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)