The Relationship Between Cognitive Performance Using Tests Assessing a Range of Cognitive Domains and Future Dementia Diagnosis in a British Cohort: A Ten-Year Prospective Study.

BACKGROUND: Exploring the domains of cognitive function which are most strongly associated with future dementia may help with understanding risk factors for, and the natural history of dementia. OBJECTIVE: To examine the association of performance on a range of cognitive tests (both global and domain specific) with subsequent diagnosis of dementia through health services in a population of relatively healthy men and women and risk of future dementia. METHODS: We examined the association between performance on different cognitive tests as well as a global score and future dementia risk ascertained through health record linkage in a cohort of 8,581 individuals (aged 48-92 years) between 2004-2019 with almost 15 years follow-up (average of 10 years) before and after adjustment for socio-demographic, lifestyle, and health characteristics. RESULTS: Those with poor performance for global cognition (bottom 10%) were almost four times as likely to receive a dementia diagnosis from health services over the next 15 years than those who performed well HR = 3.51 (95% CI 2.61, 4.71 p < 0.001) after adjustment for socioeconomic, lifestyle, and biological factors and also prevalent disease. Poor cognition performance in multiple tests was associated with 10-fold increased risk compared to those not performing poorly in any test HR = 10.82 (95% CI 6.85, 17.10 p < 0.001). CONCLUSION: Deficits across multiple cognitive domains substantially increase risk of future dementia over and above neuropsychological test scores ten years prior to a clinical diagnosis. These findings may help further understanding of the natural history of dementia and how such measures could contribute to strengthening future models of dementia.This work was supported by the Medical Research Council, UK (MRC) http://www.mrc.ac.uk/ (Ref: MR/N003284/1) Cancer Research UK http://www.cancerresearchuk. org/ (CRUK, Ref: C864/A8257) and NIHR https://www.nihr.ac.uk (Ref: NF-SI-0616-10090 to [CB]). The clinic for EPIC- Norfolk 3HC was funded by Research into Aging, now known as Age UK http://www.ageuk.org.uk/ (Grant Ref: 262). The pilot phase was supported by MRC (Ref: G9502233) and CRUK (Ref: C864/ A2883)

Cardiovascular risk factors associated with polymyalgia rheumatica and giant cell arteritis in a prospective cohort: EPIC-Norfolk Study.

OBJECTIVES: PMR and GCA are associated with increased risk of vascular disease. However, it remains unclear whether this relationship is causal or reflects a common underlying propensity. The aim of this study was to identify whether known cardiovascular risk factors increase the risk of PMR and GCA. METHODS: Clinical records were examined using key word searches to identify cases of PMR and GCA, applying current classification criteria in a population-based cohort. Associations between cardiovascular risk factors and incident PMR and GCA were analysed using Cox proportional hazards. RESULTS: In 315 022 person years of follow-up, there were 395 incident diagnoses of PMR and 118 incident diagnoses of GCA that met the clinical definition. Raised diastolic blood pressure (>90 mmHg) at baseline/recruitment was associated with subsequent incident PMR [hazard ratio=1.35 (95% CI 1.01, 1.80) P=0.045], and ever-smoking was associated with incident GCA [hazard ratio=2.01 (95% CI 1.26, 3.20) P=0.003]. Estimates were similar when the analysis was restricted to individuals whose diagnoses satisfied the current classification criteria sets. CONCLUSION: PMR and GCA shares common risk factors with vascular disease onset, suggesting a common underlying propensity. This may indicate a potential for disease prevention strategies through modifying cardiovascular risk

Understanding the relationship between cognition and death: a within cohort examination of cognitive measures and mortality.

Despite several studies demonstrating an independent and inverse association between cognition and mortality, the nature of this association still remains unclear. To examine the association of cognition and mortality after accounting for sociodemographic, health and lifestyle factors and to explore both test and population characteristics influencing this relationship. In a population based cohort of 8585 men and women aged 48-92 years, who had cognitive assessments in 2006-2011 and were followed up till 2016 for mortality, we examined the relationship between individual cognitive tests as well as a global cognition score to compare their ability in predicting mortality and whether these differed by population characteristics. Risk of death was estimated using Cox proportional hazard regression models including sociodemographic, lifestyle and health variables, and self-reported comorbidities, as covariates in the models. Poor cognitive performance (bottom quartile of combined cognition score) was associated with higher risk of mortality, Hazard Ratio = 1.32 (95% Confidence Interval 1.09, 1.60); individual cognitive tests varied in their mortality associations and also performed differently in middle-age and older age groups. Poor cognitive performance is independently associated with higher mortality. This association is observed for global cognition and for specific cognitive abilities. Associations vary depending on the cognitive test (and domain) as well as population characteristics, namely age and education.This work was supported by the Medical Research Council, UK http://www.mrc.ac.uk/ (Ref: G0401527) and Cancer Research UK http://www.cancerresearchuk. org/ (CRUK, Ref: C864/A8257). The clinic for EPIC- Norfolk 3 was funded by Research into Ageing, now known as Age UK http://www.ageuk.org.uk/ (Grant Ref: 262). The pilot phase was supported by MRC (Ref: G9502233) and CRUK (Ref: C864/ A2883). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Cognitive function in a general population of men and women: a cross sectional study in the European Investigation of Cancer-Norfolk cohort (EPIC-Norfolk).

BACKGROUND: Although ageing is strongly associated with cognitive decline, a wide range of cognitive ability is observed in older populations with varying rates of change across different cognitive domains. METHODS: Cognitive function was measured as part of the third health examination of the European Prospective Investigation of Cancer in Norfolk (EPIC-Norfolk 3) between 2006 and 2011 (including measures from the pilot phase from 2004 to 2006). This was done using a battery consisting of seven previously validated cognitive function tests assessing both global function and specific domains. The battery included a shortened version of the Extended Mental State Exam (SF-EMSE); letter cancellation task; Hopkins Verbal Learning Test (HVLT); Cambridge Neuropsychological Test Automated Battery Paired Associates Learning Test (CANTAB-PAL); Visual Sensitivity Test (VST); Shortened version of the National Adult Reading Test (Short-NART) and a task to test for prospective memory. We report the distribution of cognitive function in different cognitive domains by age and sex and compare the utility of a number of assessment tests in a general population of older men and women. RESULTS: Cognitive test data were available for 8585 men and women taking part in EPIC-Norfolk 3. Increasing age was generally associated with declining mean cognitive function, but there was a wide range observed within each age group as well as variability across different cognitive domains. Some sex differences were also observed. CONCLUSION: Descriptive data are presented for this general population sample of older men and women. There is a wide range of cognitive performance seen in this population. Though average performance declines with age, there is large individual variability across different cognitive domains. These variations may provide insights into the determinants of cognitive function in later life.The infrastructure for this study was supported by the Medical Research Council, UK (G0401527) and Cancer Research UK (CRUK, C864/A8257). The clinic for EPIC-Norfolk 3 was funded by Research into Ageing (262). The pilot phase was supported by MRC (G9502233) and CRUK (C864/A2883).This is the final published version. It first appeared at http://www.biomedcentral.com/1471-2318/14/142

Physical capability predicts mortality in late mid-life as well as in old age: Findings from a large British cohort study.

INTRODUCTION: Low physical capability predicts mortality, perhaps by association with co-morbidity. However, few studies include participants 0.05) and those with lower physical capability had higher mortality risk. For example, in those <70years old hazard ratios (95% confidence interval) for mortality in the third, second and lowest sex-specific quartiles of UWS compared to the highest were 1.21 (0.75, 1.96), 2.11 (1.35, 3.28) and 2.91 (1.84, 4.62) and in participants ≥70years old were 1.19 (0.73, 1.95), 2.09 (1.35, 3.24) and 2.64 (1.73, 4.02) respectively. In the whole cohort, strong associations between all physical capability tests and mortality persisted after multivariable adjustment and after excluding participants with co-morbidity. CONCLUSIONS: Physical capability was independently predictive of future mortality risk with similar associations in late mid-life, when co-morbidity burden is lower, as at older age

A Common Glaucoma-risk Variant of SIX6 Alters Retinal Nerve Fiber Layer and Optic Disc Measures in a European Population: The EPIC-Norfolk Eye Study.

PURPOSE: A common missense variant in the SIX6 gene (rs33912345) is strongly associated with primary open-angle glaucoma (POAG). We aimed to examine the association of rs33912345 with optic disc and retinal nerve fiber layer (RNFL) measures in a European population. METHODS: We examined participants of the population-based EPIC-Norfolk Eye Study. Participants underwent confocal laser scanning tomography (Heidelberg Retina Tomograph II, HRT) to estimate optic disc rim area and vertical cup-disc ratio (VCDR). Scanning laser polarimetry (GDxVCC) was used to estimate average RNFL thickness. The mean of right and left eye values was considered for each participant. Genotyping was performed using the Affymetrix UK Biobank Axiom Array. Multivariable linear regression with the optic nerve head parameter as outcome variable and dosage of rs33912345 genotype as primary explanatory variable was used, adjusted for age, sex, disc area, axial length, and intraocular pressure. We further repeated analyses stratified into age tertiles. RESULTS: In total, 5433 participants with HRT data and 3699 participants with GDxVCC data were included. Each "C" allele of rs33912345 was associated with a smaller rim area (-0.030 mm [95% CI -0.040, -0.020]; P=5.4×10), a larger VCDR (0.025 [95% CI 0.017, 0.033]; P=3.3×10) and a thinner RNFL (-0.39 μm [95% CI -0.62, -0.15]; P=0.001). The RNFL association was strongest in the oldest age tertile, whereas rim area and VCDR associations were strongest in the youngest and oldest age tertiles. CONCLUSIONS: The protein-coding SIX6 variant rs33912345, previously associated with POAG, has a functional effect on glaucoma-associated optic nerve head traits in Europeans.EPIC-Norfolk infrastructure and core functions are supported by grants from the Medical Research Council (G1000143) and Cancer Research UK (C864/A14136). The clinic for the third health examination was funded by Research into Ageing (262). Genotyping was funded by the Medical Research Council (MC_PC_13048). Mr Khawaja is supported by a Moorfields Eye Charity grant. Miss Chan is a joint Medical Research Council/Royal College of Ophthalmologists Research Fellow, and received additional support from the International Glaucoma Association. Professor Foster has received additional support from the Richard Desmond Charitable Trust (via Fight for Sight) and the Department for Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital and the UCL Institute of Ophthalmology for a specialist Biomedical Research Centre for Ophthalmology

Mediterranean diet adherence and cognitive function in older, UK adults: The EPIC-Norfolk study

Background In Mediterranean countries, adherence to a traditional Mediterranean dietary pattern (MedDiet) is associated with better cognitive function and reduced dementia risk. It is unclear if similar benefits exist in non-Mediterranean regions. Objective To examine associations between MedDiet adherence and cognitive function in an older, UK population. To investigate whether associations differed between individuals with high versus low cardiovascular disease (CVD) risk. Design We conducted an analysis in 8009 older individuals with dietary data at Health Check 1 (1993-1997) and cognitive function data at Health Check 3 (2006-2011) of the European Prospective Investigation of Cancer, Norfolk (EPIC-Norfolk). Associations were explored between MedDiet adherence and global and domain specific cognitive test scores and risk of poor cognitive performance in the entire cohort, and when stratified according to CVD risk status. Results Higher MedDiet adherence defined by the Pyramid MedDiet score was associated with better global cognition (β±SE=-0.012±0.002; P<0.001), verbal episodic memory (β±SE=-0.009±0.002; P<0.001), and simple processing speed (β±SE=-0.002±0.001; P=0.013). Lower risk of poor verbal episodic memory (OR(95%CI)=0.784 (0.641,0.959); P=0.018), complex processing speed (OR(95%CI)=0.739 (0.601,0.907); P=0.004), and prospective memory (OR(95%CI)=0.841 (0.724,0.977); P=0.023) was also observed for the highest versus lowest Pyramid MedDiet tertiles. The effect of a one-point increase in Pyramid score on global cognitive function was equivalent to 1.7 fewer years of cognitive ageing. MedDiet adherence defined by the MEDAS score (mapped using both binary and continuous scoring) showed similar, albeit less consistent, associations. In stratified analyses, associations were evident in individuals at higher CVD risk only (P<0.05). Conclusions Higher adherence to the MedDiet is associated with better cognitive function and lower risk of poor cognition in older, UK adults. This evidence underpins the development of interventions to enhance MedDiet adherence, particularly in individuals at higher CVD risk, aiming to reduce the risk of age-related cognitive decline in non-Mediterranean populations

Retinal Vasculometry Associations with Cardiometabolic Risk Factors in the European Prospective Investigation of Cancer-Norfolk Study.

PURPOSE: To examine associations between retinal vessel morphometry and cardiometabolic risk factors in older British men and women. DESIGN: Retinal imaging examination as part of the European Prospective Investigation into Cancer-Norfolk Eye Study. PARTICIPANTS: Retinal imaging and clinical assessments were carried out in 7411 participants. Retinal images were analyzed using a fully automated validated computerized system that provides novel measures of vessel morphometry. METHODS: Associations between cardiometabolic risk factors, chronic disease, and retinal markers were analyzed using multilevel linear regression, adjusted for age, gender, and within-person clustering, to provide percentage differences in tortuosity and absolute differences in width. MAIN OUTCOMES MEASURES: Retinal arteriolar and venular tortuosity and width. RESULTS: In all, 279 802 arterioles and 285 791 venules from 5947 participants (mean age, 67.6 years; standard deviation [SD], 7.6 years; 57% female) were analyzed. Increased venular tortuosity was associated with higher body mass index (BMI; 2.5%; 95% confidence interval [CI], 1.7%-3.3% per 5 kg/m2), hemoglobin A1c (HbA1c) level (2.2%; 95% CI, 1.0%-3.5% per 1%), and prevalent type 2 diabetes (6.5%; 95% CI, 2.8%-10.4%); wider venules were associated with older age (2.6 μm; 95% CI, 2.2-2.9 μm per decade), higher triglyceride levels (0.6 μm; 95% CI, 0.3-0.9 μm per 1 mmol/l), BMI (0.7 μm; 95% CI, 0.4-1.0 per 5 kg/m2), HbA1c level (0.4 μm; 95% CI, -0.1 to 0.9 per 1%), and being a current smoker (3.0 μm; 95% CI, 1.7-4.3 μm); smoking also was associated with wider arterioles (2.1 μm; 95% CI, 1.3-2.9 μm). Thinner venules were associated with high-density lipoprotein (HDL) (1.4 μm; 95% CI, 0.7-2.2 per 1 mmol/l). Arteriolar tortuosity increased with age (5.4%; 95% CI, 3.8%-7.1% per decade), higher systolic blood pressure (1.2%; 95% CI, 0.5%-1.9% per 10 mmHg), in females (3.8%; 95% CI, 1.4%-6.4%), and in those with prevalent stroke (8.3%; 95% CI, -0.6% to 18%); no association was observed with prevalent myocardial infarction. Narrower arterioles were associated with age (0.8 μm; 95% CI, 0.6-1.0 μm per decade), higher systolic blood pressure (0.5 μm; 95% CI, 0.4-0.6 μm per 10 mmHg), total cholesterol level (0.2 μm; 95% CI, 0.0-0.3 μm per 1 mmol/l), and HDL (1.2 μm; 95% CI, 0.7-1.6 μm per 1 mmol/l). CONCLUSIONS: Metabolic risk factors showed a graded association with both tortuosity and width of retinal venules, even among people without clinical diabetes, whereas atherosclerotic risk factors correlated more closely with arteriolar width, even excluding those with hypertension and cardiovascular disease. These noninvasive microvasculature measures should be evaluated further as predictors of future cardiometabolic disease.EPIC was funded by the Medical Research Council, UK (G0401527), and Research into Ageing, UK (262). The retinal vessel morphometry work was supported by the Medical Research Council Population and Systems Medicine Board (MR/L02005X/1) and British Heart Foundation (PG/15/101/31889). Prof Foster has received additional support from the Richard Desmond Charitable Trust (via Fight for Sight) and the Department for Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital and the UCL Institute of Ophthalmology for a Biomedical Research Centre. The views expressed in this article are those of the authors and not necessarily those of the Department for Health