3 research outputs found
Inflammation and cognition : the association between biomarker levels, their genetic determinants, and age-related cognitive decline.
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
Inflammation and cognition : the association between biomarker levels, their genetic determinants, and age-related cognitive decline
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.EThOS - Electronic Theses Online ServiceGBUnited Kingdo
New insights into the genetic etiology of Alzheimerâs disease and related dementias
Characterization of the genetic landscape of Alzheimerâs disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/âproxyâ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE Δ4 allele