Markers of low-grade inflammation and endothelial dysfunction are related to reduced information processing speed and executive functioning in an older population – the Hoorn Study
Introduction
Cognitive impairment and dementia are important public health problems. To date, no cure is available, but some factors contributing to cognitive decline are potentially modifiable. These include vascular risk factors such as diabetes, hypertension, dyslipidemia, obesity, and smoking, which are part of a complex cascade of subclinical vascular abnormalities that occurs in aging (Knopman and Roberts, 2010). Eventually, such abnormalities can lead to cardiovascular events such as ischemic heart disease and stroke, but also to more insidious global changes in the brain and to cognitive decrements. In this vascular cascade, chronic low-grade inflammation and endothelial dysfunction are thought to play an important role (Gorelick, 2010).
The relation between low-grade inflammation and endothelial dysfunction, vascular risk factors, cardiovascular disease, and cognitive functioning is complex (see Fig. 1). Low-grade inflammation and endothelial dysfunction are closely linked: inflammatory cytokines can induce endothelial dysfunction, and endothelial dysfunction is a pro-inflammatory state (Zhang, 2008). These processes may have a direct effect on the brain due to their role in neurotransmitter and neuroendocrine responses (Wilson et al., 2002). However, low-grade inflammation and endothelial dysfunction may also affect the brain through vascular insufficiency. Low-grade inflammation, endothelial dysfunction and vascular risk factors reinforce each other (Esposito and Giugliano, 2004, Dharmashankar and Widlansky, 2010, Granger et al., 2010) and can lead to cardiovascular and cerebrovascular disease, by themselves and in interaction (Cosentino and Volpe, 2005, Granger et al., 2010). Furthermore, ischemia as a result of vascular disease may lead to an inflammatory response (Galea and Brough, 2013). Moreover, inflammatory and vascular disease do not only result in cognitive decrements but also in depressive symptoms (Alexopoulos and Morimoto, 2011), which are known to interact with cognitive performance (Taylor et al., 2013, Thomas and O’Brien, 2008).
Low-grade inflammation and endothelial dysfunction could thus have their own influence on cognitive performance and at the same time may be intermediate processes between vascular risk factors, cardiovascular disease and cognitive impairment. Results from previous studies provide evidence for associations between biomarkers of inflammation and/or endothelial dysfunction and cognitive dysfunctioning (Kuo et al., 2005, Gorelick, 2010, Quinn et al., 2011, Hedges et al., 2012, Bettcher and Kramer, 2013). To our knowledge however, thus far no studies have addressed this relation by combining multiple circulating biomarkers for both low-grade inflammation and endothelial dysfunction with extensive neuropsychological examination on a wide range of cognitive domains.
The aim of the present study was to examine the relation between circulating biomarkers of low-grade inflammation and of endothelial dysfunction and a detailed assessment of cognitive functioning, in a population-based sample of older individuals. We provide additional analyses to further explore the complex relation between low-grade inflammation, endothelial dysfunction, cognitive functioning, vascular factors, and depressive symptoms.
Section snippets
Participants
The Hoorn Study is a population-based cohort study on glucose metabolism, which started in 1989 and included 2484 participants aged 50–75 years at baseline. Follow-up examinations of this cohort were performed in 1996–1998, 2000–2001 and 2005–2008. Details on the design of the baseline study and the follow-up have been described elsewhere (Mooy et al., 1995, De Vegt et al., 2001, Van den Berg et al., 2008). Circulating biomarkers of low-grade inflammation and endothelial dysfunction were
Results
Table 1 shows the characteristics of participants with circulating biomarkers measurements in 2000–2001 and/or in 2005–2008, and with cognitive measurement in 2005–2008. Patients were on average 68 years old in 2000–2001, and 73 years in 2005–2008. In 2000–2001 and 2005–2008 respectively, 50% and 52% were men, 14% and 16% had a history of cardiovascular disease, 62% and 71% had hypertension, and 17% and 22% had type 2 diabetes. None of the participants had cognitive dysfunction severe enough to
Discussion
The present study shows that in a population-based sample of older persons, circulating biomarkers of low-grade inflammation and endothelial dysfunction were associated with decrements in cognitive functioning on the domains information processing speed, and attention and executive functioning.
This is the first time that the relation between low-grade inflammation and endothelial dysfunction and cognitive functioning is examined with composite scores of multiple circulating biomarkers in
Role of the funding source
The funding agencies (see Acknowledgements) had no role in the preparation of the manuscript.
Conflict of interest
None of the authors have conflicts of interest to declare.
Acknowledgements
The research of GJB is supported by grant 2003.01.004 of the Dutch Diabetes Research Foundation and grant 2010T073 from the Netherlands Heart Foundation. SMH is supported by a Internationale Stichting Alzheimer Onderzoek (ISAO) grant 10506. The authors have no relevant conflict of interest.
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