Cerebral small vessel disease and C-reactive protein: Results of a cross-sectional study in community-based Japanese elderly

https://doi.org/10.1016/j.jns.2007.06.053Get rights and content

Abstract

Background and purpose

Inflammatory processes are involved in the pathogenesis of atherosclerosis. Inflammation has been known as a risk factor for coronary heart disease, whereas inflammation as a risk for cerebrovascular disease is less well established. Whether inflammatory processes, excluded from their involvement in large-vessel disease, are implicated in the pathogenesis of cerebral small vessel disease remains unclear. We assessed whether higher C-reactive protein (CRP) levels were associated with an increased number of lacunar infarcts or severity of white matter lesions.

Methods and results

In a community-based group of Japanese elderly (n = 689), CRP concentrations were measured using a highly sensitive assay. All participants underwent magnetic resonance imaging (MRI), and cerebral small vessel disease-related lesions (lacunar infarcts and white matter hyperintensity) were subsequently evaluated. Furthermore, carotid atherosclerosis was also assessed with ultrasonography. As the grades of white matter hyperintensity and the numbers of lacunes were considered small vessel disease-related lesions, we evaluated the relationships between CRP levels and small vessel disease-related brain lesions. Interestingly, the median CRP concentration of our participants was remarkably lower, being approximately one third or one quarter of the value of Western populations. Subjects with higher CRP levels tended to have more small vessel disease-related lesions; however, these associations were not seen after adjustment for cardiovascular risk factors and carotid atherosclerosis.

Conclusions

The relationship between CRP levels and small vessel disease-related lesions was not apparent in the community-based Japanese elderly. The impact of inflammation in the pathogenesis of small vessel disease-related brain lesions seems to be weak among the Japanese elderly.

Introduction

Inflammatory processes are thought to be involved in the pathogenesis of atherosclerosis. Several separate lines of evidence suggest that inflammatory processes play a crucial role in the development of myocardial infarction and peripheral arterial disease [1], [2]; however, inflammation as a risk factor for cerebrovascular disease is less well established.

Over the past decade or more, potential targets for measurement as a means to identify and monitor the ongoing inflammatory process, have been provided by many pathophysiological studies. C-reactive protein (CRP), a non-specific inflammatory reactant, has been identified as a reliable and widely available marker for cardiovascular risk [3], [4]. Large population-based studies have shown a dose–response relationship between the level of CRP and the risk of incident coronary disease; however, a characteristic of these studies is, notably, their limitation to white North American or European populations, with the exception of Japanese–American men in the Honolulu Heart Study [5]. Several epidemiological investigations have revealed that CRP levels vary remarkably with ethnic status [6], [7]. Asian populations seem to have low levels of CRP [8], which may reflect the low rates of coronary heart disease in comparison with those of Western populations [9].

CRP elevation has been known as a risk factor for coronary heart disease over the past decade [1], [2], whereas the role of CRP as a risk factor for cerebrovascular disease has been poorly understood. Only a few studies addressing the relationship between CRP and carotid atherosclerosis have been reported so far [10], [11], [12]. Furthermore, only two studies explored the role of CRP in cerebral small-vessel disease (SVD), and the results of two studies were controversial [12], [13]. Cerebral SVD-related brain lesions, known as lacunar infarction and white matter hyperintensity, are associated with an increased risk of future stroke or dementia [14], [15]. Increased age and hypertension are considered to be major risk factors for cerebral SVD; however, the pathophysiology of the disease remains to be clarified. CRP has been known to be involved in the endothelial inflammatory response [4], [16]; thereby, elevation of CRP is likely to increase the risk for ischemic stroke. If the level of CRP is associated with cerebral SVD, CRP is potentially a useful marker for monitoring cerebral small vessel disease-related brain lesions. The main objective of the present investigation was to assess whether higher levels of CRP are associated with the presence of cerebral SVD-related lesions among the community-based Japanese elderly.

Section snippets

Study population

Details of the present study have been described previously [17]. Samples used for this study were obtained from two different communities in Yamagata Prefecture, Japan, namely, Takahata town and Sagae city. All subjects aged 61 (306 subjects) and 72 years (346 subjects) in Takahata town were invited to participate in the present study, and, from this group, 223 (72.8%) of the 61-year-old residents and 217 (62.7%) of the 72-year-old residents were enrolled in this study. In Sagae city, we

Clinical variables and small vessel disease-related brain abnormalities of study subjects

The detailed clinical characteristics of the participants are shown in Table 1, Table 2. In this study, 196 subjects (28.4%) were found to have one or more lacunar infarcts on their MRIs. According to the Fazekas scale, at least one WMH lesion was seen in 492 subjects, and 175 subjects showed moderate WMH (mWMH; grades 2 and 3 on the Fazekas scale) lesions on their MRIs. The age, prevalence of hypertension, systolic and diastolic BP, plaque score, and thrombomodulin were higher in subjects with

Discussion

As in several previous studies, the present investigation suggested a relationship between CRP levels and the severity of carotid atherosclerosis in community-based elderly subjects. However, our data did not show associations between the CRP levels and severity of cerebral SVD, as reflected by the rating scale of white matter hyperintensities or prevalent lacunar infarcts on brain MRI of our participants. Subjects with high CRP levels had more severe white matter lesions than subjects with low

Acknowledgments

This work was partially supported by the 21st Century Center of Excellence (COE) program #F03 (“Molecular Epidemiological Study Utilizing Regional Characteristics,” Yamagata University) funded by the Ministry of Education, Culture, Sports, Science and Technology, Japan.

References (24)

  • K. Ichikawa et al.

    Diagnosis and epidemiological implication of regional differences in serum concentrations of proteins observed in six Asian cities

    Clin Chem Lab Med

    (2004)
  • I. Saito et al.

    Comparison of fatal coronary heart disease occurrence based on population surveys in Japan and the USA

    Int J Epidemiol

    (2000)
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