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The Lancet Neurology

Volume 4, Issue 6, June 2005, Pages 371-380
The Lancet Neurology

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Relation of C-reactive protein to stroke, cognitive disorders, and depression in the general population: systematic review and meta-analysis

https://doi.org/10.1016/S1474-4422(05)70099-5Get rights and content

Summary

Evidence suggests that a high concentration of C-reactive protein (CRP) is a cardiovascular risk factor and an important correlate of cognitive disorders and depression. Recently, population-based studies examining the association between CRP and stroke, cognitive impairment, or depression have been done but have not yet been systematically reviewed. Here we present a systematic review of the associations between CRP and stroke, cognitive impairment, and depression. Hospital or clinic-based studies were excluded because the inferences might not be easily applicable to the general population. 19 eligible studies of CRP were selected: seven for stroke, six for cognitive disorders, and six for depression. Raised CRP concentrations were associated with history of stroke and increased risk of incident stroke. Meta-analysis of studies with long follow-up (>8 years) showed that the risk for stroke in healthy individuals with the highest quartile of CRP concentrations increased nearly 70% compared to those with the lowest quartile. High concentrations of CRP were predictive of cognitive decline and dementia. The relations of CRP to depression were all cross-sectional and were not consistent. We conclude that high concentrations of CRP are associated with increased risk of stroke and cognitive impairment. The association between CRP and depression should be studied prospectively.

Introduction

C-reactive protein (CRP), composed of five 23 kDa subunits, is a hepatically derived pentraxin that has a crucial role in the human immune system.1 CRP, largely regulated by interleukin 6, has been widely used to study various inflammatory states.2 Inflammatory processes are now well recognised to play a central part in the pathogenesis of atherosclerosis and its complications. In addition to signalling the underlying inflammatory or atherosclerotic processes, CRP has been shown to be an active participant in the atherosclerotic process in a recent animal study.3

To date, compelling epidemiological evidence has supported the notion that CRP is a risk factor for cardiovascular events. Highly consistent clinical data across the USA and Europe have indicated a predictive role of CRP in various cardiovascular diseases.4, 5, 6, 7, 8, 9, 10, 11, 12, 13 However, the studies linking CRP to cardiovascular disease have mostly focused on coronary heart disease or combined vascular events. Data examining the association between CRP and stroke, although existent, are relatively sparse and have not yet been systematically assessed.

Cerebral atherosclerotic changes, including large observable stroke or leucoaraiosis, may interrupt the integrity of the frontal-subcortical circuit and thus result in cognitive impairment and depressive disorder. Increased CRP concentrations and chronic inflammation, both important atherosclerotic risk factors, have been proposed as an underlying mechanism associated with dementing illness14, 15 and depression.16, 17 CRP, a marker of chronic inflammation, has been detected in the senile plaques and neurofibrillary tangles of patients with Alzheimer's disease.18, 19 In addition, higher concentrations of CRP have been found in the patients with depressive disorders compared with controls.20, 21, 22 Unfortunately, many of these studies were limited to selected clinical samples or failed to control for important confounding factors. Recently, studies based on broader population samples and that examine the association between CRP and cognitive impairment or depression have been done. However, these studies have not been systematically reviewed.

We therefore did a systematic review to assess the association between CRP and stroke, cognitive disorders, and depression. We sought to describe epidemiological inferences that were more applicable to the general population.

Section snippets

Methods

We searched the MEDLINE database for English language studies published between January, 1966, and September, 2004. We did separate searches of the following medical subject headings (MeSH) or textwords: “cerebrovascular accident” (MeSH), “stroke” (textwords), “cognition disorders” (MeSH), “dementia” (MeSH or textwords), “cognitive impairment” (textwords), “depressive disorders” (MeSH), and “depression” (MeSH or textwords), combined with the MeSH term “C-reactive protein”. Additional references

Results

We identified 385 potentially relevant studies based on the MEDLINE search strategies. Of these, 19 studies were included because they met the predefined selection criteria. The selection process is outlined in figure 1. Studies included were for an association between CRP and stroke (seven studies; table 1),6, 24, 25, 26, 27, 28, 29 cognitive disorders (six studies; table 2),30, 31, 32, 33, 34, 35 and depression (six studies; table 3).36, 37, 38, 39, 40, 41

Proposed mechanisms

The possible explanations for the association between increased serum concentrations of CRP and stroke, cognitive disorders, and depression are summarised below and in figure 3.

Implication of clinical practice and research

The epidemiological data that support the role of CRP as a predictor of vascular disease are consistent across different study populations. Ridker and colleagues5 assessed the predictive role of CRP and several inflammatory and lipid markers in the development of cardiovascular events in the prospective Women's Health Study. Of the 12 markers examined, CRP was identified as the strongest univariate predictor of the risk of cardiovascular events. In a separate analysis with the same study

Conclusions

CRP, an acute-phase reactant produced by the liver, is an indicator of underlying systemic inflammation and a novel plasma marker for atherothrombotic disease. Our meta-analysis indicates that the risk for stroke in healthy individuals with highest quartile of CRP concentrations increases nearly 70% compared to those with the lowest quartile after more than 8 years of follow-up. In addition, various population-based prospective studies suggest that CRP is associated with the development of

References (84)

  • BW Penninx et al.

    Inflammatory markers and depressed mood in older persons: results from the Health, Aging and Body Composition study

    Biol Psychiatry

    (2003)
  • J Cermak et al.

    C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor

    Blood

    (1993)
  • R Ross

    Atherosclerosis is an inflammatory disease

    Am Heart J

    (1999)
  • T Duong et al.

    The in vitro neuronal toxicity of pentraxins associated with Alzheimer's disease brain lesions

    Brain Res

    (1998)
  • BT Mast

    Cerebrovascular disease and late-life depression: a latent-variable analysis of depressive symptoms after stroke

    Am J Geriatr Psychiatry

    (2004)
  • GJ Blake et al.

    Projected life-expectancy gains with statin therapy for individuals with elevated C-reactive protein levels

    J Am Coll Cardiol

    (2002)
  • K Fassbender et al.

    Proinflammatory cytokines in serum of patients with acute cerebral ischemia: kinetics of secretion and relation to the extent of brain damage and outcome of disease

    J Neurol Sci

    (1994)
  • MA Albert et al.

    Effect of physical activity on serum C-reactive protein

    Am J Cardiol

    (2004)
  • C Chrysohoou et al.

    Adherence to the Mediterranean diet attenuates inflammation and coagulation process in healthy adults: the ATTICA Study

    J Am Coll Cardiol

    (2004)
  • JS Pankow et al.

    Familial and genetic determinants of systemic markers of inflammation: the NHLBI family heart study

    Atherosclerosis

    (2001)
  • PM Ridker

    Clinical application of C-reactive protein for cardiovascular disease detection and prevention

    Circulation

    (2003)
  • C Gabay et al.

    Acute-phase proteins and other systemic responses to inflammation

    N Engl J Med

    (1999)
  • A Paul et al.

    C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice

    Circulation

    (2004)
  • PM Ridker et al.

    Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events

    N Engl J Med

    (2001)
  • PM Ridker et al.

    C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women

    N Engl J Med

    (2000)
  • PM Ridker et al.

    Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men

    N Engl J Med

    (1997)
  • W Koenig et al.

    C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992

    Circulation

    (1999)
  • RP Tracy et al.

    Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project

    Arterioscler Thromb Vasc Biol

    (1997)
  • AD Pradhan et al.

    Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women's Health Initiative observational study

    JAMA

    (2002)
  • J Danesh et al.

    Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses

    BMJ

    (2000)
  • CM Albert et al.

    Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death

    Circulation

    (2002)
  • LH Kuller et al.

    Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Multiple Risk Factor Intervention Trial

    Am J Epidemiol

    (1996)
  • MA Mendall et al.

    C-reactive protein: relation to total mortality, cardiovascular mortality and cardiovascular risk factors in men

    Eur Heart J

    (2000)
  • M Hull et al.

    Inflammatory mechanisms in Alzheimer's disease

    Eur Arch Psychiatry Clin Neurosci

    (1996)
  • JJ Deeks et al.

    Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis

  • ES Ford et al.

    Serum C-reactive protein and self-reported stroke: findings from the Third National Health and Nutrition Examination Survey

    Arterioscler Thromb Vasc Biol

    (2000)
  • E van Exel et al.

    Inflammation and stroke: the Leiden 85-Plus Study

    Stroke

    (2002)
  • NS Rost et al.

    Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study

    Stroke

    (2001)
  • JD Curb et al.

    C-reactive protein and the future risk of thromboembolic stroke in healthy men

    Circulation

    (2003)
  • JJ Cao et al.

    C-reactive protein, carotid intima-media thickness, and incidence of ischemic stroke in the elderly: the Cardiovascular Health Study

    Circulation

    (2003)
  • M Cesari et al.

    Inflammatory markers and onset of cardiovascular events: results from the Health ABC Study

    Circulation

    (2003)
  • G Ravaglia et al.

    The clock-drawing test in elderly Italian community dwellers: associations with sociodemographic status and risk factors for vascular cognitive impairment

    Dement Geriatr Cogn Disord

    (2003)
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