© 1999 American Heart Association, Inc.
Original Contributions |
Relationships of Cerebral MRI Findings to Ultrasonographic Carotid Atherosclerosis in Older Adults
The Cardiovascular Health Study
From the Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Bethesda, Md (T.A.M.); the Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (G.L.B., G.E.); the Department of Radiology, Tufts New England Medical Center, Boston, Mass (D.H.O.); the Department of Radiology, Johns Hopkins University, Maryland, Baltimore, Md (N.B.); the Department of Neurology, University of Pittsburgh, Pa (L.K.); and the Department of Biostatistics, University of Washington, Seattle, Wash (B.W.).
Correspondence to Teri Manolio, MD, MHS, National Heart, Lung, and Blood Institute, 6701 Rockledge Dr, Room 8160, Bethesda, MD 20892-7934. E-mail manolio{at}nih.gov
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Abstract |
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Abstract—Cerebral magnetic resonance imaging (MRI) has demonstrated a high prevalence of infarct-like lesions, white matter hyperintensities, and evidence of cerebral atrophy in older adults. While these findings are generally believed to be related to ischemia and atherosclerosis, their relationship to atherosclerosis in the carotid arteries remains to be explored. Study subjects were part of the multicenter Cardiovascular Health Study, a cross-sectional study of 3502 women and men
65 years of age undergoing cranial MRI and
carotid ultrasonography. MRI infarcts were detected in 1068
participants (29.3%) and measurable carotid plaque in 2745 (75.3%).
MRI infarcts, ventricular and sulcal widening, and white
matter score were strongly associated with carotid intimal-medial
thickness (IMT) and stenosis degree after adjustment for age
and sex (all P<0.01). Associations with plaque
characteristics were less strong and less consistent; MRI
infarcts were weakly associated only with surface irregularity, and
ventricular size was weakly associated only with lesion
density (both P<0.04). In contrast, sulcal widening was
strongly related to plaque characteristics, with scores being higher in
those with heterogeneous and irregular plaque (both
P<0.009). Adjustment for other risk factors, and
for carotid IMT/stenosis, removed associations of MRI findings
with plaque characteristics except for weak relationships remaining
between MRI infarcts and surface irregularity and between sulcal score
and heterogeneous plaque (both P<0.03). MRI
abnormalities show strong and consistent relationships with
increasing carotid IMT and stenosis degree but less strong
associations with plaque characteristics, especially after adjusting
for IMT and stenosis.
Key Words: stroke • cerebrovascular disorders • carotid arteries • atherosclerosis • aged • epidemiology • risk factors
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Introduction |
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Cerebral magnetic resonance imaging (MRI) has demonstrated a high prevalence of infarct-like lesions, white matter hyperintensities, and evidence of cerebral atrophy in older adults.1 2 3 While these findings are related to standard risk factors for cardiovascular disease and are believed to be consequences of ischemia,4 5 6 their relationship to atherosclerosis in the carotid arteries has not been widely explored.
Because the carotid arteries provide the majority of the brain's blood supply, detailed information on extent, severity, and characteristics of carotid atherosclerosis can be used to explore its relationships to cerebral MRI findings. Lesion characteristics such as increased density, heterogeneity, and surface irregularity have been shown to relate to prevalent clinically defined transient ischemic attack and stroke,6 but these associations have not been examined for cerebral MRI findings.
The Cardiovascular Health Study (CHS) cohort represents a large, multicenter sample of older men and women examined by both carotid ultrasonography and cerebral MRI. Cross-sectional data from these examinations were analyzed (1) to describe prevalences of MRI-defined infarcts, infarct-like lesions, and gray and white matter changes by quintile of common and internal carotid intimal-medial thickness (IMT); degree of carotid stenosis; and characteristics of carotid plaque; (2) to determine independence of carotid atherosclerosis/MRI abnormality associations from known clinical and subclinical cardiovascular disease and cardiovascular disease risk factors; and (3) to define relationships of MRI infarcts and ipsilateral carotid artery disease.
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Methods |
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CHS participants were recruited from a random sample of the Medicare eligibility lists of the Health Care Financing Administration 4 US communities: Forsyth County, NC; Sacramento County, Calif; Washington County, Md; and Pittsburgh (Allegheny County), Pa. Details of design and methods have been previously published.1 7 8 The baseline examinations were conducted between June 1989 and May 1990 for 5201 participants of the original cohort and between June 1992 and May 1993 for an additional 687 black participants. Carotid ultrasound was performed at entry for both cohorts and was repeated in the original cohort during the 1992 to 1993 examination. Cerebral MRI was performed in 1992 to 1994, spanning 2 annual examinations due to limited scanner availability, but is considered part of the 1992 to 1993 examination data set. Carotid data as well as other risk factors and clinical disease data used in the current analysis are limited to the 1992 to 1993 examination for all participants.
Carotid Ultrasound
Near- and far-wall maximal IMT of the carotid arteries were
measured by trained readers and averaged as an indicator of
atherosclerosis; separate measurements were made for
common and internal carotid arteries. Plaque was defined as any focal
thickening of the intimal-medial layer of the common or internal
carotid arteries or carotid bulb. Stenosis degrees of <50%
were judged visually as 1% to 24% or 25% to 49%. Stenosis
of 50% to 74% was defined by duplex ultrasonography as Doppler
peak flow velocity1.5 m/s; 75% to 99% as flow velocity2.5 m/s;
and 100% stenosis as absent flow. Individual participants were
characterized by the degree of stenosis in the most severely
affected vessel; that is, a 100% left-sided stenosis and 25%
right-sided stenosis would place a participant in the 100%
stenosis category. CHS ultrasound methods and initial quality
control results have been previously published.9
Focal lesions were evaluated on the basis of gray-scale images for
texture, surface irregularity, and density. Lesion texture was
classified as homogeneous or heterogeneous
(uniform versus nonuniform echogenicity throughout lesion,
respectively). Lesion surface was classified as smooth, mildly
irregular (height variations
0.4 mm), markedly irregular (height
variations>0.4 mm), and ulcerated (discrete depression>2 mm
in width extending into the media). Lesion density was characterized as
calcified (hyperdense at one interface with acoustic shadowing
underneath), hyperdense, isodense, or hypodense relative to uninvolved
adjacent intima-media. Due to the small number of ulcerated lesions,
the ulcerated and markedly irregular categories were combined for the
purpose of analysis. Right- and left-sided analyses
were limited to plaque characteristics of the most severe focal lesion,
with severity defined hierarchically as above. Thus, a right carotid
system with a homogeneous lesion at the bifurcation and a
heterogeneous lesion in the internal carotid would be
classified as having a heterogeneous plaque. Similarly, a
participant with a smooth lesion in the right carotid system and a
markedly irregular lesion in the left system would be classified as
having markedly irregular plaque. Distributions and associations of
plaque characteristics, as well as representative
gray-scale images used to characterize them, have been previously
published.10
Cerebral MRI
Cerebral MRI was performed according to a standard
protocol.1 11 Infarcts by MRI were defined as lesions with
abnormal signal in a vascular distribution and no mass effect. Infarcts
of the cortical gray matter and deep nuclear regions and capsule were
defined as lesions bright on spin density and
T2-weighted images compared with normal gray
matter and isointense or hypointense on
T1-weighted images. Infarcts in the cerebral
white matter and brain stem were also bright on spin density and on
T2-weighted images but, in addition, were
hypointense on T1-weighted images, approximating
the intensity of cerebrospinal fluid. In this report, presumed infarcts
in any region were classified as "small infarct-like lesions" if
<3 mm in size and as "MRI infarcts" when 3 mm in size.
Intrareader and interreader reliability for MRI infarcts in the first
300 participants was high (
=0.71 and 0.78, respectively) but not so
for infarct-like lesions (=0.71 and 0.32 for intrareader and
interreader, respectively). The protocol was thus modified to include
duplicate readings of infarcts and small infarct-like lesions in all
subjects. MRI infarcts and infarct-like lesions were classified without
reference to clinical signs or symptoms; their relationship to symptoms
and clinically recognized stroke has been reported
previously.12
Cerebral ventricular size was assessed on a scale of 0 to 9 by comparison with a series of 8 studies with successively increasing ventricular size ranging from small (grade 1) to severe enlargement (grade 8). Studies considered to have ventricles smaller than those in grade 1 received grade 0, and worse than grade 8 received grade 9. Similarly, sulcal widening was assessed by comparison with 8 studies with successively increasing sulcal size, with grades 0 and 9 assigned for ventricular size. Focal atrophy was assessed as focal volume loss in brain parenchyma without abnormal signal intensity. Perivascular spaces were assessed in the high parietal convexity and inferior basal ganglia as lesions isointense on spin density images, bright on T2 images, and dark on T1 relative to gray matter. Bifrontal distance was the largest right-left diameter from the lateral border of the frontal horn of the right lateral ventricle to the corresponding point along the lateral border of the frontal horn of the left lateral ventricle. Inner table width was the largest right-left diameter from the inner table of the skull measured along the same line as the bifrontal diameter.
"White matter disease" was estimated as the total volume of periventricular and subcortical white matter signal abnormality on spin density–weighted axial images compared with 8 studies successively increasing from barely detectable white matter changes (grade 1) to extensive, confluent changes (grade 8). Studies with no white matter changes received grade 0, and those with changes worse than grade 8 received grade 9. White matter changes were also characterized for predominant location (periventricular versus subcortical). All studies were assessed without knowledge of information such as subject's age, gender, clinical disease status, prior imaging findings, or other cardiovascular disease risk factors. Intraclass correlation coefficients for repeated readings were 0.52 for sulcal scores, 0.74 for ventricular scores, 0.80 for white matter scores, 0.85 for bifrontal distance, and 0.80 for inner table distance. For analytic purposes, ventricular, sulcal, and white matter scores with very low frequencies were collapsed into the next most frequent category (0 combined with 1, and 6 and above combined into a single category). Design and methodology of the MRI study have been described previously.1 11
Statistical Analysis
Associations between MRI infarcts and infarct-like lesions
with categorical and continuous variables were assessed by
2 testing and ANOVA, respectively.
Associations between ultrasound and categorical MRI variables were
assessed by logistic regression after adjustment for age and sex,
though prevalence and associations differed little by sex. Significance
levels were estimated for continuous measures of carotid IMT (despite
use of quintiles for data presentation in tables), ordered
categories for stenosis degree and surface irregularity, and
unordered categories for lesion heterogeneity and
density. Associations with continuous MRI variables were assessed
by linear regression after adjustment for age and sex, with
significance levels estimated as above. Associations between MRI
characteristics and plaque characteristics were assessed only in
persons with measurable plaque (n=2745). Multiple logistic or linear
regression analyses assessing independent associations of
ultrasound and categorical or continuous MRI variables,
respectively, were estimated by allowing correlates of MRI
variables identified in previous analyses to enter forward
stepwise predictive models of each MRI variable
separately.3 7 13 Significant correlates were then forced
into a model with each carotid variable separately. Because plaque
characteristics have been shown to be strongly related to increasing
IMT and carotid stenosis,7 models for plaque
characteristics were repeated with forced inclusion of
IMT/stenosis in addition to other significant covariates.
Prevalence of ipsilateral versus contralateral MRI infarcts were
compared by 2 testing for the highest IMT
quintile versus quintiles 1 to 4 and by presence or absence of
stenosis50%, plaque irregularity, and hyperdense plaque in
the right and left carotid arteries separately. Because of the large
number of comparisons performed, associations at P<0.01
were considered to be statistically significant, and those at
0.01<P<0.05 were considered to be of borderline
significance. All analyses were performed using the
SPSS/Windows System, version 6.1.
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Results |
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Cerebral MRI was performed in 3660 participants, of whom 3502 also had carotid ultrasound data and MRI scans interpretable for presence of MRI infarcts. MRI infarcts were detected in 1068 of these 3502 participants while smaller infarct-like lesions (with or without MRI infarcts) were found in 467. Data on infarct-like lesions were missing in 11 participants. A total of 1253 participants had either MRI infarcts or small infarct-like lesions. Measurable plaque was detected in the right carotid in 2225 participants and in the left carotid in 2151 participants. MRI infarcts were associated with older age, higher blood pressures and creatinine levels, lower high-density lipoprotein cholesterol, more frequent aspirin use, and higher prevalences of prior cardiovascular disease (Table 1
). Associations with infarct-like
lesions were inconsistent but prevalence and levels, in
general, were intermediate between those in participants with MRI
infarcts and participants with neither MRI infarcts nor infarct-like
lesions.
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MRI infarcts were strongly associated with common and internal carotid
IMT and degree of carotid stenosis after adjustment for age and
sex (all P<0.0001, Figure 1).
Participants in the highest quintile of common carotid IMT had 50%
greater prevalence of MRI infarcts, and those in the highest quintile
of internal carotid IMT had 40% greater prevalence, compared with
those in the lowest quintile after adjustment for age and sex. Subjects
with 75% stenosis were nearly twice as likely to have MRI
infarcts as those without stenosis. In contrast, smaller
infarct-like lesions were not associated with IMT or stenosis
degree (P>0.2).
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Associations of MRI infarcts with plaque characteristics were less
strong than for IMT and carotid stenosis (Figure 2) and reached significance only for
surface irregularity; infarct prevalence increased modestly with
increasing surface irregularity (P<0.04). Smaller
infarct-like lesions were strongly associated with
heterogeneous plaque (P<0.008), being 33% more
common in those with heterogeneous versus
homogeneous plaque.
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Sulcal score was associated with all 6 carotid variables, including
common and internal IMT and stenosis, heterogeneous
texture, surface irregularity, and increased density (Table 2). The highest quintile of common
carotid IMT was associated with a mean 0.13 U greater sulcal score
compared with the lowest quintile. Ventricular size showed
similar associations with IMT and stenosis but its only
relation to plaque characteristics was a weak association with
increased lesion density. Bifrontal distance was associated only with
common carotid IMT, whereas focal atrophy showed no relationships at
all with carotid variables (data not shown).
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Severity of white matter disease increased with increasing IMT and
stenosis but was not related to lesion characteristics after
adjustment for age and sex, though there was a nonsignificant trend
toward increased white matter disease with increasing surface
irregularity and lesion density (Table 2
, last column). The
highest common carotid quintile had a mean 0.30 greater white matter
score than the lowest quintile. Periventricular
concentration of white matter disease and increased perivascular spaces
were not related to carotid IMT, stenosis, or plaque
characteristics (data not shown).
Multivariate analyses adjusting for factors in
addition to age and sex showed common and internal carotid IMT to
remain significantly associated with MRI infarcts after adjustment for
age, sex, hypertension, echo-LVH, aspirin use (aspirin taken on more
than 7 days in a 2 week period), systolic and
diastolic blood pressures, creatinine, and
smoking status (Table 3). A 0.25-mm
increment in common carotid IMT (1 interquartile range difference) was
associated with a 1.19-fold odds on presence of MRI infarct. Degree of
carotid stenosis, particularly >50%, was also associated with
increased prevalence of MRI infarcts. Plaque
heterogeneity was not associated with MRI infarcts, but
surface irregularity showed a weak inverse relationship
(P<0.03) only when IMT and stenosis were included
in the model. In contrast, lesion density showed a weak relationship
(P<0.02) only when IMT and stenosis were not
included in the model. This association was limited to calcified
plaque, which had a nearly 2-fold increased prevalence of MRI infarct
compared with isodense plaque. Infarct-like lesions were associated
only with heterogeneous plaque texture, but this
association was strong, independent of age, sex, diastolic
blood pressure, and creatinine, and persisted after
adjustment for IMT and stenosis.
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Sulcal score was independently associated with IMT and stenosis
as well as plaque heterogeneity, surface irregularity,
and weakly to lesion density, after adjustment for age, sex, aspirin
use, and hypertension (Table 4). A
0.25 mm increment in common carotid IMT was associated with a
0.07 unit increase in sulcal score after multiple
adjustment. Further adjustment for IMT and stenosis weakened
the relationship of sulcal score to heterogeneous plaque
and removed it for surface irregularity and lesion density.
Ventricular size was associated with IMT after adjustment
for other covariates but was unassociated with plaque characteristics
other than a trend toward increased size with plaque
heterogeneity that disappeared after adjustment for IMT
and stenosis.
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Bifrontal distance was associated only with common carotid IMT (Table 5), after adjustment for inner table
distance, age, sex, systolic blood pressure, atrial
fibrillation, high-density lipoprotein cholesterol, and
aspirin use, and showed no multivariate relationships
with plaque characteristics. White matter disease was associated only
with IMT after adjustment for age, sex, systolic and
diastolic blood pressures, hypertension status, and smoking
status. White matter disease was not associated with plaque
characteristics though there were nonsignificant trends toward
increased severity of white matter disease with surface irregularity
and increased plaque density.
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Examination of ipsilateral versus contralateral MRI infarcts
related to disease in the right or left carotid artery showed little
evidence of stronger associations on the ipsilateral side (Table 6), as might be suspected if carotid
ultrasound were to detect vascular abnormalities leading to cerebral
disease in the distribution of the ipsilateral carotid artery. Limiting
analyses to MRI infarcts 15 mm in diameter or in
watershed vascular distributions showed nearly identical associations
with carotid atherosclerosis and plaque characteristics
as shown for MRI infarcts as a group (data not shown).
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Discussion |
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MRI infarcts, ventricular and sulcal widening, and white matter disease were strongly associated with carotid IMT and stenosis after adjustment for age, sex, and a variety of other cardiovascular and cerebrovascular disease risk factors in this population-based sample of older adults. Though MRI abnormalities showed some associations with plaque characteristics after adjustment for age and sex, many of these were eliminated after adjustment for other risk factors and for severity of carotid atherosclerosis. Only infarct-like lesions retained a significant association (with heterogeneous plaque) after multivariate adjustment; relationships of MRI infarcts (with decreasing surface irregularity) and sulcal widening (with heterogeneous plaque) were only of borderline significance after adjustment. There was no evidence of stronger associations of MRI infarcts with ipsilateral versus contralateral carotid disease, nor of differing associations for large (
15 mm) or watershed
infarcts.
Carotid Disease and the Brain
While carotid IMT and stenosis have been demonstrated to
have strong associations with clinically-evident
stroke,10 14 15 CT-defined infarcts,16 17 and
more recently with MRI-defined infarcts,18 19 less
information is available on relationships of
atherosclerosis severity to other MRI abnormalities
such as ventricular and sulcal widening and white matter
disease. Previous analyses from the CHS have demonstrated
strong and graded relationships between white matter disease and
carotid IMT and stenosis3 and between
ventricular and sulcal enlargement and severity of carotid
atherosclerosis.2 Given the strong and
consistent relationships of MRI abnormalities to severity of
carotid atherosclerosis, the question arises whether
there are other ultrasound-definable characteristics of carotid disease
that are related to MRI abnormalities.
Clinical studies of carotid atherectomy specimens suggest that ulcerated,20 less organized,15 and hemorrhagic21 22 plaques are associated with symptoms. Some of these associations have been disputed, however, with other investigators failing to demonstrate more frequent symptoms associated with ulcerations14 21 and plaque hemorrhage.23 24 The documented ability of B-mode ultrasonographic scanning to detect plaque ulceration,25 heterogeneity,26 27 and hemorrhage,28 though disputed by some,24 29 30 has led to the demonstration that these ultrasound-defined characteristics are also associated with ipsilateral neurologic symptoms,31 clinical events,26 and MRI-defined infarcts.18 32
The mechanisms by which carotid artery disease may be associated with neurological symptoms and stroke include (1) thrombotic occlusion of large vessels such as the carotid and middle cerebral arteries with hypoperfusion in the vascular distribution supplied by these vessels; (2) cerebral embolism of either atheromatous material from a ruptured or ulcerated carotid plaque or of fibrin-platelet material from a thrombotic plaque to distal vessels; or (3) manifestation or general marker of systemic atherosclerosis occurring at the large and small vessel level. Previous studies have demonstrated a strong relationship between CT-defined small cerebral infarcts and ulcerated carotid plaque, even suggesting that small CT lesions may be markers of active plaque ulceration.33 Pathological evidence of embolic material in small arteries supplying infarcted tissue34 and clinical trials demonstrating reduced stroke incidence after carotid endarterectomy in persons with severe carotid stenosis35 provide support for a direct pathogenic role of carotid disease in clinically evident stroke, but the smaller and more frequently silent infarcts detected by MRI may not share the same pathogenic mechanisms.
MRI Infarcts and Plaque Characteristics
The strong relationship of MRI infarcts to severity of carotid
atherosclerosis as measured by IMT and stenosis
does not help to distinguish among the above possibilities, but
associations of MRI infarcts with surface irregularity and
heterogeneous (presumably hemorrhagic29 )
plaque would support artery-to-artery embolism of atherothrombotic
material. That these associations were relatively weak and
inconsistent, particularly after adjusting for
IMT/stenosis, does not lend support for a direct pathogenic
mechanism. Limiting analyses to large or watershed infarcts,
which are more likely to be due to large-vessel
atherosclerosis than to small-vessel hypertensive
disease,2 36 did not increase the strength of
relationships with carotid plaque characteristics and thus also fails
to support a direct pathogenic role for carotid disease. Conversely,
the strong and consistent associations of small infarct-like
lesions with plaque heterogeneity, especially given the
lack of association of these lesions with carotid
atherosclerosis severity and many other
cardiovascular disease risk factors, raises questions
about the pathogenesis of these mysterious lesions that may merit
further investigation.
Similarly, the lack of association of MRI infarcts with plaque characteristics in the ipsilateral carotid artery does not support these lesions being manifestations of carotid arterial disease. That associations with carotid atherosclerosis severity did not differ between ipsilateral and contralateral arteries is puzzling, given prior pathologic and clinical trial evidence. These findings are consistent with data from over 800 patients in the Asymptomatic Carotid Atherosclerosis Study,37 though they conflict with smaller studies showing associations with ipsilateral disease.16 17 One explanation is that MRI detects far more small lesions than large ones,2 which, as described above, are less likely to be related to atherosclerotic large-vessel disease.36
MRI-Defined Gray and White Matter Changes
Little is known about the significance or pathogenesis of
increased ventricular and sulcal sizes and increased
bifrontal distance, but they are generally believed to indicate loss of
functioning cerebral tissue38 and to be related to
cognitive decline.39 Given their generally symmetric
nature, one might not expect to find them in association with
unilateral carotid stenosis or high-risk plaque, but if
ultrasound-defined carotid disease is a general marker of systemic
atherosclerosis, as appears to be the
case,10 then some relationships with these MRI
abnormalities might be expected. Carotid IMT was related to all these
findings even after adjustment for other cardiovascular
disease risk factors, but plaque characteristics for the most part were
not, suggesting that these atrophic changes are more strongly related
to atherosclerosis severity than to any particular type
of carotid plaque.
Less is known about the significance or pathogenesis of white matter disease, though it appears to be related to cognitive decline and dementia40 and is associated most strongly with age and hypertension3 as well as with atherosclerosis.6 The current study confirmed its association with atherosclerosis severity but showed no significant associations with particular plaque characteristics, though there was a suggestion of relationships with surface irregularities and hypodense plaque that may deserve further investigation. Given the generalized nature of white matter disease, its association with carotid atherosclerosis severity but not plaque characteristics may reflect a relationship with more generalized vascular disease rather than implicating an etiologic role for a specific form of carotid disease.
Limitations of the current study include the relatively selected nature
of the subgroup undergoing MRI, though with the high prevalence of
carotid disease and MRI infarct in this subgroup, selection bias is
unlikely to have a major impact on evaluating
associations.41 Reproducibility of plaque characteristics
was relatively modest, with values in the 0.4 to 0.5 range,
consistent with moderate reproducibility.42
Improved methods of plaque characterization may enhance the
identification of associations with MRI abnormalities, but future
investigations should consider the strong correlation between tissue
characteristics of plaque and atherosclerosis severity
measured by wall thickness and stenosis. Because including
severity measures in models of tissue characteristics may constitute
overadjustment (in which severity may be an intermediate in any
potential etiologic pathway between tissue characteristics and MRI
abnormalities) presentation of analyses with and
without adjustment for severity is probably prudent.
In summary, cerebral MRI findings were strongly related to carotid atherosclerosis severity but bore little relationship to ultrasound-defined plaque characteristics after adjustment for carotid IMT and stenosis. While the role of carotid atherosclerosis in cerebrovascular disease as detected by MRI remains to be defined, these data do not support an increased risk of cerebral MRI abnormalities in association with specific carotid plaque characteristics.
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Acknowledgments |
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This work was supported by contracts N01-HC-5079, N01-HC-85086, and N01-HC-15093 from the National Heart, Lung, and Blood Institute.
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Footnotes |
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1 Participating institutions and principal staff have been published previously (Stroke. 1994;25:318–327).
Received February 20, 1998; accepted July 15, 1998.
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