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DOI: 10.1148/radiol.2481070300
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(Radiology 2008;248:202-209.)
© RSNA, 2008

Neuroradiology

Brain White Matter Hyperintensities Are Associated with Carotid Intraplaque Hemorrhage1

Nishath Altaf, MRCS (Ed), Paul S. Morgan, PhD, Alan Moody, FRCR, Shane T. MacSweeney, FRCS, J. R. Gladman, FRCP, and Dorothee P. Auer, MD

1 From the Department of Academic Radiology (N.A., P.S.M., D.P.A.), Department of Vascular and Endovascular Surgery (N.A., S.T.M.), and Division of Rehabilitation and Ageing (J.R.G.), University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, England; and Department of Medical Imaging, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (A.M.). Received February 13, 2007; revision requested April 23; revision received August 7; accepted September 17; final version accepted February 7, 2008. Supported by the Stroke Association (UK), Special Trustees of Nottingham University Hospitals, and Mason Medical Research Foundation. Address correspondence to D.P.A. (e-mail: dorothee.auer@nottingham.ac.uk).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Purpose: To retrospectively assess the relationship between carotid intraplaque hemorrhage (IPH), which indicates plaque instability, and brain white matter hyperintense lesions (WMHLs) by using a within-patient design.

Materials and Methods: All patients gave written informed consent for the initial magnetic resonance (MR) studies, and the institutional review board and local research ethics committee waived initial informed consent for the pooled analysis. A total of 190 patients with symptomatic carotid artery disease underwent fluid-attenuated inversion-recovery imaging of the brain and fat-suppressed black-blood T1-weighted MR imaging of the carotid arteries. The volumes of periventricular lesions, subcortical lesions, and total WMHLs were calculated and compared between hemispheres in relation to symptoms and IPH, and their interaction was calculated and compared by using repeated measures three-factorial multivariate analysis.

Results: After exclusion of 12 patients, 178 patients (116 men, 62 women; mean age, 70.2 years ± 8.6 [standard deviation]) remained. There was no significant difference in WMHL volume between the symptomatic and asymptomatic hemispheres, and WMHL volume was not related to the degree of carotid stenosis. The presence of carotid IPH significantly interacted with the interhemispheric WMHL difference (Wilks {lambda} test, F = 9.95; df = 3; P < .001). Univariate analysis showed larger total and periventricular WMHL volumes (P < .05) in patients with ipsilateral IPH.

Conclusion: Carotid artery disease and leukoaraiosis were associated with features that indicated plaque instability, namely IPH, whereas the degree of stenosis had no effect.

© RSNA, 2008


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Leukoaraiosis is a common feature of the aging brain (1), with a conspicuous appearance on T2-weighted magnetic resonance (MR) images as white matter hyperintense lesions (WMHLs). WMHLs are strongly associated with age, arterial hypertension, diabetes, and a number of other vascular risk factors (2,3); however, they also show a prominent heritability (4). The underlying histologic findings include reduced myelin, axonal loss, and astrocytic gliosis (5–8). WMHLs are associated with dementia (9), gait abnormalities, and late-onset depression (10). Moreover, WMHLs represent an independent risk factor that can be used to predict future stroke (11–14).

The pathogenesis of WMHLs is unclear. The prevailing notion is that small-vessel disease is the main causative factor of WMHLs (15), although disruption of the blood-brain barrier also has been implicated (16). However, there is accumulating evidence that there is a link between large-vessel atherosclerosis and leukoaraiosis (17–19), as well as between large-vessel atherosclerosis and deep white matter infarcts (14,20,21). Any association between large-vessel disease and white matter ischemia may be indirect via shared vascular risk factors or causative in nature, with artery-to-artery thromboembolization and impaired hemodynamics being two possible mechanisms.

In a preliminary study, researchers examined the relationship between the histologic features of carotid endarterectomy specimens and the extent of leukoaraiosis in patients with symptomatic carotid artery disease (22). Patients with unstable carotid plaques had more ipsilateral WMHLs than did those with stable plaques (22). However, that study was too small to enable researchers to detect a difference in the total volume of WMHLs, and it did not allow for the control of other, possibly mutually associated, patient-related factors. Thus, the purpose of our study was to retrospectively assess the relationship between carotid intraplaque hemorrhage (IPH), which indicates plaque instability, and brain WMHLs by using a within-patient design.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Study Sample
Retrospective analysis was performed on a data pool that consisted of MR images obtained in 190 patients. We included patients with recent (<6 months since onset) anterior circulation transient ischemic attacks, minor strokes, and amaurosis fugax, as well as a minimum degree of stenosis (30% stenosis). The degree of stenosis was determined by using duplex ultrasonographic (US) imaging criteria, as derived with duplex imaging (23), in an attempt to correlate as closely as possible with the North American Symptomatic Carotid Endarterectomy Trial angiographic stenosis criteria (24). The patients were previously recruited as part of other studies (25–27).

Informed consent had been obtained from all patients previously recruited for other institutional review board–approved studies. A waiver of informed consent for the pooled analysis in the current study was approved by the Nottingham Local Research Ethics Committee.

MR Examination and Evaluation
MR studies were performed on a 1.5-T Vision (Siemens, Erlangen, Germany) imager. MR imaging of the carotid plaque was performed as previously described (28) with a coronal water-only excitation T1-weighted magnetization-prepared three-dimensional gradient-echo sequence (repetition time msec/echo time msec/inversion time msec, 10.3/4.0/20; 15° flip angle; 350 x 300-mm field of view; 256 x 140 matrix; 140 partitions; 120–150-mm volume thickness). The number of partitions and the inversion time were chosen such that the effective inversion time allowed us to null blood. Selective water excitations ensured that the resulting images did not contain signals from fat or lipids. This technique was found to have high accuracy in the detection of unstable carotid plaques (28). In addition, a standard fluid-attenuated inversion-recovery (FLAIR) sequence (9000/110/2500, 180 x 240-mm field of view, 176 x 256 matrix, 4-mm section thickness, 2-mm intersection gap, two signals acquired) was performed.

Carotid plaques were classified on the basis of relative signal intensity by a trained investigator (N.A., 1 year of experience) who was blinded to clinical and FLAIR data. Supervised training in the assessment of carotid plaques and WMHL recognition was performed over a 1-year period. This training was supervised by an experienced academic neuroradiologist (D.P.A., with 20 years of experience in MR neuroimaging). The relative signal was rated as hyperintense or not hyperintense compared with adjacent skeletal muscle defined qualitatively. Signal intensities were measured where they were highest at the level of the carotid plaque (1 cm above or below the common carotid artery bifurcation) and in the adjacent sternocleidomastoid muscle in 50 carotid plaques that were judged to be equivocal at qualitative assessment. A commercial image processing tool (Java Image, http://xinapse.com) was used to draw regions of interest to calculate the mean signal intensity within the hyperintense-appearing carotid plaque (range of region of interest area, 9.7–64.0 mm2). A comparison region of interest with the same area was placed on the adjacent sternocleidomastoid muscle, and the average signal intensity was calculated. Presence of hyperintensity was defined on the basis of a signal intensity of more than 150% of that of the adjacent skeletal muscle (29). As T1 hyperintensity on fat-suppressed blood-nulled images is likely to represent methemoglobin, we defined presence or absence of IPH on the basis of the presence or absence of plaque T1 hyperintensity, respectively.

Volumetric quantification of WMHL was performed on axial FLAIR images by using a semiautomated analysis program (30); thus, we were able to exclude lacunae that resembled cerebrospinal fluid. Readers (N.A.) who were blinded to the plaque signal intensity findings and the clinical data performed analysis separately for each hemisphere, as described in detail elsewhere (22). An experienced trained researcher (N.A., 1 year of experience) performed all analyses at a different time (separated by 1 month) than analysis of the MR carotid status. This was done with the reader blinded to clinical data and carotid IPH status. In brief, WMHLs were manually outlined on each of the 15 FLAIR axial sections that covered the majority of supratentorial white matter. To enhance reliability and to overcome intersubject variability and coil-related and section ordering–related inhomogeneities, FLAIR images were manually thresholded so that WMHL was defined accurately according to the signal intensity of normal-appearing white matter for each respective hemisphere and each axial FLAIR section. The cutoff threshold was the mean ± 3 standard deviations. An experienced investigator (N.A.) prepared all of the images. A minimum size criterion of more than 3 mm in diameter was applied. WMHLs were further separated into confluent periventricular lesions and isolated subcortical lesions according to whether hyperintense lesions were contiguous with the lateral ventricular border (periventricular lesions) or distinct and subcortical (including those lesions found in the deep white matter) according to the Rotterdam criteria (17). Subcortical extensions from cortical and lacunar infarcts were excluded. Respective lesion volumes were calculated automatically.

The principal investigator (N.A.) and a junior radiologist (as part of supervised training over 6 months) had previously assessed intra- and interobserver variability on 20 hemispheric WMHL volumes, with two measurements obtained 3 months apart.

Statistical Analysis
Statistical calculations were performed by using SPSS software (version 11.0; SPSS, Chicago, Ill). Statistical significance was set at P < .05. Qualitative patient demographics were compared with the {chi}2 test. Quantitative data were compared with the Student t test and the Mann-Whitney U test for parametric and nonparametric variables, respectively.

Multifactorial multivariate analysis of variance with a repeated measures design was used to assess the effect of recent symptoms on WMHL volumes (within-subject factor), the presence of ipsilateral and contralateral IPH (between-subject factors), and the interaction between these factors while controlling for age, sex, and hypertension. The dependent variables were periventricular lesions, subcortical lesions, and total WMHLs. Univariate F tests were used to determine if there was any significance according to the multivariate tests (Wilks {lambda}).

Effects from the degree of stenosis on ipsilateral WMHL volumes were assessed by using partial correlation analysis and controlling for age. The intraclass correlation coefficient was determined along with intra- and interobserver agreement in the assessment of carotid IPH status and WMHL volume.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Assessment of Carotid Plaque Status and WMHL Volume
Our results showed good agreement, with intraclass correlation coefficients of 0.70 and 0.80 for intraobserver testing of periventricular WMHL and subcortical WMHL, respectively, and 0.71 and 0.70 for interobserver testing of periventricular WMHL and subcortical WMHL, respectively. Additionally, there was excellent agreement in the identification of carotid plaque signal intensity on MR images of 50 plaques ({kappa} = 0.94 for intraobserver testing, {kappa} = 0.82 for interobserver testing).

IPH and Patient Characteristics
Of the 190 patients recruited, three had images that could not be interpreted because of movement artifacts, whereas nine had images that could not be analyzed for the extent of WMHL because of large hemispheric cortical infarcts (>50% of the hemisphere). Of the remaining 178 patients, 115 (64.6%) had signs of carotid IPH ipsilateral to the symptomatic hemisphere on MR images. There were no significant clinical differences between patients with and those without IPH of the symptomatic carotid artery, with the exception that a higher proportion of men had IPH (Table 1). In particular, there were no significant differences in the type of antiplatelet agents used and the interval between the start of symptoms and MR imaging between the two groups (Table 1). Also, the degree of stenosis did not differ between the groups. A total of 62 patients (34.6%) had IPH in the asymptomatic carotid plaque. Of these patients, 52 had bilateral IPH (Table 2).


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  		Table 1. Demographic and Risk Factors of Patients according to the Ipsilateral Symptomatic MR Plaque Intensity

 

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  		Table 2. Total WMHL Volume Interhemispheric Difference in Patients with Presence and/or Absence of IPH in Symptomatic and Asymptomatic Carotid Plaque

 
IPH, Symptoms, and WMHL
The interhemispheric difference in total WMHL between the symptomatic and asymptomatic hemispheres showed a qualitative dependence on the IPH status (Table 2): In patients with unilateral IPH, WMHL volumes were larger on the side of the brain with IPH. In contrast, WMHL volumes were largely similar between hemispheres in patients with bilateral presence or absence of IPH.

Multivariate analysis of variance showed that cerebral ischemic symptoms in the previous 6 months were not significantly related to WMHL volumes (F = 1.08, df = 3) (Table 3). There was no effect of ipsilateral or contralateral IPH at between-subject analysis (F = 0.62 and F = 0.15, respectively; df = 3). There was, however, a significant interaction between IPH and symptom status on WMHL volumes for both ipsilateral IPH (F = 9.95, df = 3, P < .01) and contralateral asymptomatic carotid IPH (F = 9.89, df = 3, P < .01).


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  		Table 3. Mean Periventricular, Subcortical, and Total WMHL Volumes, as Determined with IPH Status of Symptomatic and Asymptomatic Carotid Plaque of the Cerebral Hemispheres

 
Locating Interaction Effects between IPH and Symptoms
Univariate analysis was used to locate the interaction between the symptoms and IPH of the symptomatic carotid artery (a) total WMHL (F = 29.9, P < .001) and (b) periventricular WMHL volume (F = 29.1, P < .001) (Table 3). In the presence of ipsilateral IPH, the ipsilateral WMHL volume was greater than the contralateral WMHL volume (Figure, part a). The partial eta2 (a measure of the effect size) was 0.149 for total WMHL volume and 0.145 for periventricular WMHL volume. Subcortical lesion volume was not significantly larger in patients with IPH (Table 3).


Figure 1A
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  		Figure a: (a, b) Scatterplots show the relationship between total WMHL volume in the symptomatic and asymptomatic cerebral hemispheres and the presence or absence of IPH in the symptomatic (ipsilateral) and asymptomatic (contralateral) carotid plaques.

 
Similar univariate results were obtained for IPH in the asymptomatic carotid artery with a significant interaction with symptoms for total WMHL volume (F = 29.3, partial eta2 = 0.146) and periventricular WMHL volume (F = 29.6, partial eta2 = 0.148, P < .001) (Table 3) but not for subcortical WMHL volume (F = 0.48, P = .49) (Table 3). In the presence of contralateral IPH, the WMHL volume difference between the asymptomatic and symptomatic hemispheres was reduced (Figure, part b).


Figure 1B
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  		Figure b: (a, b) Scatterplots show the relationship between total WMHL volume in the symptomatic and asymptomatic cerebral hemispheres and the presence or absence of IPH in the symptomatic (ipsilateral) and asymptomatic (contralateral) carotid plaques.

 
Between-Subject Comparison of WMHL Volume
Age was the only significant factor that influenced WMHL volume between subjects (F = 4.18, df = 3, P < .01). At the univariate level, only age had a significant influence on total and periventricular WMHL volumes (F = 12.3 and F = 12.0, respectively), with a trend for subcortical WMHL volume (F = 2.6, P = .1). When we controlled for age, there was no association between the degree of carotid artery stenosis, as measured herein, and WMHL volumes (R2 = 0.01, P = .60).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
Our main finding was that a significant association exists between leukoaraiosis, as determined with WMHL volume, and the presence or absence of MR imaging signs of carotid IPH in patients with symptomatic carotid disease. Carotid IPH was associated with larger WMHL volumes, in both the symptomatic hemisphere and the asymptomatic hemisphere, whereas neither the degree of stenosis nor the symptoms alone showed such an association.

This study extends the previously demonstrated link between the number of WMHLs and the histologically complicated carotid plaques (22). Our findings also are in agreement with findings of previous diffusion-weighted imaging studies that showed that both acute and chronic ischemic lesions may result in WMHLs at T2-weighted or FLAIR MR imaging (14,31). Furthermore, acute deep white matter medullary infarcts were noted to contribute to WMHL volume load (20,21). Of note, the majority of patients with deep white matter medullary infarcts were shown to have large-vessel disease and often had further embolic-appearing cortical diffusion abnormalities (20). This supports the interpretation that embolic events from unstable carotid plaques may contribute to the development of WMHL.

Our findings challenge previously held assumptions. In earlier studies, researchers concluded that there was no link between carotid disease and WHMLs (32,33). However, these researchers may well have missed important associations because they used the degree of stenosis as the indicator of carotid disease that was also unrelated to leukoaraiosis in our study. This mainly reflects the fact that the degree of stenosis accords only variably with the abnormal state of the plaque. A study that was performed to investigate the interrelation between WMHL and carotid plaque morphology assessed with US (34) showed that hypoechoic carotid plaques were unrelated to the extent of leukoaraiosis; however, the discrepancy between that study and our study may stem from the fact that US is inferior to MR imaging in the depiction of features of carotid plaque instability (28,35,36).

The observed association between IPH and WMHL, however, does not allow a causal relationship to be inferred. Indirect associations between IPH and leukoaraiosis may exist via shared pathogenetic risk factors. Advanced atherosclerosis affecting both small and large cerebral vessels may favor IPH, as well as progression of WMHL. There are a number of common pathogenetic factors between small- and large-vessel disease, including amyloid deposition, which is now recognized not only as an important feature in atherosclerosis (37,38) but also as being associated with WMHL and intracerebral bleeding (39). While we cannot firmly exclude such an indirect association, it is difficult to conceive how commonly shared pathogenetic factors would act unilaterally to explain the interhemispheric effects. This is a perceived strength of the chosen within-subject interhemispheric comparison design, which allowed control of interindividual variability that may otherwise have confounded any association between carotid and cerebral disease. With use of this method, the effect of IPH on WMHL could be identified as being independent of genetic and epidemiologic vascular risk factors that may be shared by small- and large-vessel disease.

Apart from embolic events, only hemodynamic effects are plausible factors for an ipsilateral association between carotid disease and WMHL. In this study sample, no effect was seen from the degree of stenosis; however, no data on cerebrovascular reactivity (CVR) were available. Impaired CVR has been shown in patients with WMHL (40) and carotid artery disease (41), but there are no grounds for speculation on a specific association between IPH and impaired CVR.

In contrast, carotid plaque morphology is known to play an important role in determining the subsequent risk of embolic stroke (35,42). A large postmortem study revealed that carotid IPH is strongly associated with plaque instability, independent of the time from the last event (43). Longitudinal data also suggest that the presence of carotid IPH increases the risk of repeated hemorrhage within the plaque and causes progression of atherosclerosis (44). This process occurs over the course of several years, causing plaques to progressively destabilize and resulting in plaque rupture and associated thromboembolism. Plaques may then heal and repeat the same process over the course of several years. The clinical relevance of carotid IPH as a marker of thromboembolism potential has further been shown, as IPH was found to enable the prediction of cerebral ischemic events in asymptomatic (45) and symptomatic (29) patients with carotid disease. Further direct evidence comes from an association seen between IPH and microembolic activity (46). Taken together, embolic ischemic events associated with unstable carotid plaques may contribute to the development of leukoaraiosis in patients with carotid disease.

The association between leukoaraiosis and IPH proved significant for periventricular WMHLs and total WMHLs but not for subcortical lesion volume. However, the lack of association between IPH and ipsilateral subcortical WHML volumes must be interpreted cautiously. First, we deliberately excluded subcortical lesions adjoining cortical infarcts to limit the effect from the tissue ischemia caused by the most recent clinical event. Second, despite adhering to established methods (17), the separation between subcortical and periventricular disease on two-dimensional MR images is arbitrary, as previously demonstrated (47). With increasing lesion load, deep white matter lesions will coalesce with periventricular lesions. Similarly, deep white matter medullary infarcts are also likely to cluster with periventricular lesion load, especially in older people with preexisting leukoaraiosis. This may be the reason why a link between the presence of carotid plaques and the severity of periventricular rather than subcortical disease was noted in a population study (17). Third, the small subcortical lesion load may have reduced the statistical power and thereby precluded the detection of any true effect. Against this background, we can conclude only that the association between IPH and leukoaraiosis in this sample was confined to periventricular and coalescent deep white matter lesions. Nevertheless, in light of a recent neuropathologic MR imaging postmortem study that highlighted the biologic differences between periventricular and deep subcortical WMHLs, it is tempting to speculate on potentially different pathogenetic mechanisms in these two brain regions (7,48). To assess the regional predilection of various pathogenetic factors, such as MR IPH, more refined noncategorical classification methods, such as voxel-based morphometry, would be needed—preferably in a sample of patients with asymptomatic carotid artery disease only.

This study was also limited due to its cross-sectional design. We were unable to assess whether the presence of carotid IPH predated the interhemispheric WMHL noted in this study. However, longitudinal studies have shown that carotid IPH is stable over time (49) and that IPH increases the risk of recurrent bleeding (44). The varying interval between appearance of symptoms and MR imaging may be perceived as a further limitation. There was, however, no difference between subgroups for this interval, making bias due to the timing of MR imaging unlikely.

In summary, this study showed an unconfounded association between leukoaraiosis, assessed as WMHL volume, and carotid intraplaque hemorrhage, as assessed with carotid MR imaging in patients with symptomatic carotid disease. This suggests that IPH may be related to a yet-unknown process underlying IPH and unilateral WMHL or that thromboembolism may contribute to the development of ischemic leukoaraiosis


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   ACKNOWLEDGMENTS
 
We thank Sarah Armstrong, PhD, Medical Statistician, Trent Research and Development Support Unit, University of Nottingham, for statistical advice.


   FOOTNOTES
 

Abbreviations: FLAIR = fluid-attenuated inversion recovery • IPH = intraplaque hemorrhage • WMHL = white matter hyperintense lesion

Author contributions: Guarantor of integrity of entire study, D.P.A.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, N.A., A.M., S.T.M., J.R.G., D.P.A.; clinical studies, N.A., D.P.A.; experimental studies, N.A., P.S.M., D.P.A.; statistical analysis, N.A., J.R.G., D.P.A.; and manuscript editing, all authors

Authors stated no financial relationship to disclose.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

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