Personal ViewRelation of C-reactive protein to stroke, cognitive disorders, and depression in the general population: systematic review and meta-analysis
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)
- et al.
Inflammatory hypotheses: novel mechanisms of Alzheimer's neurodegeneration and new therapeutic targets?
Neurobiol Aging
(2000) - et al.
Increased serum interleukin-1-receptor-antagonist concentrations in major depression
J Affect Disord
(1995) - et al.
Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression
J Affect Disord
(1995) - et al.
C-reactive protein-like immunoreactivity in the neurofibrillary tangles of Alzheimer's disease
Brain Res
(1997) - et al.
Demonstration of CRP immunoreactivity in brains of Alzheimer's disease: immunohistochemical study using formic acid pretreatment of tissue sections
Neurosci Lett
(1994) - et al.
Acute phase proteins in major depression
J Psychosom Res
(1997) - et al.
Clinical depression and inflammatory risk markers for coronary heart disease
Am J Cardiol
(2002) - et al.
Disturbances in acute phase plasma proteins during melancholia: additional evidence for the presence of an inflammatory process during that illness
Prog Neuropsychopharmacol Biol Psychiatry
(1992) - et al.
Inflammation markers in relation to cognition in a healthy aging population
J Neuroimmunol
(2003) - et al.
Inflammation and coagulation factors in persons >65 years of age with symptoms of depression but without evidence of myocardial ischemia
Am J Cardiol
(2002)
Inflammatory markers and depressed mood in older persons: results from the Health, Aging and Body Composition study
Biol Psychiatry
C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor
Blood
Atherosclerosis is an inflammatory disease
Am Heart J
The in vitro neuronal toxicity of pentraxins associated with Alzheimer's disease brain lesions
Brain Res
Cerebrovascular disease and late-life depression: a latent-variable analysis of depressive symptoms after stroke
Am J Geriatr Psychiatry
Projected life-expectancy gains with statin therapy for individuals with elevated C-reactive protein levels
J Am Coll Cardiol
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
Effect of physical activity on serum C-reactive protein
Am J Cardiol
Adherence to the Mediterranean diet attenuates inflammation and coagulation process in healthy adults: the ATTICA Study
J Am Coll Cardiol
Familial and genetic determinants of systemic markers of inflammation: the NHLBI family heart study
Atherosclerosis
Clinical application of C-reactive protein for cardiovascular disease detection and prevention
Circulation
Acute-phase proteins and other systemic responses to inflammation
N Engl J Med
C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice
Circulation
Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events
N Engl J Med
C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women
N Engl J Med
Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men
N Engl J Med
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
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
Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women's Health Initiative observational study
JAMA
Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses
BMJ
Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death
Circulation
Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Multiple Risk Factor Intervention Trial
Am J Epidemiol
C-reactive protein: relation to total mortality, cardiovascular mortality and cardiovascular risk factors in men
Eur Heart J
Inflammatory mechanisms in Alzheimer's disease
Eur Arch Psychiatry Clin Neurosci
Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis
Serum C-reactive protein and self-reported stroke: findings from the Third National Health and Nutrition Examination Survey
Arterioscler Thromb Vasc Biol
Inflammation and stroke: the Leiden 85-Plus Study
Stroke
Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study
Stroke
C-reactive protein and the future risk of thromboembolic stroke in healthy men
Circulation
C-reactive protein, carotid intima-media thickness, and incidence of ischemic stroke in the elderly: the Cardiovascular Health Study
Circulation
Inflammatory markers and onset of cardiovascular events: results from the Health ABC Study
Circulation
The clock-drawing test in elderly Italian community dwellers: associations with sociodemographic status and risk factors for vascular cognitive impairment
Dement Geriatr Cogn Disord
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