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(Circulation. 2005;112:900-905.)
© 2005 American Heart Association, Inc.

Stroke

C-Reactive Protein and Cerebral Small-Vessel Disease

The Rotterdam Scan Study

E. J. van Dijk, MD, PhD; N. D. Prins, MD, PhD; S. E. Vermeer, MD, PhD; H. A. Vrooman, PhD; A. Hofman, MD, PhD; P. J. Koudstaal, MD, PhD; M. M.B. Breteler, MD, PhD

From the Department of Epidemiology & Biostatistics (E.J.v.D., N.D.P., S.E.V., A.H., M.M.B.B.), Department of Neurology (E.J.v.D., N.D.P., S.E.V., P.J.K.), and Department of Medical Informatics and Department of Radiology (H.A.V.), Erasmus Medical Center, Rotterdam, the Netherlands.

Correspondence to M.M.B. Breteler, MD, PhD, Department of Epidemiology & Biostatistics, Erasmus Medical Center, PO Box 1738, 3000DR Rotterdam, The Netherlands. E-mail m.breteler{at}erasmusmc.nl

Received September 11, 2004; revision received March 17, 2005; accepted April 12, 2005.

	Abstract

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Background— Inflammatory processes are involved in the development and consequences of atherosclerosis. Whether these processes are also involved in cerebral small-vessel disease is unknown. Cerebral white matter lesions and lacunar brain infarcts are caused by small-vessel disease and are commonly observed on MRI scans in elderly people. These lesions are associated with an increased risk of stroke and dementia. We assessed whether higher C-reactive protein (CRP) levels were related to white matter lesion and lacunar infarcts.

Methods and Results— We based our study on 1033 participants of the population-based Rotterdam Scan Study for whom complete data on CRP levels were available and who underwent brain MRI scanning. Subjects were 60 to 90 years of age and free of dementia at baseline. Six hundred thirty-six subjects had a second MRI scan on average 3.3 years later. We used multivariate regression models to assess the associations between CRP levels and markers of small-vessel disease. Higher CRP levels were associated with presence and progression of white matter lesions, particularly with marked lesion progression (ORs for highest versus lowest quartile of CRP 3.1 [95% CI 1.3 to 7.2] and 2.5 [95% CI 1.1 to 5.6] for periventricular and subcortical white matter lesion progression, respectively). These associations persisted after adjustment for cardiovascular risk factors and carotid atherosclerosis. Persons with higher CRP levels tended to have more prevalent and incident lacunar infarcts.

Conclusions— Inflammatory processes may be involved in the pathogenesis of cerebral small-vessel disease, in particular, the development of white matter lesions.

Key Words: inflammation • magnetic resonance imaging • cerebral infarction • microcirculation • cerebral ischemia

	Introduction

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Inflammatory processes are implied in the pathogenesis of atherosclerosis and are a risk factor for myocardial infarction, stroke, and peripheral arterial disease.^1,2 Furthermore, these processes probably play a role in the response to ischemic events that result from atherosclerosis.³ Whether inflammatory processes, apart from their involvement in large-vessel disease, are also involved in the development and consequences of cerebral small-vessel disease is yet unknown.

See p 781

Lacunar brain infarcts and cerebral white matter lesions are caused by small-vessel disease.^4–6 These lesions are commonly observed on MRI scans of elderly people and are associated with an increased risk of stroke, dementia, and depression.^7–9 Although the pathophysiology of cerebral small-vessel disease is not clear, increased age and hypertension are considered the main risk factors. Narrowing of the vascular lumen and failure of cerebral autoregulation result in ischemic damage of the cerebral white and subcortical gray matter.^5,10

The acute-phase reactant C-reactive protein (CRP) has proven to be a sensitive systemic marker of inflammation and to be involved in the endothelial inflammatory response.^11–13 We hypothesized that higher levels of CRP are positively associated with the presence and progression of cerebral small-vessel disease in the elderly.

	Methods

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Study Population
The Rotterdam Scan Study is a prospective, population-based cohort study. We randomly selected participants aged 60 to 90 years in strata of age and sex from 2 large ongoing population-based studies.^14,15 The characteristics of the 1077 nondemented participants have been described previously.¹⁰ Baseline examination in 1995 to 1996 comprised a structured interview, neuropsychological tests, physical examination, blood sampling, and an MRI scan of the brain. In 1999 to 2000, 668 (70%) of the 951 participants who were alive and eligible underwent a second MRI and were reexamined (Figure). Each subject gave written informed consent to participate in the present study, which had been approved by the local medical ethics committee.

View larger version (28K): [in this window] [in a new window]   Flow diagram of study population.

MRI Scanning
In 1995 to 1996, we made axial T1-, T2-, and proton density (PD)–weighted cerebral magnetic resonance (MR) scans on a 1.5-T scanner (MR VISION, Siemens, MR Gyroscan, Philips).¹⁶ In 1999 to 2000, participants underwent a second MRI with the use of the MR VISION scanner and the same sequences.

White Matter Lesions
We considered white matter lesions to be in the periventricular region if they were directly adjacent to the ventricle; otherwise, we considered them subcortical. Baseline white matter lesion severity was scored on hard copy with a visual rating scale.¹⁰ We scored periventricular white matter lesions semiquantitatively in 3 regions (lesions adjacent to the frontal horns, the lateral walls, and the occipital horns of the lateral ventricle), which resulted in a total score that ranged from 0 to 9. For subcortical white matter lesions, we approximated a total volume based on number and size of lesions (range 0 to 29.5 mL).

Two raters independently assessed progression of white matter lesion severity on digital T2-weighted and PD-weighted images by direct scan comparison.¹⁷ Raters were blinded to all clinical information. We scored differences in white mater lesion severity in the 3 periventricular regions of both hemispheres (periventricular score range –6 to 6) and in the subcortical white matter of the 4 lobes of both hemispheres (subcortical score range –8 to 8).¹⁷ The change rating showed good interobserver agreement (intraclass correlation coefficient 0.75 to 0.79) and good to very good intraobserver agreement (intraclass correlation coefficient 0.70 to 0.93). If raters disagreed by 1 point or less on the scale, we used the mean of the ratings; otherwise, we held a consensus meeting. Adjudication by consensus meeting was required in 9% of the periventricular and 11% of the subcortical white matter lesion ratings. Progression was defined as an increase of 1 point or more between baseline and follow-up. We categorized progression into categories of no progression (score <1), minor progression (score 1 to 2.5), and marked progression (score 3). Hyperintensities on PD- and T2-weighted images around an incident infarct were not considered as progression of white matter lesions.

Cerebral Infarcts
The presence of brain infarcts was rated similarly at the baseline and second MRI.⁹ We defined brain infarcts as areas of focal hyperintensity on T2-weighted images sized 3 mm. Areas of hyperintensity in the white matter also had to have corresponding prominent hypointensity on T1-weighted images to distinguish them from white matter lesions. We defined lacunar infarcts as infarcts sized 3 to 20 mm and located in the subcortical white matter or basal ganglia. Nonlacunar infarcts were excluded in the analyses of lacunar infarcts.

High-Sensitivity CRP
We collected nonfasting blood samples into evacuated containers in 1995 to 1996. Plasma was collected after centrifugation for 10 minutes at 3000 rpm. Subsequently, platelet-free plasma was obtained by centrifugation for 10 minutes at 10 000 rpm, immediately frozen in liquid nitrogen, and stored at –80°C. In 2003, serum levels of CRP were determined by the rate near infrared particle immunoassay method (Immage high-sensitivity CRP, Beckman Coulter). This method has an intralaboratory imprecision of <5% according to the manufacturer’s report. CRP level distribution was highly skewed. Values 3 SDs above the sample mean of log-transformed CRP were excluded because they may indicate the presence of an active inflammatory disease.¹⁸

Cardiovascular Risk Factors
Hypertension was defined according to World Health Organization-International Society of Hypertension guidelines at time of blood pressure measurement as systolic blood pressure 160 mm Hg, diastolic blood pressure 95 mm Hg, or the use of blood pressure–lowering medication. Smoking habits were classified as never, former, or current cigarette smoking. We considered diabetes mellitus to be present if the random glucose level was 11.1 mmol/L or if a person was taking oral antidiabetic medications or insulin. Nonfasting serum total cholesterol and HDL levels were determined. Body mass index was calculated as weight divided by height squared. Participants underwent ultrasonography of both carotid arteries to obtain an atherosclerotic plaque score (range 0 to 6) and an intima-media thickness measurement.¹⁹

Data Analysis
Of the 1077 participants at baseline, we failed to obtain blood in 30, and we excluded 14 because of excessively high CRP values. Of the 668 participants with repeated MRI assessments, we failed to obtain blood in 22 and excluded 10 because of excessively high CRP values. Consequently, we performed analysis in 1033 and 636 participants, respectively (Figure).

We performed analyses with CRP levels categorized in quartiles of the baseline distribution and with CRP levels continuously per SD after logarithmic transformation. We assessed the relation of CRP levels with periventricular and subcortical white matter lesions at baseline with linear regression analyses and with white matter lesion progression with binomial logistic regression analyses (none/any progression) and with multinomial logistic regression (any/minor/marked progression; SPSS version 11.0 for Windows [DOS]). We used binomial logistic regression analyses to study the relation between quartiles of CRP levels and prevalent and incident lacunar infarcts. All analyses were adjusted for age, sex, and cardiovascular risk factors and subsequently for measurements of carotid atherosclerosis. We performed additional analyses in which we excluded people (n=125) who used nonsteroidal antiinflammatory drugs (NSAIDs; n=37) or statins (n=46) and people with a prevalent myocardial infarction (n=35) or stroke (n=27) to check whether these factors influenced the associations under study. Because age and hypertension are the main risk factors for cerebral small-vessel disease, we performed stratified analyses on hypertension (yes/no) and age (<70 and 70 years) to study effect modification.

	Results

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Selected baseline characteristics of all participants and of those with repeated MRI assessments are shown in Table 1. The mean follow-up period between the first and second MRI was 3.3 (SD 0.2) years. During this period, 172 participants (27%) showed white matter lesion progression in the periventricular region, 59 (9%) of whom showed marked progression. Two-hundred five participants (32%) showed progression in the subcortical region, 62 (10%) of whom showed marked progression. Ninety participants (14%) had a new cerebral infarct on the follow-up MRI, 76 (12%) of which were lacunar.

View this table: [in this window] [in a new window]   TABLE 1. Baseline Characteristics of All Participants and of the Participants With Repeated MRI Assessments

People with high CRP levels had more severe periventricular and subcortical white matter lesions at baseline than people with low CRP levels, adjusted for age, sex, and cardiovascular risk factors (Table 2). CRP levels were continuously associated with the presence of white matter lesions. These associations, assessed in all 1033 subjects, were similar for the 636 subjects with repeated MRI assessments. Additional adjustment for carotid plaques and intima-media thickness did not change these associations. Persons with higher CRP levels tended to have more lacunar infarcts at baseline, but this was nonsignificant.

View this table: [in this window] [in a new window]   TABLE 2. CRP in Quartiles and as a Continuous Variable in Relation to White Matter Lesion Severity (Mean Grade and Mean Increase in Grade [95% CI]) and Prevalent Infarcts (OR Compared With First Quartile and per SD [95% CI]) in 1033 Subjects at Baseline

People with high CRP levels also had more progression of periventricular and subcortical white matter lesions than people with low CRP levels, adjusted for age, sex, and cardiovascular risk factors (Table 3). CRP levels were continuously associated with the progression of white matter lesions. Additional adjustment for carotid plaques and intima-media thickness did not change these associations. The association between CRP levels and white matter lesion progression was strongest for marked lesion progression. People with higher CRP levels tended to have more new lacunar infarcts than people with lower CRP levels; however, the association was nonsignificant. Exclusion of people with prevalent myocardial infarction or stroke or of people who used statins or NSAIDs did not change these associations. The relationship between CRP and periventricular or subcortical white mater lesions or lacunar infarcts was not modified by age or hypertension (data not shown).

View this table: [in this window] [in a new window]   TABLE 3. CRP in Quartiles and as a Continuous Variable in Relation to Progression of White Matter Lesions and Incident Lacunar Infarcts (OR Compared With First Quartile and per SD [95% CI]) in 636 Subjects With Repeated MRI Scanning

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
We found in a population-based sample of nondemented elderly people that higher CRP levels were associated with presence and progression of periventricular and subcortical white matter lesions. These associations were independent of cardiovascular risk factors or carotid atherosclerosis. People with higher CRP levels tended to have more prevalent and incident lacunar infarcts than those with lower CRP levels; however, these associations were nonsignificant.

Some methodological issues need to be discussed. First, nonparticipation both at baseline and at follow-up was associated with older age.¹⁰ Participants with repeated MRI scans had lower CRP levels, fewer white matter lesions, and fewer silent brain infarcts at baseline than those without follow-up scans. This selective attrition has most likely reduced the power to find an association with risk of incident lacunar infarcts.

The cross-sectional association between CRP levels and white matter lesions, however, was not different for all participants compared with the group of participants who had repeated MRI assessments. Hence, although the potential selection of participants may have somewhat limited the range of baseline and outcome measurements, we do not think that it affected the validity of the associations. Second, although 2 experienced raters independently assessed all MRI scans with good agreement, there still is a possibility of misclassification of brain lesions. Also, CRP levels may have been measured with some error, because we only assessed them once. However, a study in which CRP was measured regularly over a 6-month period concluded that CRP levels are tightly regulated, with few short-term fluctuations.¹¹ Because CRP levels, covariates, and brain lesions were assessed independently and blindly from each other, misclassification, if any, will have been random and would have resulted in an underestimation of the associations.

Elevated CRP levels are not disease specific but are sensitive markers produced in response to tissue injury, infectious agents, immunological stimuli, and inflammation. Cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor- are highly correlated with CRP levels and their function.^12,20 Elevated CRP levels may be related to cerebral white matter lesions and lacunar infarcts via different mechanisms.

First, CRP levels may be a marker for arteriolosclerosis or small-vessel disease, as they are for atherosclerosis. Arteriolosclerosis may result in white matter lesions and lacunar infarcts through vessel occlusion, disturbed cerebral autoregulation, or increases in vascular permeability.⁵ Although no inflammatory cells are observed in the vessel wall in case of arteriolosclerosis, inflammatory endothelial activation may play a role in both small- and large-vessel disease.^4,21,22 Increased levels of inflammatory endothelial inflammation markers (eg, intercellular adhesion molecule and vascular cell adhesion molecule) have been reported in people with white matter lesions and lacunar infarcts.²² Furthermore, CRP itself is actively involved in endothelial cell activation.¹³

Second, inflammation may be a response to ischemic tissue damage.^23–25 Microglial activation is shown in chronic cerebral hypoperfusion and may contribute to even further tissue damage.^26,27 In a state of chronic low-grade inflammation, oligodendrocytes and neurons may be more susceptible to hypoperfusion and hence accelerate lesion progression.²⁸

Third, elevated CRP levels could reflect large-vessel atherosclerosis.^{1–3,12,29,30} Carotid atherosclerosis is related to cerebral white matter lesions, probably by causing reduction of the cerebral blood flow and by production of inflammatory mediators and free radicals that affect the microvascular endothelium.^2,19,31 Furthermore, carotid atherosclerosis also reflects longstanding exposure to cardiovascular risk factors, which it shares with small-vessel disease. Adjustment for carotid atherosclerosis and for cardiovascular risk factors did not change the association, which indicates that other mechanisms are more likely.

Fourth, inflammatory processes are strongly related to and probably part of the pathogenesis of Alzheimer’s disease,^20,32 in which white matter lesions and lacunar infarcts are frequently observed.^33,34 Cerebral amyloid angiopathy is a part of Alzheimer’s disease pathology and may result in white matter lesions and infarcts.^20,35 In the present study, none of the participants were demented at baseline.

At present and based on our observations, we cannot conclude which mechanism underlies the relations we found between CRP levels and small-vessel disease. More than 1 mechanism and probably a combination of mechanisms could underlie the association between high CRP levels and white matter lesions.³ Interaction between hypertension and inflammation in relation to progression of atherosclerosis has been suggested. Although we did not observe such an interaction in relation to cerebral small-vessel disease, this warrants further study.

The observation that CRP as a marker of inflammation may be involved in the pathophysiology of cerebral small-vessel disease is in line with observations made in relation to stroke and dementia. However, mechanisms other than causal mechanisms may underlie the observed association. Therefore, confirmation by other studies is needed. Furthermore, more insight into the exact mechanisms that underlie the association and their relative contributions are necessary. Because statins, NSAIDs, and aspirin could possibly reduce inflammatory activity, they are potential candidates to attenuate progression of lesions related to small-vessel disease and their consequences.³⁶

	Acknowledgments

 
This study was supported by grants from the Netherlands Organization for Scientific Research (No. 904-61-093 and 904-61-096) and the Netherlands Heart Foundation (No. 97.152). We thank our colleagues for their efforts in data collection.

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