (P ¼ .08). Approximately 49.4% of all stenosis patients were impaired in at least
two cognitive domains. Precisely 50% of stenosis patients demonstrated a reduced BHI. Stenosis patients with reduced
BHI performed worse on the overall composite cognitive score (t ¼ 2.1; P ¼ .02; d ¼ 0.53) and tests for learning/memory
(t ¼ 2.7; P ¼ .01; d ¼ 0.66). Cognitive function did not correlate with measures of plaque burden (degree of stenosis, least
luminal diameter, and plaque area) or with plaque gray-scale median.
Conclusions: Asymptomatic carotid stenosis is associated with cognitive impairment independent of known vascular risk
factors for vascular cognitive impairment. Approximately 49.4% of these patients demonstrate impairment in at least two
neuropsychological domains. The deficit is driven primarily by reduced motor/processing speed and learning/memory
and is mild to moderate in severity. The mechanism for impairment is likely to be hemodynamic as evidenced by
reduced cerebrovascular reserve and the likely result of hypoperfusion from a pressure drop across the stenosis in the
presence of inadequate collateralization. (J Vasc Surg 2017;66:1083-92.)

Carotid artery stenosis is a well-recognized cause of METHODS

atheroembolic stroke. Cognitive impairment can coexist
in patients with stroke or with vascular risk factors such
as diabetes, hypertension, and hyperlipidemia (vascular
cognitive impairment).1 There is limited knowledge on
the isolated impact of neurologically asymptomatic
carotid stenosis (no stroke or transient ischemic attack)
on cognitive function because these patients tend to
have concomitant vascular risk factors with potential
confounding vascular cognitive impairment. Microem-
bolic ischemic brain injury from an unstable carotid
plaque and cerebrovascular hemodynamic impairment
may be potential mechanisms mediating such an
impairment.
Cognitive impairment affects patients’ well-being and
their ability to live independent productive lives.2 It pla-
ces large demands on societal, hospital, and financial
resources.3 Asymptomatic carotid stenosis ($50%)
occurs in 4.2% of adults; prevalence increases to up
to 12.5% of men and 6.9% of women $70 years of
age.4,5 An undetected cognitive morbidity in such a
large population has potentially important public
health implications.
We assessed whether patients with asymptomatic
carotid stenosis differed in overall and domain-specific
cognitive function compared with age-matched controls
without carotid stenosis but with similar vascular risk
profiles. Our primary hypothesis was that there would
be no difference in overall cognitive function (a compos-
ite of scores for the domains of learning/memory, motor/
processing speed, executive function, attention, and
language) between those with and those without carotid
stenosis. We also evaluated potential mechanisms of
injury by measuring breath-holding index (BHI) and
microembolization by transcranial Doppler (TCD)
and percentage stenosis, arterial least luminal diameter,
and plaque gray-scale median by duplex ultrasound
(DUS) in these patients.
Patients and study design. The Asymptomatic Carotid
Stenosis and Cognitive Function (ACCOF) study is a
prospective study of patients with asymptomatic carotid
stenosis (stenosis group) vs patients with vascular risk
factors but no stenosis (control group). Patients were
enrolled after approval by the University of Maryland
Institutional Review Board, and informed consent was
obtained. Patients recruited to the study had a
diameter-reducing carotid artery stenosis of $50%. This
identification was made by DUS in our Intersocietal
Accreditation Commission-accredited vascular labora-
tory.6 Doppler waveforms were acquired at a 60-degree
angle between the ultrasound beam and the long axis
of the artery. The highest peak systolic and end-diastolic
velocity measurement from each index carotid pathway
was used to quantify the stenosis. Doppler velocity
thresholds to determine the degree of stenosis were
according to consensus criteria used by our group pre-
viously (<50% stenosis when internal carotid artery [ICA]
peak systolic velocity [PSV] is <125 cm/s; 50%-69% ste-
nosis when ICA PSV is 125-230 cm/s; $70% stenosis to
near occlusion when ICA PSV is >230 cm/s).7,8 Asymp-
tomatic status was confirmed by history, physical
examination, and numeric National Institutes of Health
Stroke Scale as in our prior carotid studies.9,10 Vascular
risk factors as defined by consensus criteria for hyper-
tension, diabetes mellitus, hyperlipidemia, prior or
current smoking, coronary artery disease, and peripheral
arterial disease were recorded.11 Patients with a previous
stroke or transient ischemic attack referable to any
hemisphere (ie, never symptomatic), carotid revasculari-
zation on any side, contralateral arterial occlusion, known
vertebral-basilar or intracranial stenosis or occlusion,
documented dementia, poor transtemporal windows for
TCD testing, and other medical conditions precluding
complete testing were excluded from the study. Control
subjects with one or more vascular risk factors were also
Journal of Vascular Surgery Lal et al 1085
Volume 66, Number 4

enrolled. On enrollment, each stenosis patient and

stenosis-free control subject underwent recording of ARTICLE HIGHLIGHTS
demographic features, vascular risk factor profile, d
Type of Research: Single-center prospective case-
neurologic history and examination, National Institutes controlled Asymptomatic Carotid Stenosis and
of Health Stroke Scale, cognitive function testing, carotid Cognitive Function trial
DUS testing, and TCD testing. d
Take Home Message: In this study, 49.2% of 82
patients with a carotid artery stenosis $50% demon-
Cognitive testing. A comprehensive battery of stan- strated impairment in at least two neuropsychologi-
dardized neuropsychological tests assessing a range of cal domains compared with 62 controls with
cognitive domains (Table I) was selected, in part, on matched vascular comorbidities.
the basis of the National Institute of Neurological d
Recommendation: The study suggests that half of
Disorders and Stroke-Canadian Stroke Network vascular the patients with asymptomatic carotid artery steno-
cognitive impairment harmonization standards sis $50% develop cognitive impairment, probably
60-minute protocol as well as previous work from our because of decreased cerebral perfusion and not
group and others.11-19 All participants were administered atheroembolism.
the full cognitive battery. Testing was conducted in a
quiet room and administered by a master’s-level
neuropsychology technician blinded to study partici-
pant status (stenosis vs control), under the supervision of Table I. Cognitive function test battery
a senior neuropsychologist. Tests were administered in Cognitive domain Cognitive test
accordance with standardized published procedures Learning and memory a
Hopkins Verbal Learning
cited in Table I. The order of administration was TestdRevised47
consistent. Verbally and visually mediated tasks were a
Brief Visuospatial Memory
not administered during delay intervals of verbal and TestdRevised48
visual memory tests, respectively, in an effort to mini- Motor and processing a
Trail Making TestdPart A49
mize interference effects. The total testing time varied speed
a
modestly among participants from 70 to 90 minutes Grooved Pegboard Test, dominant
because of interindividual variability in completion time vs nondominant hand50
a
for tests without specific time limits. Test batteries were Executive and Trail Making TestdPart B49
scored by a single neuropsychologist and adjusted for visuospatial function
a
age, sex, education, and race using standardized Copy trial of the Rey Complex
normative data as described in Table I. Given that Figure Test51
a
premorbid intellect may influence performance, we Attention and working Wechsler Adult Intelligence
memory Scale-III: Digit Span Forward52
used a reading measure, the Hopkins Adult Reading a
Test, to quantify estimated intelligence level.20 Because Wechsler Adult Intelligence
Scale-III: Digit Span Backward52
mood could also influence results, a depression ques-
Language b
Verbal fluency (phonemic and
tionnaire (Center for Epidemiologic Studies Depression
semantic)53
Scale 20-item self-report inventory) was given concur- b
Boston Naming Test, 2nd edition54
rently with the tests.21
a
Raw scores adjusted using Calibrated Neuropsychological Normative
TCD testing. Simultaneous bilateral TCD monitoring of System.29
b
Raw scores adjusted using Heaton.30
the middle cerebral artery was accomplished by a
trained vascular technologist. Testing was performed
through transtemporal windows using bilateral 2-MHz
pulsed wave probes fitted to a head frame at an insona- determine the reactivity of the middle cerebral artery to
tion depth of 48 to 58 mm (optimized for each patient) hypercapnia associated with breath-holding to assess
with an ST3 TCD machine (Spencer Technologies, Seat- cerebrovascular hemodynamics.23 BHI testing was
tle, Wash). For real-time in vivo detection of cerebral performed in the morning. After a few minutes of normal
microemboli, the velocity scale of the recording was room air breathing, the mean flow velocity (MFV) at rest
adjusted to 100 to 150 cm/s, and the machine software (MFVrest) was recorded. Next, the breath-holding MFV
was configured to automatically detect high-intensity (MFVapnea) was recorded after breath-holding for
transient signals based on an international consensus 30 seconds. The BHI was calculated from the following
on distinguishing features that correspond to particulate equation: BHI ¼ (MFVapnea  MFVrest)/MFVrest  (100/30).
emboli.22 Examinations were digitally recorded for All participants performed three evaluations per
60 minutes and audited with manual remeasurement of side, and the mean of three readings was used in the
embolic counts to ensure accuracy. TCD was also used to analysis.
1086 Lal et al Journal of Vascular Surgery
October 2017

B-mode imaging. B-mode images of the index carotid Table II. Clinical characteristics of patients
artery plaque were acquired with an L9-4/38 transducer Patients with
and a SonixMDP system (Ultrasonix, British Columbia, asymptomatic
Canada). These techniques have been reported by our carotid stenosis Controls
group.24-26 The sonographer selected the optimal inso- Risk factor (n ¼ 82) (n ¼ 62) P
nation angle to obtain the best image of the plaque. Age, years 68.9 6 7 67.8 6 7 .12
The transducer was placed directly over the carotid Male sex 97 94 .42
artery segment containing the plaque to obtain a White race 80 50 .005
longitudinal image; it was then swept from the base of Diabetes 54 53 .34
the neck to the angle of the mandible to identify and Hypertension 85 89 .82
record the cross-sectional image where the tightest Dyslipidemia 71 73 .32
stenosis was visualized. The images were digitally
Coronary artery diseasea 11 14 .27
recorded and analyzed offline with a computer-assisted
Peripheral vascular 49 44 .19
image analysis program by independent observers disease
blinded to clinical findings, using previously described
Smoking 73 78 .32
approaches.24-26 The longitudinal sectional image that
Antiplatelet treatment 81.0 70.2 .28
showed the largest amount of plaque was selected for
Lipid-lowering 78.3 71.9 .21
each patient for analysis. The plaque region was
treatmentb
manually outlined. The least luminal diameter was
Education, years 12.9 6 2 13.3 6 2 .11
measured from the longitudinal image where the
Estimated depression 12.2 6 7.5 12.2 6 10.2 .90
plaque was thickest, as measured by our group previ-
(CES-D score)
ously.27 This was compared with the normal luminal
diameter distal to the plaque to obtain percentage
Estimated intelligence 105.5 6 8.4 104.9 6 11.0 .72
stenosis. The plaque was then outlined in that view to
(HART score)
measure plaque area and gray-scale median pixel value
Stenosis features
inside the segmented plaque region after appropriate
Right 58.4%
normalization.24,25,28
50%-69% stenosis 75.3%
Statistical analysis. Data analysis was performed using 70%-79% stenosis 13.0%
SPSS version 22.0 (IBM Corp, Armonk, NY). Raw cognitive
80%-99% stenosis 11.7%
test scores were transformed into standardized t scores
CES-D, Center for Epidemiologic Studies Depression Scale; HART,
(mean, 50; standard deviation [SD], 10) using normative Hopkins Adult Reading Test.
data with adjustments for age, sex, education, and Categorical variables are presented as number (%). Continuous vari-
ables are presented as mean 6 standard deviation (SD).
race.29,30 For all analyses, significant outliers were a
Coronary artery disease was defined as a positive history of myocardial
removed (ie, >3 SD; n ¼ 1). All P values were reported as infarction or angina.
b
Use of lipid-lowering medication was recorded only in those who
two tailed, and significance was set at P # .05. As were noted to have dyslipidemia.
outlined in Table I, composite scores for five cognitive
domains were computed by averaging the t scores for
the relevant variables. For example, the learning and
memory domain was calculated by averaging the potential mechanisms underlying cognitive impairment
immediate and delayed recall t scores from the Hopkins in patients with a stenosis, the group was divided
Verbal Learning Test and the Brief Visuospatial Memory according to normal vs pathologic ipsilateral BHI.
Test. Overall cognitive function was calculated by aver- Pathologic BHI was defined as BHI <0.69, and normal
aging the individual t scores for each variable that was defined as BHI $0.69.33 Independent samples t-tests
contributed to the five-cognitive domain composite were used to evaluate cognitive composite scores of
score. Independent samples t-tests were used to eval- stenosis patients with normal vs pathologic BHI. Cohen’s
uate composite cognitive scores of stenosis vs control d was calculated for each comparison to determine
groups. Cohen’s d was calculated for each comparison to effect sizes. Associations with plaque morphology were
categorize effect sizes into small (d ¼ 0.20-0.49), examined by correlating cognitive function with plaque
medium (d ¼ 0.50-0.79), and large (d $ 0.80).31 The gray-scale median. To assess the relationship between
frequency of impairment by group (ie, stenosis patients cognitive test scores and plaque burden, the degree of
vs controls) was calculated. Impairment was defined as stenosis was analyzed with linear regression by
t scores that were 1 SD or more below the mean (ie, comparing mean scores of three categories of stenosis
t < 40).32 Contingency table analyses using the c2 sta- (50%-69%, 70%-79%, 80%-99%) as well as with least
tistic were used to determine whether frequencies of luminal diameter and plaque area measurements;
impairment differed between the groups. To explore controls were excluded.
Journal of Vascular Surgery Lal et al 1087
Volume 66, Number 4

Table III. Overall and domain-specific cognitive function in patients with asymptomatic carotid stenosis vs control subjects
with similar vascular risk factors
Mean scorea (SD)
Patients with asymptomatic
Cognitive domain tested carotid stenosis (n ¼ 82) Controls (n ¼ 62) t score P Cohen’s d
Learning and memory 43.1 (8.5) 46.5 (7.8) 2.4 .02 0.42
Motor and processing speed 43.2 (8.4) 48.6 (8.3) 3.7 .01 0.65
Executive and visuospatial function 41.5 (8.6) 44.0 (7.6) 1.7 .08 0.31
Attention and working memory 46.5 (8.7) 47.9 (9.1) 0.93 .36 0.16
Language 50.0 (8.2) 50.2 (8.4) .17 .83 0.02
Total cognitive composite score 45.5 (6.0) 47.9 (5.0) 2.3 .02 0.43
SD, Standard deviation.
a
Scores have been adjusted for age, sex, race, and education based on standardized normative data.29,30

Table IV. Raw scores on individual cognitive function tests for patients with asymptomatic carotid stenosis and for controls
with similar vascular risk factors
Stenosis Controls
Name of test Domain Raw score SD Raw score SD
HVLT-R immediate recall Learning and memory 20.3 5.5 22.4 4.7
HVLT-R delayed recall Learning and memory 5.7 3.4 7.0 3.1
BVMT-R immediate recall Learning and memory 12.5 6.0 14.0 6.3
BVMT-R delayed recall Learning and memory 5.3 2.5 5.9 2.6
Trail Making TestdPart A, time to completiona Motor/processing speed 47.5 17.7 41.6 17.4
Grooved Pegboard Test, dominant hand, Motor/processing speed 114.2 38.5 93.7 22.4
time to completiona
Grooved Pegboard Test, nondominant hand, Motor/processing speed 127.2 46.6 110.0 38.3
time to completiona
Trail Making TestdPart Ba Executive function 134.0 65.7 115.6 55.9
Rey Complex Figure Copy score Executive function 22.0 7.0 24.0 5.1
WAIS-III: Digit Span, longest forward Attention/working memory 6.0 1.2 6.1 1.4
WAIS-III: Digit Span, longest backward Attention/working memory 4.4 1.2 4.5 1.3
Phonemic fluency, total score Language 32.4 11.6 33.1 11.0
Semantic fluency, total score Language 16.9 4.5 16.9 4.9
Boston Naming Test, total correct Language 53.7 5.0 54.2 4.4
BVMT-R, Brief Visuospatial Memory TestdRevised; HVLT-R, Hopkins Verbal Learning TestdRevised; SD, standard deviation; WAIS-III, Wechsler Adult
Intelligence Scale-III.
a
For the Grooved Pegboard Test and Trail Making Test, lower scores reflect better performance.

RESULTS was similar in both groups. There were no differences in

Clinical characteristics. The authors had full access to
all the data in the study and take responsibility for its
integrity and the data analysis. Of the 240 patients and
controls screened at the Baltimore Veterans Affairs Med-
ical Center, 54 were excluded for prior transient ischemic
attacks or vertebral-basilar symptoms, 5 for diagnosed
dementia, 5 for contralateral carotid artery occlusion, 11
for coexisting severe congestive heart failure, and 15 for
active cancer treatment; 6 declined to participate. This
resulted in 82 stenosis patients and 62 controls. The
baseline clinical characteristics of patients analyzed are
detailed in Table II. The mean age was 68.9 years (SD, 7;
range, 45-82) in the stenosis group and 67.8 years (SD, 7;
range, 43-79) in the control group. The proportion of men
the proportion of patients with diabetes, hypertension,
coronary disease, peripheral vascular disease, hyperlip-
idemia, or smoking or in the use of antiplatelet and lipid-
lowering therapy between stenosis and control groups.
Patients did not differ from controls with respect to
education levels, depression (Center for Epidemiologic
Studies Depression Scale score), or estimated intelli-
gence (Hopkins Adult Reading Test score). The control
group had more African Americans (50%) than the
stenosis group (20%; P ¼ .005).
Cognitive function results. All patients and control sub-
jects completed all cognitive function testing (Table III).
Asymptomatic carotid stenosis patients performed
1088 Lal et al Journal of Vascular Surgery
October 2017

60

#
50
ProporƟon of PaƟents with Impairment (%)

*
40

#
30

Stenosis
*
Controls
20

10

0
Total Learning & Attention & Motor & Executive & Language
Composite Memory Working Processing Visuospatial
Memory Speed Function
Cognitive Domains
Fig 1. Proportion of carotid stenosis patients vs controls demonstrating impairment in individual cognitive
domains. *P ¼ .01; #P ¼ .03.

Table V. Overall and domain-specific cognitive function in patients with asymptomatic carotid stenosis with and without
an impaired breath-holding index (BHI)
Mean scorea (SD)
Cognitive domain tested Impaired BHI Normal BHI t score P Cohen’s d
Learning and memory 39.5 (6.4) 45.0 (9.3) 2.7 .01 0.66
Attention and working memory 44.6 (8.9) 48.4 (7.9) 1.8 .07 0.46
Motor and processing speed 41.5 (9.8) 44.8 (6.9) 1.5 .14 0.38
Executive and visuospatial function 40.2 (9.7) 42.8 (8.3) 1.2 .26 0.30
Language 50.4 (8.0) 49.8 (6.8) 0.33 .74 0.08
Total cognitive composite score 43.8 (6.2) 47.0 (5.0) 2.1 .04 0.53
SD, Standard deviation.
a
Scores have been adjusted for age, sex, race, and education based on standardized normative data.29,30

worse on the overall cognitive composite score from all difference in performance for tests related to language
tests in the battery (t ¼ 2.3; P ¼ .02 compared with and attention/working memory. Table IV describes the
controls); the effect size of this difference was small raw scores of each of the tests performed to evaluate
(d ¼ 0.43). Patients performed significantly worse on tests individual cognitive domains. We compared the pro-
assessing the neuropsychological domains of learning portion of individuals with impaired function within each
and memory function (t ¼ 2.4; P ¼ .02) as well as motor cognitive domain (ie, a score >1 SD below the norm) for
and processing speed (t ¼ 3.7; P ¼ .01). The effect size of patients with a stenosis vs controls (Fig 1). A significantly
these differences for learning and memory (d ¼ 0.42) and higher proportion of stenosis patients had impaired
for motor and processing speed (d ¼ 0.65) were small learning and memory (P ¼ .01) and motor and processing
and medium, respectively. Performance scores were speed (P ¼ .02) compared with controls. Approximately
numerically reduced for executive/visuospatial function 49.4% of all stenosis patients (compared with 22.6% of
(t ¼ .17; P ¼ .08; d ¼ 0.31); however, these did not reach controls) were impaired in at least two neuropsycholog-
statistical significance. There was no significant ical domains.
Journal of Vascular Surgery Lal et al 1089
Volume 66, Number 4

60
#

ProporƟon of PaƟents with Impairment (%)

50

40

30
*
Impaired BHI
Nomral BHI
20

10

0
Total Learning & Attention & Motor & Executive & Language
Composite Memory Working Processing Visuospatial
Memory Speed Function
Cognitive Domains
Fig 2. Proportion of carotid stenosis patients with normal vs abnormal breath-holding index (BHI)
demonstrating impairment in individual cognitive domains. *P ¼ .01; #P ¼ .02.

Mechanisms. Overall cognitive function did not differ DISCUSSION

on the basis of the degree of stenosis derived from DUS Conventional vascular risk factors (hypertension,
velocity measurements (50%-69% vs $70%; t ¼ 1.23; diabetes, dyslipidemia, smoking, and cardiovascular
P ¼ .23). Overall cognitive function did not correlate disease) are known to increase the risk for stroke, for
with the least luminal diameter (r ¼ 0.12; P ¼ .33), the development of carotid plaques, and for cognitive
percentage stenosis (r ¼ 0.19; P ¼ .13), or plaque area impairment. In this report, we demonstrate a relation-
(r ¼ 0.16; P ¼ .20) as measured on B-mode imaging. ship between carotid stenosis and cognitive impairment
No correlation was observed between the composite independent of vascular risk factors and of stroke.
cognitive scores and gray-scale median within the Patients with otherwise asymptomatic carotid stenosis
segmented plaque (r ¼ 0.30; P ¼ .14). A total of seven performed worse than controls on the overall composite
patients with stenosis were confirmed to have micro- cognitive score and on domain-specific neuropsycholog-
embolic high-intensity transient signals on TCD, and their ical tests of learning and memory and of motor and pro-
composite cognitive scores did not differ from those of cessing speed. The proportion of stenosis patients with
patients who did not demonstrate microembolization. an impaired score was higher than that in controls,
BHI was measured using TCD. Patients were assigned with nearly 50% of the patients demonstrating impaired
to high vs low BHI groups using a cutoff score of 0.69 function in two cognitive domains (23% in controls).
(Table V). Fifty percent of carotid stenosis patients Impaired performance correlated with a reduced BHI
demonstrated an abnormal BHI (ie, impaired cerebrovas- on TCD testing but did not correlate with silent micro-
cular hemodynamics). Those with low BHI demonstrated embolization or with carotid plaque burden and
worse overall composite cognitive scores (t ¼ 2.1; morphologic features.
P ¼ .04) with a medium effect size (d ¼ 0.53) and per- Few studies have evaluated cognitive function in
formed worse on tests for learning and memory patients with asymptomatic carotid stenosis. Most have
(t ¼ 2.7; P ¼ .01), also with a medium effect size focused on patients undergoing carotid endarterectomy
(d ¼ 0.66). Trends emerged for processing speed or stenting.14 Cognitive impairment has been reported in
(t ¼ 1.5; P ¼ .14; d ¼ 0.38) and attention/working memory patients with carotid stenosis, although others have not
(t ¼ 1.8; P ¼ .07; d ¼ 0.46) but did not reach significance. found an association.11,15-19,34,35 In these reports, the coex-
As displayed in Fig 2, those with impaired BHI demon- istence of stenosis with other confounding risk factors for
strated a higher frequency of composite as well as cognitive impairment makes the findings difficult to
domain-specific cognitive impairment. interpret. Our study was a response to the stated need
1090 Lal et al
for an adequately powered analysis with appropriately
selected controls to resolve this controversy.19,36 In our
study, we did not make comparisons to healthy controls.
Instead, stenosis patients and controls were well
matched for known vascular risk factors for cognitive
impairment and antiplatelet and lipid-lowering medica-
tions. Because stroke predisposes an individual to
cognitive impairment, we excluded patients with prior
strokes or transient ischemic attacks attributable to
either hemisphere. Patients with diagnosed dementia,
occlusion of the contralateral carotid artery, or prior
revascularization of either carotid artery were also
excluded. Premorbid intellect and mood can both affect
cognitive performance but were not found to differ be-
tween stenosis and control groups. Finally, we used
normative data to correct for any potential effects of
age, sex, race, and education on cognitive test perfor-
mance. Once these potential confounders were
eliminated, our study identified a unique but definitive
contribution of the carotid artery stenosis to reduction
in overall cognitive function. The incidence of carotid
bifurcation stenosis is lower, and that of intracranial
stenosis higher, among African Americans. Our control
cohort had more African Americans and controls had
better cognitive performance, thereby further strength-
ening the newly identified role of carotid bifurcation
stenosis for cognitive impairment.
Cognitive testing in patients with carotid stenosis is
challenging as deficits may be subtle. In a subset analysis
of the Cardiovascular Health Study, 11 of 32 patients
with asymptomatic carotid stenosis demonstrated
cognitive decline during 5 years based on a modified
Mini-Mental State Examination.15 The authors cautioned
that the results based on this screening test were prelim-
inary and limited to patients with left-sided stenosis
because of the absence of an ideal cognitive test battery.
Conversely, Martinic-Popovic et al reported normal
Mini-Mental State Examination scores in 26 patients
with stenosis, although they had reduced Montreal
Cognitive Assessment scores.16 Our assessment involved
a neuropsychological battery spanning multiple cogni-
tive domains with an analysis of both composite and
domain-specific outcomes.37 Guidelines for cognitive
assessment in vascular disease have been derived largely
from cardiac surgery and medical treatment outcome
studies.12,38,39 The selection of our test battery was guided
by these recommendations and by previous studies
showing effects on motor speed, information processing,
attention, and memory.11,14-19 Our battery was therefore
comprehensive and used tests sensitive to changes in
cognitive domains expected to be impaired in this target
population.
As cerebral perfusion pressure falls, cerebral blood
flow is maintained by collateral circulation and autore-
gulatory vasodilation of cerebral arterioles. A vasodilatory
challenge with carbon dioxide (eg, by breath-holding)
Journal of Vascular Surgery
October 2017
will fail to dilate cerebral arterioles any further, resulting
in a reduced BHI measured by TCD.33 Transient or
chronic occlusion of the carotid artery results in impaired
brain perfusion with associated impaired cognitive func-
tion.40,41 Half of our patients with carotid artery stenosis
also demonstrated impaired cerebral hemodynamics
with a reduced ipsilateral BHI. These patients had worse
composite and domain-specific cognitive function
compared with those with a normal BHI, indicating
that impaired hemodynamics in the presence of a steno-
sis contributed to the observed cognitive impairment.
Not all patients with a bifurcation stenosis demonstrated
hypoperfusion. This is likely the result of effective cross-
collateralization from the contralateral carotid through
the circle of Willis in many patients. This may also explain
why hypoperfusion did not correlate with the degree of
stenosis, although this may also be the result of a type
II error.
Silent microinfarctions in patients without carotid
stenosis have been associated with cognitive impair-
ment.42,43 Cerebrovascular microembolization and
subsequent brain microinfarctions have been detected
in 15% to 19% of patients with asymptomatic carotid ste-
nosis, raising the possibility that this ischemic injury may
lead to cognitive impairment.44,45 Our study did not
identify a difference in microembolization rates between
patients with carotid stenosis who had cognitive impair-
ment and those who were not impaired. Cerebral micro-
infarctions in patients with asymptomatic carotid
stenosis have also not correlated with cognitive impair-
ment.18 Consistent with these reports, measures of
plaque burden (velocity-based degree of stenosis, least
luminal diameter, percentage stenosis, plaque area)
and of plaque morphology (low gray-scale median
values) also did not correlate with cognitive impairment.
This argues against a role for plaque disruption and athe-
roembolic brain injury in the cognitive impairment
observed in our patients.
Limitations. The overall rate of microembolization in our
cohort was low, and these findings must be interpreted
with caution. The concordant findings on measures of pla-
que burden and morphology, however, argue against an
important role for microembolic ischemic brain injury in
causing the cognitive impairment. Plaque assessments
were performed using DUS, with known operator vari-
ability. The protocols implemented in this study have,
however, been validated in other reports. We did not
perform independent measurement of cerebral perfusion
or brain magnetic resonance imaging to document silent
cerebral microinfarctions. Nonetheless, our TCD findings
were compelling, and additional studies are being
planned using perfusion magnetic resonance imaging
scanning. Our study was powered for the primary analysis
of impact, composite cognitive function, and demon-
strated a strong relationship between asymptomatic
Journal of Vascular Surgery
Volume 66, Number 4
stenosis and cognitive impairment. Domain-specific
subset analyses must be interpreted with caution; how-
ever, the numeric and statistical relationships between
stenosis and learning/memory and motor/processing
speed were compelling and provide insight into optimal
tests to be used for future studies.
CONCLUSIONS
We present evidence that cognitive impairment is an
under-recognized morbidity in patients with otherwise
“asymptomatic” carotid artery stenosis. It is an important
clinical outcome that must be included as a defined end
point in future trials testing the efficacy of treatment stra-
tegies for carotid stenosis. It is likely the result of
impaired hemodynamics from reduced cerebral perfu-
sion rather than of microembolic ischemic injury. These
findings prompt additional studies on whether revascu-
larization strategies (stenting or endarterectomy) can
reverse this impairment by improving cerebrovascular
hemodynamics and whether stenosis is a modifiable
risk factor for cognitive impairment, testing preventive
(statin therapy for plaque stabilization) or therapeutic
(cognitive training or carotid revascularization) strategies.
Further studies are also required to assess whether
abnormal cerebral hemodynamics or cognitive impair-
ment can improve the selection of patients requiring
carotid artery revascularization with an aim to reduce
unnecessary procedures.46
AUTHOR CONTRIBUTIONS
Conception and design: BL
Analysis and interpretation: BL, MD, SS, AK
Data collection: CG, JY, LZ
Writing the article: BL, MD
Critical revision of the article: SS, CG, AK, JY, LZ
Final approval of the article: BL, MD, SS, CG, AK, JY, LZ
Statistical analysis: BL, MD, SS, CG
Obtained funding: BL
Overall responsibility: BL
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Submitted Jan 12, 2017; accepted Apr 10, 2017.
The CME exam for this article can be accessed at
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