Systemic inflammation and late-life cognitive ability

Objectives – Cognitive ageing is an inevitable part of human life. Research from disciplines such as epidemiology, medicine and neuroscience implicate a wide range of determinants in the pathophysiological processes that lead to clinical symptoms of neurodegeneration. Markers of systemic inflammation are postulated to play an important role in mechanisms underlying a neuro-pathological cascade, either directly, through neuro-inflammatory processes, or through the mediating effect of diseases that are associated with cognitive deficits, such as cardiovascular disease and variation and disruption to cerebral blood flow. This may be particularly important in people with type 2 diabetes, where the increased prevalence of vascular events and glycaemic upset along with elevated levels of various circulating biomarkers, have been implicated in accelerated cognitive decline. Increasingly, evidence suggests a contribution of vascular disease state in the development of Alzheimer’s disease in which inflammation could be a significant factor. Determining the direction of association between individual markers of inflammation and altered cognitive performance is important in order to understand the possible role of inflammation in the development of cognitive decline and to inform the development of preventive clinical interventions. Therefore investigating these risk factors in relation to the trajectory of age related cognitive decline is crucial; in this respect, longitudinal evidence, detecting change in cognitive performance over a defined period of time, is most appropriate. To date, the majority of evidence is inconclusive, predominantly due to methodological obstacles embedded in the prospective design of cognitive ageing studies and in the investigation of a complex disease state, such as insufficient follow up period and restricted cognitive assessment. Since associations reported from modelling late life cognitive change in epidemiological studies may be the result of confounding variables, such as gender, vascular risk factors/disease, education attainment and social status, investigating the causal nature of inflammatory mediators in cognitive decline, has proved more problematic. Additionally, even a casual association may be due to ‘reverse causation’. One method of unravelling such associations is through the use of genetic association, where the exposure variable of interest (such as genetic variants affecting plasma biomarker levels) is modelled against the outcome, thereby overcoming some of the problems of confounding and reverse causation inherent in non-genetic epidemiological studies. Aim – The primary aim of this thesis was to test for associations of baseline measures of acute-phase proteins (fibrinogen and C-reactive protein) and central pro-inflammatory cytokines (interleukin – 6 and tumour necrosis –α) with four-year change and estimated life-time change in cognitive ability in older people with type 2 diabetes. The second aim was to explore the association between fibrinogen-related SNPs (SNPs shown previously to be associated with altered plasma fibrinogen levels) and cognitive ability in the general population. Methods –Data from the Edinburgh Type 2 Diabetes Study (the ET2DS), a prospective epidemiological study of older people with type 2 diabetes were available, including that collected at a baseline clinic (2006-07) on 1066 participants, mean age 67.9 years (SD 4.2). For the present study, follow up cognitive assessment was carried out after four-years (2010-11) at which cognitive data was collected on 828 survivors. Cognitive ability at both time points was assessed using the same, comprehensive, seven neuropsychological tests battery, including measures of fluid as well as crystallised intelligence (vocabulary test). Principal component analysis was conducted to derive a general cognitive factor ‘g’ and a general inflammatory factor, derived from individual cognitive scores and from baseline measures of four inflammatory markers (fibrinogen and C-reactive protein, interleukin – 6 and tumour necrosis –α), respectively. Genotype and cognitive data were collected from seven, well-established population-based cohorts with clearly defined sampling frames and data collection procedures. Five cohorts comprised of community-dwelling elderly people, living in central Scotland (AAA Trial, n = 2061, EAS, n = 534; ET2DS, n = 1045; LBC 21, n = 517; LBC 36, n=1005) and two large were cohorts based in England (ELSA; n = 5458; and Whitehall II; n = 3400). In total, genotype and cognitive data were available for 14033 participants, age range between 60 to 80 years. In all studies cognition was assessed on three cognitive domains: memory, executive functioning and information processing. Compatibility of cognitive data allowed for calculation of a general cognitive factor ‘g’ that was comparable between all cohorts. The instrument variables consisted of 61 fibrinogen-related polymorphisms within 13 different loci. These were identified through a detailed literature search as well as through search of relevant, genetic databases. Results – in the ET2DS, the age and sex-adjusted analyses revealed statistically significant associations between raised plasma inflammatory markers and poorer ‘g’ at follow-up; this was observed for all biomarkers, with the strongest associations detected for IL-6 and the general inflammation factor (p values <0.001). These findings persisted in linear regression models of baseline biomarker levels with four-year cognitive change as well as estimated life-time change – here the general inflammatory factor and plasma IL-6 levels were the strongest predictors. Adjustment for conventional vascular risk factors and cardiovascular disease attenuated the associations of cognitive decline with fibrinogen, CRP and TNF-α; associations were largely attenuated in analyses assessing IL-6 and the general inflammation factor and tended to remain statistically significant. Meta-analysis was conducted in order to explore associations between pre-selected fibrinogen-related SNPs and impairment in general cognitive ability as indexed by ‘g’. The analysis identified five plasma fibrinogen-related SNPs that were significantly associated with impaired ‘g’ at the nominal threshold level of p < 0.05. These were: rs2070016 (FGB gene); rs2070016 (FGA gene); rs1800497 (ANKK1 gene); rs4251961 (IL1RN gene) and rs1130864 (CRP gene). Discussion – the results of the ET2DS indicate that in an elderly diabetic population, there is a significant relationship between baseline levels of circulating inflammatory markers and four-year cognitive change as well as estimated life-time cognitive decline. These associations were generally independent of common cardiovascular risk factors and events, suggesting a possible pathway where cytokine-induced activation of glial cells may be responsible for the consequent neuro-inflammatory processes resulting in declined cognitive ability. The lack of some associations may be due to a relatively short follow up period. The main strength of the ET2DS was the availability of prospective cognitive data, the large sample size and the use of a comprehensive cognitive battery, including a vocabulary test for crystallised intelligence and thus calculation of estimated life-time cognitive change. Genetic association analysis indicated a significant association between five preselected SNPs each located within different genes (in general, genes associated with inflammation), and impaired general cognitive ability. This provides some support for a causal role of inflammation in age-related general cognitive impairment. One of the major strength was the use of a large dataset and the applied methodological approach. Meta-analysis was conducted on raw, prospectively generated data, allowing determination of the cognitive phenotype variable. The main outcomes of this thesis suggest that systemic inflammation may indeed be involved in aetiology of age-related cognitive decline, possibly via neuro-inflammation. Further epidemiological investigation should involve a measurement of biomarkers trajectories in modelling cognitive change. Use of a stronger genetic instrument for inflammatory biomarkers, modeled against cognitive decline rather than cognitive ability as in the current study could further advance knowledge of the bio-pathological mechanisms underlying age-related cognitive decline. Results could ultimately inform subsequent investigations in the form of a randomised control trial, testing an evidence-based anti-inflammatory clinical intervention in diabetic populations as well as the general populations

Cardiovascular risk factors and cognitive decline in older people with type 2 diabetes

AIMS/HYPOTHESIS: The aim of this work was to assess the role of well-established cardiovascular risk factors in the late-life cognitive decline of patients with type 2 diabetes. METHODS: Data from 831 participants (aged 60-75 years) attending the 4 year follow-up of the Edinburgh Type 2 Diabetes Study (ET2DS) were used. Smoking history (pack-years), BP, HbA1c, plasma glucose and cholesterol were determined at baseline clinics (single time measurements) and/or from serial data recorded on a clinical management database from diagnosis until recruitment ('historical' data). Principal component analysis derived a factor, g, of general ability from seven cognitive tests. Linear regression models of follow-up g were adjusted for baseline g to represent 4 year cognitive change. 'Accelerated late-life cognitive decline' was defined as scoring in the lowest tertile of '4 year cognitive change' regression scores. Analyses controlled for age and sex. RESULTS: A baseline history of moderate/heavy smoking (>/= 10 pack-years) and a 1% increased historical HbA1c (equivalent to an increase by 11 mmol/mol) predicted a 64% (OR 1.64; 95% CI 1.14, 2.34; p = 0.007) and 21% (OR 1.21; 95% CI 1.00, 1.45; p = 0.046) increased risk of accelerated cognitive decline, respectively. When treated as continuous measures, higher pack-years, historical HbA1c and historical BP emerged as significant independent predictors of 4 year decline in g (standardised beta range -0.07 to -0.14; all p </= 0.05). CONCLUSIONS/INTERPRETATION: Increased smoking and poorer glycaemic control (with relatively weaker findings for BP) during the life-course were independently associated with accelerated late-life cognitive decline. Where possible, evaluation is warranted of these risk factors as targets for intervention to reduce the burden of cognitive impairment in diabetes

Measurement of the top quark forward-backward production asymmetry and the anomalous chromoelectric and chromomagnetic moments in pp collisions at √s = 13 TeV

Abstract The parton-level top quark (t) forward-backward asymmetry and the anomalous chromoelectric (d̂ t) and chromomagnetic (μ̂ t) moments have been measured using LHC pp collisions at a center-of-mass energy of 13 TeV, collected in the CMS detector in a data sample corresponding to an integrated luminosity of 35.9 fb−1. The linearized variable AFB(1) is used to approximate the asymmetry. Candidate t t ¯ events decaying to a muon or electron and jets in final states with low and high Lorentz boosts are selected and reconstructed using a fit of the kinematic distributions of the decay products to those expected for t t ¯ final states. The values found for the parameters are AFB(1)=0.048−0.087+0.095(stat)−0.029+0.020(syst),μ̂t=−0.024−0.009+0.013(stat)−0.011+0.016(syst), and a limit is placed on the magnitude of | d̂ t| &lt; 0.03 at 95% confidence level. [Figure not available: see fulltext.

Measurement of t(t)over-bar normalised multi-differential cross sections in pp collisions at root s=13 TeV, and simultaneous determination of the strong coupling strength, top quark pole mass, and parton distribution functions

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An embedding technique to determine ττ backgrounds in proton-proton collision data

An embedding technique is presented to estimate standard model tau tau backgrounds from data with minimal simulation input. In the data, the muons are removed from reconstructed mu mu events and replaced with simulated tau leptons with the same kinematic properties. In this way, a set of hybrid events is obtained that does not rely on simulation except for the decay of the tau leptons. The challenges in describing the underlying event or the production of associated jets in the simulation are avoided. The technique described in this paper was developed for CMS. Its validation and the inherent uncertainties are also discussed. The demonstration of the performance of the technique is based on a sample of proton-proton collisions collected by CMS in 2017 at root s = 13 TeV corresponding to an integrated luminosity of 41.5 fb(-1).Peer reviewe

Search for Physics beyond the Standard Model in Events with Overlapping Photons and Jets

Results are reported from a search for new particles that decay into a photon and two gluons, in events with jets. Novel jet substructure techniques are developed that allow photons to be identified in an environment densely populated with hadrons. The analyzed proton-proton collision data were collected by the CMS experiment at the LHC, in 2016 at root s = 13 TeV, and correspond to an integrated luminosity of 35.9 fb(-1). The spectra of total transverse hadronic energy of candidate events are examined for deviations from the standard model predictions. No statistically significant excess is observed over the expected background. The first cross section limits on new physics processes resulting in such events are set. The results are interpreted as upper limits on the rate of gluino pair production, utilizing a simplified stealth supersymmetry model. The excluded gluino masses extend up to 1.7 TeV, for a neutralino mass of 200 GeV and exceed previous mass constraints set by analyses targeting events with isolated photons.Peer reviewe

Calibration of the CMS hadron calorimeters using proton-proton collision data at root s=13 TeV

Methods are presented for calibrating the hadron calorimeter system of theCMSetector at the LHC. The hadron calorimeters of the CMS experiment are sampling calorimeters of brass and scintillator, and are in the form of one central detector and two endcaps. These calorimeters cover pseudorapidities vertical bar eta vertical bar ee data. The energy scale of the outer calorimeters has been determined with test beam data and is confirmed through data with high transverse momentum jets. In this paper, we present the details of the calibration methods and accuracy.Peer reviewe

Measurement of the Jet Mass Distribution and Top Quark Mass in Hadronic Decays of Boosted Top Quarks in pp Collisions at root s=13 TeV

A measurement is reported of the jet mass distribution in hadronic decays of boosted top quarks produced in pp collisions at root s = 13 TeV. The data were collected with the CMS detector at the LHC and correspond to an integrated luminosity of 35.9 fb(-1). The measurement is performed in the lepton + jets channel of t (t) over bar events, where the lepton is an electron or muon. The products of the hadronic top quark decay t -> bW -> bq (q) over bar' are reconstructed as a single jet with transverse momentum larger than 400 GeV. The t (t) over bar cross section as a function of the jet mass is unfolded at the particle level and used to extract a value of the top quark mass of 172.6 +/- 2.5 GeV. A novel jet reconstruction technique is used for the first time at the LHC, which improves the precision by a factor of 3 relative to an earlier measurement. This highlights the potential of measurements using boosted top quarks, where the new technique will enable future precision measurements.Peer reviewe

Bose-Einstein correlations of charged hadrons in proton-proton collisions at s\sqrt s = 13 TeV

Bose-Einstein correlations of charged hadrons are measured over a broad multiplicity range, from a few particles up to about 250 reconstructed charged hadrons in proton-proton collisions at $\sqrt{s}$ = 13 TeV. The results are based on data collected using the CMS detector at the LHC during runs with a special low-pileup configuration. Three analysis techniques with different degrees of dependence on simulations are used to remove the non-Bose-Einstein background from the correlation functions. All three methods give consistent results. The measured lengths of homogeneity are studied as functions of particle multiplicity as well as average pair transverse momentum and mass. The results are compared with data from both CMS and ATLAS at $\sqrt{s}$ = 7 TeV, as well as with theoretical predictions.[graphic not available: see fulltext]Bose-Einstein correlations of charged hadrons are measured over a broad multiplicity range, from a few particles up to about 250 reconstructed charged hadrons in proton-proton collisions at $\sqrt{s} =$ 13 TeV. The results are based on data collected using the CMS detector at the LHC during runs with a special low-pileup configuration. Three analysis techniques with different degrees of dependence on simulations are used to remove the non-Bose-Einstein background from the correlation functions. All three methods give consistent results. The measured lengths of homogeneity are studied as functions of particle multiplicity as well as average pair transverse momentum and mass. The results are compared with data from both CMS and ATLAS at $\sqrt{s} =$ 7 TeV, as well as with theoretical predictions

Search for dark matter in events with a leptoquark and missing transverse momentum in proton-proton collisions at 13 TeV

A search is presented for dark matter in proton-proton collisions at a center-of-mass energy of root s= 13 TeV using events with at least one high transverse momentum (p(T)) muon, at least one high-p(T) jet, and large missing transverse momentum. The data were collected with the CMS detector at the CERN LHC in 2016 and 2017, and correspond to an integrated luminosity of 77.4 fb(-1). In the examined scenario, a pair of scalar leptoquarks is assumed to be produced. One leptoquark decays to a muon and a jet while the other decays to dark matter and low-p(T) standard model particles. The signature for signal events would be significant missing transverse momentum from the dark matter in conjunction with a peak at the leptoquark mass in the invariant mass distribution of the highest p(T) muon and jet. The data are observed to be consistent with the background predicted by the standard model. For the first benchmark scenario considered, dark matter masses up to 500 GeV are excluded for leptoquark masses m(LQ) approximate to 1400 GeV, and up to 300 GeV for m(LQ) approximate to 1500 GeV. For the second benchmark scenario, dark matter masses up to 600 GeV are excluded for m(LQ) approximate to 1400 GeV. (C) 2019 The Author(s). Published by Elsevier B.V.Peer reviewe