Inflammation and cognition : the association between biomarker levels, their genetic determinants, and age-related cognitive decline.
Marioni, Riccardo Emilio
Chronic in ammation and variations in blood flow have been implicated in the pathogenesis of cardiovascular disease. It is also possible that inflammatory and rheological processes are involved in the development of mild cognitive impairment and dementia, either through their association with vascular disease or via some other, more direct effect on the brain. Evidence is increasing for a causal relationship between Alzheimer's disease and inflammation, possibly related to inflammatory activation of microglia. Inflammatory processes may also be involved in the pathogenesis of cerebral small vessel disease, which in turn has been linked to cognitive impairment and dementia. There is also evidence showing that rheological factors affect cerebral blood flow. However, despite these findings, the associations between inflammatory and rheological markers and cognitive ability have not been extensively studied in large groups of ageing people. The primary aim of this thesis was to test for associations between late-life levels of inflammatory and rheological markers (C-reactive protein (CRP), fibrinogen, tumor necrosis factor (TNF)-α, interleukin (IL)-6, plasma viscosity, and haematocrit) and cognitive ability. A genetic analysis was then performed to model single nucleotide polymorphisms (SNPs) in the genes encoding the markers against cognition in an attempt to determine the weight of evidence for a causal inflammation-cognition association. Four studies were used to test these aims with the majority of the analysis being performed on the Aspirin for Asymptomatic Atherosclerosis (AAA) Trial (n = 3,350), and the Edinburgh Type 2 Diabetes Study (ET2DS) (n = 1,066). The Edinburgh Artery Study (n = 534), and the 1936 Lothian Birth Cohort (n = 1,091), were used as replication cohorts for the genetic analysis. All cohorts comprised community-dwelling, elderly citizens (aged around 70 years) living in central Scotland. With the exception of the ET2DS, all data used were for secondary analyses. Cognitive ability was assessed in all studies using comprehensive batteries of neuropsychological tests that included a measure of crystallised intelligence in the form of a vocabulary test. As performance on such tests varies little across a lifespan, adjusting for these scores in the late-life models enabled the determination of estimated lifetime cognitive change. In the case of the 1936 Lothian Birth Cohort an actual age-11 IQ measure was available in addition to the cognitive follow-up scores recorded at age-70. Linear regression showed small but significant associations between CRP, fibrinogen, and plasma viscosity, and cognition and estimated lifetime cognitive decline in the AAA Trial. Similar results were observed in the ET2DS for CRP, IL-6, and TNF-α. These associations tended to be of a magnitude whereby the markers explained 1% of the variance of the cognitive test scores. The cognitive domains most consistently associated with the markers were processing speed, and a data derived general intelligence factor. A novel genetic analysis was then undertaken to model SNPs against cognitive ability and decline. Most of the results generated were null findings. However, strongly significant associations were found between the rs2227412 fibrinogen beta gene SNP and the cognitive test scores in the ET2DS. Furthermore, the genotype associated with the lowest cognitive scores was also related to higher levels of plasma fibrinogen. Whilst replication of the association between the fibrinogen SNPs and cognition was not found across all cohorts, these results still indicate a potentially causal role for this haemostatic/inflammatory marker. To date, the majority of inflammation-cognition associations have focussed on the acute-phase protein CRP. The main outcomes from this thesis suggest that its close correlate, fibrinogen, is an equally, if not more important factor in the complex process of cognitive ageing.