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
