Association of Thyroid Dysfunction With Cognitive Function: An Individual Participant Data Analysis.

Importance: In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings. Objective: To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia. Design, Setting, and Participants: This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021. Exposures: Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values. Main Outcomes and Measures: The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated. Results: Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism-cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia. Conclusions and Relevance: In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.

Prevention of dementia using mobile phone applications (PRODEMOS): protocol for an international randomised controlled trial.

INTRODUCTION: Profiles of high risk for future dementia are well understood and are likely to concern mostly those in low-income and middle-income countries and people at greater disadvantage in high-income countries. Approximately 30%-40% of dementia cases have been estimated to be attributed to modifiable risk factors, including hypertension, smoking and sedentary lifestyle. Tailored interventions targeting these risk factors can potentially prevent or delay the onset of dementia. Mobile health (mHealth) improves accessibility of such prevention strategies in hard-to-reach populations while at the same time tailoring such approaches. In the current study, we will investigate the effectiveness and implementation of a coach-supported mHealth intervention, targeting dementia risk factors, to reduce dementia risk. METHODS AND ANALYSIS: The prevention of dementia using mobile phone applications (PRODEMOS) randomised controlled trial will follow an effectiveness-implementation hybrid design, taking place in the UK and China. People are eligible if they are 55-75 years old, of low socioeconomic status (UK) or from the general population (China); have ≥2 dementia risk factors; and own a smartphone. 2400 participants will be randomised to either a coach-supported, interactive mHealth platform, facilitating self-management of dementia risk factors, or a static control platform. The intervention and follow-up period will be 18 months. The primary effectiveness outcome is change in the previously validated Cardiovascular Risk Factors, Ageing and Incidence of Dementia dementia risk score. The main secondary outcomes include improvement of individual risk factors and cost-effectiveness. Implementation outcomes include acceptability, adoption, feasibility and sustainability of the intervention. ETHICS AND DISSEMINATION: The PRODEMOS trial is sponsored in the UK by the University of Cambridge and is granted ethical approval by the London-Brighton and Sussex Research Ethics Committee (reference: 20/LO/01440). In China, the trial is approved by the medical ethics committees of Capital Medical University, Beijing Tiantan Hospital, Beijing Geriatric Hospital, Chinese People's Liberation Army General Hospital, Taishan Medical University and Xuanwu Hospital. Results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ISRCTN15986016.

Hospitalisation without delirium is not associated with cognitive decline in a population-based sample of older people-results from a nested, longitudinal cohort study.

BACKGROUND: Acute hospitalisation and delirium have individually been shown to adversely affect trajectories of cognitive decline but have not previously been considered together. This work aimed to explore the impact on cognition of hospital admission with and without delirium, compared to a control group with no hospital admissions. METHODS: The Delirium and Cognitive Impact in Dementia (DECIDE) study was nested within the Cognitive Function and Ageing Study II (CFAS II)-Newcastle cohort. CFAS II participants completed two baseline interviews, including the Mini-Mental State Examination (MMSE). During 2016, surviving participants from CFAS II-Newcastle were recruited to DECIDE on admission to hospital. Participants were reviewed daily to determine delirium status.During 2017, all DECIDE participants and age, sex and years of education matched controls without hospital admissions during 2016 were invited to repeat the CFAS II interview. Delirium was excluded in the control group using the Informant Assessment of Geriatric Delirium Scale (i-AGeD). Linear mixed effects modelling determined predictors of cognitive decline. RESULTS: During 2016, 82 of 205 (40%) DECIDE participants had at least one episode of delirium. At 1 year, 135 of 205 hospitalised participants completed an interview along with 100 controls. No controls experienced delirium (i-AGeD>4). Delirium was associated with a faster rate of cognitive decline compared to those without delirium (ß = -2.2, P < 0.001), but number of hospital admissions was not (P = 0.447). CONCLUSIONS: These results suggest that delirium during hospitalisation rather than hospitalisation per se is a risk factor for future cognitive decline, emphasising the need for dementia prevention studies that focus on delirium intervention.

Recurrent delirium over 12 months predicts dementia: results of the Delirium and Cognitive Impact in Dementia (DECIDE) study.

BACKGROUND: Delirium is common, distressing and associated with poor outcomes. Previous studies investigating the impact of delirium on cognitive outcomes have been limited by incomplete ascertainment of baseline cognition or lack of prospective delirium assessments. This study quantified the association between delirium and cognitive function over time by prospectively ascertaining delirium in a cohort aged ≥ 65 years in whom baseline cognition had previously been established. METHODS: For 12 months, we assessed participants from the Cognitive Function and Ageing Study II-Newcastle for delirium daily during hospital admissions. At 1-year, we assessed cognitive decline and dementia in those with and without delirium. We evaluated the effect of delirium (including its duration and number of episodes) on cognitive function over time, independently of baseline cognition and illness severity. RESULTS: Eighty two of 205 participants recruited developed delirium in hospital (40%). One-year outcome data were available for 173 participants: 18 had a new dementia diagnosis, 38 had died. Delirium was associated with cognitive decline (-1.8 Mini-Mental State Examination points [95% CI -3.5 to -0.2]) and an increased risk of new dementia diagnosis at follow up (OR 8.8 [95% CI 1.9-41.4]). More than one episode and more days with delirium (>5 days) were associated with worse cognitive outcomes. CONCLUSIONS: Delirium increases risk of future cognitive decline and dementia, independent of illness severity and baseline cognition, with more episodes associated with worse cognitive outcomes. Given that delirium has been shown to be preventable in some cases, we propose that delirium is a potentially modifiable risk factor for dementia.

Dementia Research Fit for the Planet: Reflections on Population Studies of Dementia for Researchers and Policy Makers Alike.

In recent years, a rapidly increasing collection of investigative methods in addition to changes in diagnostic criteria for dementia have followed "high-tech" trends in medicine, with the aim to better define the dementia syndrome and its biological substrates, mainly in order to predict risk prior to clinical expression. These approaches are not without challenge. A set of guidelines have been developed by a group of European experts in population-based cohort research through a series of workshops, funded by the Joint Program for Neurodegenerative Disorders (JPND). The aims of the guidelines are to assist policy makers and researchers to understand (1) What population studies for ageing populations should encompass and (2) How to interpret the findings from population studies. Such studies are essential to provide evidence relevant to the understanding of healthy and frail brain ageing, including the dementia syndrome for contemporary and future societies by drawing on the past.

Changing prevalence and treatment of depression among older people over two decades.

BACKGROUND: Depression is a leading cause of disability, with older people particularly susceptible to poor outcomes. AIMS: To investigate whether the prevalence of depression and antidepressant use have changed across two decades in older people. METHOD: The Cognitive Function and Ageing Studies (CFAS I and CFAS II) are two English population-based cohort studies of older people aged ≥65 years, with baseline measurements for each cohort conducted two decades apart (between 1990 and 1993 and between 2008 and 2011). Depression was assessed by the Geriatric Mental State examination and diagnosed with the Automated Geriatric Examination for Computer-Assisted Taxonomy algorithm. RESULTS: In CFAS I, 7635 people aged ≥65 years were interviewed, of whom 1457 were diagnostically assessed. In CFAS II, 7762 people were interviewed and diagnostically assessed. Age-standardised depression prevalence in CFAS II was 6.8% (95% CI 6.3-7.5%), representing a non-significant decline from CFAS I (risk ratio 0.82, 95% CI 0.64-1.07, P = 0.14). At the time of CFAS II, 10.7% of the population (95% CI 10.0-11.5%) were taking antidepressant medication, more than twice that of CFAS I (risk ratio 2.79, 95% CI 1.96-3.97, P < 0.0001). Among care home residents, depression prevalence was unchanged, but the use of antidepressants increased from 7.4% (95% CI 3.8-13.8%) to 29.2% (95% CI 22.6-36.7%). CONCLUSIONS: A substantial increase in the proportion of the population reporting taking antidepressant medication is seen across two decades for people aged ≥65 years. However there was no evidence for a change in age-specific prevalence of depression.

Micro-scale environment and mental health in later life: Results from the Cognitive Function and Ageing Study II (CFAS II).

BACKGROUND: Poor micro-scale environmental features, such as graffiti and broken windows, have been associated with crime and signs of social disorder with a potential impact on mental health. The aim of this study is to investigate the association between micro-scale environment and mental health problems in later life, including cognitive (cognitive impairment and dementia) and common mental disorders (depressive and anxiety symptoms). METHODS: The method of visual image audits was used to collect micro-scale environmental data for 3590 participants in the Cognitive Function and Ageing Study II, a population-based multicentre cohort of people aged 65 or above in England. Multilevel logistic regression was used to examine the associations between the quality of micro-scale environment and mental health problems taking into account urban/rural difference. RESULTS: Poor quality of micro-scale environment was associated with nearly 20% increased odds of depressive (OR: 1.19; 95% CI: 0.99, 1.44) and anxiety symptoms (OR: 1.17; 95% CI: 0.99, 1.38) while the direction of association for cognitive disorders differed across urban and rural settings. Although higher odds of cognitive disorders were found in rural settings, living in a poor quality environment was associated with nearly twice higher odds of cognitive impairment (OR: 1.88; 95% CI: 1.18, 2.97) in urban conurbations but 20% lower odds in rural areas (OR: 0.80; 95% CI: 0.57, 1.11). LIMITATIONS: The causal direction could not be fully determined due to the cross-sectional nature of the data. The visual nature of the environmental assessment tool means it likely does not fully capture features related to the availability of local support services, or opportunities for social participation and interaction. CONCLUSIONS: The quality of micro-scale environment appears to be important to mental health in older people. Interventions may incorporate the environmental aspect to reduce cognitive and common mental disorders.

Land use mix and five-year mortality in later life: Results from the Cognitive Function and Ageing Study.

This study explores the potential modifying effect of age and mediation effect of co-morbidity on the association between land use mix, a measure of neighbourhood walkability, and five-year mortality among the 2424 individuals participating in the year-10 follow-up of the Cognitive Function and Ageing Study in England. Postcodes of participants were mapped onto Lower-layer Super Output Areas, a small area level geographical unit in the UK, and linked to Generalised Land Use data. Cox regression models were fitted to investigate the association. For the younger older age group (75-79 years), the effect of high land use mix on an elevated risk of mortality was mediated by co-morbidity. For older old age groups (80-84, 85+ years), a higher land use mix was directly associated with a 10% lower risk of five-year mortality. The findings suggest differential impacts of land use mix on the health of the younger and older old.

Community environment, cognitive impairment and dementia in later life: results from the Cognitive Function and Ageing Study.

BACKGROUND: Few studies have investigated the impact of the community environment, as distinct from area deprivation, on cognition in later life. This study explores cross-sectional associations between cognitive impairment and dementia and environmental features at the community level in older people. METHOD: The postcodes of the 2,424 participants in the year-10 interview of the Cognitive Function and Ageing Study in England were mapped into small area level geographical units (Lower-layer Super Output Areas) and linked to environmental data in government statistics. Multilevel logistic regression was conducted to investigate associations between cognitive impairment (defined as MMSE ≤ 25), dementia (organicity level ≥3 in GMS-AGECAT) and community level measurements including area deprivation, natural environment, land use mix and crime. Sensitivity analyses tested the impact of people moving residence within the last two years. RESULTS: Higher levels of area deprivation and crime were not significantly associated with cognitive impairment and dementia after accounting for individual level factors. Living in areas with high land use mix was significantly associated with a nearly 60% reduced odds of dementia (OR: 0.4; 95% CI: 0.2, 0.8) after adjusting for individual level factors and area deprivation, but there was no linear trend for cognitive impairment. Increased odds of dementia (OR: 2.2, 95% CI: 1.2, 4.2) and cognitive impairment (OR: 1.4, 95% CI: 1.0, 2.0) were found in the highest quartile of natural environment availability. Findings were robust to exclusion of the recently relocated. CONCLUSION: Features of land use have complex associations with cognitive impairment and dementia. Further investigations should focus on environmental influences on cognition to inform health and social policies.

Changing non-participation in epidemiological studies of older people: evidence from the Cognitive Function and Ageing Study I and II.

BACKGROUND: non-participation in epidemiological studies threatens the generalisability of findings. OBJECTIVE: to investigate the change in non-participation between the Medical Research Council Cognitive Function and Ageing Study (CFAS) I and II. DESIGN: a comparison of two epidemiological studies of older people using identical methods. SETTING: three geographical areas of the United Kingdom. SUBJECTS: older people aged 65 years and over. METHODS: the two studies were conducted approximately two decades apart between 1989 and 1994 (CFAS I) and between 2008 and 2011 (CFAS II). Random samples were drawn from primary care lists. We compared demographic factors associated with non-participation. RESULTS: non-participation in CFAS II was higher than in CFAS I (45.3 versus 18.3%). After adjustment for confounders, in both CFAS I and CFAS II, women were more likely to decline to take part (CFAS I: odds ratio (OR) 1.3 95% confidence interval (CI) 1.2 to 1.4; CFAS II: 1.1 95% CI 1.1 to 1.2). Deprivation was associated with non-participation in both studies (highest versus lowest Townsend deprivation quintile, CFAS I: OR 1.4 95% CI 1.2 to 1.6; CFAS II: 2.0 95% CI 1.8 to 2.2). Age was not associated with non-participation in either study (CFAS I, P = 0.21; CFAS II, P = 0.47). CONCLUSIONS: non-participation in epidemiological studies of older people has increased substantially in the past two decades and public willingness to take part in studies of this kind would appear to be declining. As communities become more diverse and older people have increasing commitments on their time, new ways to engage prospective participants are urgently needed.

Relocation at older age: results from the Cognitive Function and Ageing Study.

BACKGROUND: Community environment might play an important role in supporting ageing in place. This paper aims to explore relocation at older age and its associations with individual and community level factors. METHODS: The postcodes of the 2424 people in the year-10 interview of the Cognitive Function and Ageing Study (CFAS) in England were mapped onto Enumeration Districts and linked to their corresponding Townsend deprivation score and the 2011 rural/urban categories. Multilevel logistic regression was conducted to examine the influence of the baseline individual (age, gender, education and social class) and community (rural/urban categories and area deprivation) level factors on relocation over 10 years. RESULTS: One-third of people moved residence after the age of 65 years and over. Older age, low education, low social class and living in rural areas at baseline were associated with higher probability of moving later in life. The likelihood of relocation in later life increased from least to most deprived areas (odds ratio: 2.0, 95% confidence interval: 1.4, 2.8). CONCLUSIONS: Urban/rural contexts and area deprivation are associated with relocation at older age and indicate that community environment may be relevant to ageing in place.

Assessing environmental features related to mental health: a reliability study of visual streetscape images.

BACKGROUND: An association between depressive symptoms and features of built environment has been reported in the literature. A remaining research challenge is the development of methods to efficiently capture pertinent environmental features in relevant study settings. Visual streetscape images have been used to replace traditional physical audits and directly observe the built environment of communities. The aim of this work is to examine the inter-method reliability of the two audit methods for assessing community environments with a specific focus on physical features related to mental health. METHODS: Forty-eight postcodes in urban and rural areas of Cambridgeshire, England were randomly selected from an alphabetical list of streets hosted on a UK property website. The assessment was conducted in July and August 2012 by both physical and visual image audits based on the items in Residential Environment Assessment Tool (REAT), an observational instrument targeting the micro-scale environmental features related to mental health in UK postcodes. The assessor used the images of Google Street View and virtually "walked through" the streets to conduct the property and street level assessments. Gwet's AC1 coefficients and Bland-Altman plots were used to compare the concordance of two audits. RESULTS: The results of conducting the REAT by visual image audits generally correspond to direct observations. More variations were found in property level items regarding physical incivilities, with broad limits of agreement which importantly lead to most of the variation in the overall REAT score. Postcodes in urban areas had lower consistency between the two methods than rural areas. CONCLUSIONS: Google Street View has the potential to assess environmental features related to mental health with fair reliability and provide a less resource intense method of assessing community environments than physical audits.

The descriptive epidemiology of delirium symptoms in a large population-based cohort study: results from the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS).

BACKGROUND: In the general population, the epidemiological relationships between delirium and adverse outcomes are not well defined. The aims of this study were to: (1) construct an algorithm for the diagnosis of delirium using the Geriatric Mental State (GMS) examination; (2) test the criterion validity of this algorithm against mortality and dementia risk; (3) report the age-specific prevalence of delirium as determined by this algorithm. METHODS: Participant and informant data in a randomly weighted subsample of the Cognitive Function and Ageing Study were taken from a standardized assessment battery. The algorithmic definition of delirium was based on the DSM-IV classification. Outcomes were: proportional hazard ratios for death; odds ratios of dementia at 2-year follow-up. RESULTS: Data from 2197 persons (representative of 13,004) were used, median age 77 years, 64% women. Study-defined delirium was associated with a new dementia diagnosis at two years (OR 8.82, 95% CI 2.76 to 28.2) and death (HR 1.28, 95% CI 1.03 to 1.60), even after adjustment for acute illness severity. Similar associations were seen for study-defined subsyndromal delirium. Age-specific prevalence as determined by the algorithm increased with age from 1.8% in the 65-69 year age group to 10.1% in the ≥85 age group (p < 0.01 for trend). For study-defined subsyndromal delirium, age-specific period prevalence ranged from 8.2% (65-69 years) to 36.1% (≥85 years). CONCLUSIONS: These results demonstrate the possibility of constructing an algorithmic diagnosis for study-defined delirium using data from the GMS schedule, with predictive criterion validity for mortality and dementia risk. These are the first population-based analyses able to account prospectively for both illness severity and an earlier study diagnosis of dementia.

A two-decade comparison of prevalence of dementia in individuals aged 65 years and older from three geographical areas of England: results of the Cognitive Function and Ageing Study I and II.

BACKGROUND: The prevalence of dementia is of interest worldwide. Contemporary estimates are needed to plan for future care provision, but much evidence is decades old. We aimed to investigate whether the prevalence of dementia had changed in the past two decades by repeating the same approach and diagnostic methods as used in the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS) in three of the original study areas in England. METHODS: Between 1989 and 1994, MRC CFAS investigators did baseline interviews in populations aged 65 years and older in six geographically defined areas in England and Wales. A two stage process, with screening followed by diagnostic assessment, was used to obtain data for algorithmic diagnoses (geriatric mental state-automated geriatric examination for computer assisted taxonomy), which were then used to estimate dementia prevalence. Data from three of these areas--Cambridgeshire, Newcastle, and Nottingham--were selected for CFAS I. Between 2008 and 2011, new fieldwork was done in the same three areas for the CFAS II study. For both CFAS I and II, each area needed to include 2500 individuals aged 65 years and older to provide power for geographical and generational comparison. Sampling was stratified according to age group (65-74 years vs ≥75 years). CFAS II used identical sampling, approach, and diagnostic methods to CFAS I, except that screening and assessement were combined into one stage. Prevalence estimates were calculated using inverse probability weighting methods to adjust for sampling design and non-response. Full likelihood Bayesian models were used to investigate informative non-response. FINDINGS: 7635 people aged 65 years or older were interviewed in CFAS I (9602 approached, 80% response) in Cambridgeshire, Newcastle, and Nottingham, with 1457 being diagnostically assessed. In the same geographical areas, the CFAS II investigators interviewed 7796 individuals (14,242 approached, 242 with limited frailty information, 56% response). Using CFAS I age and sex specific estimates of prevalence in individuals aged 65 years or older, standardised to the 2011 population, 8·3% (884,000) of this population would be expected to have dementia in 2011. However, CFAS II shows that the prevalence is lower (6·5%; 670,000), a decrease of 1·8% (odds ratio for CFAS II vs CFAS I 0·7, 95% CI 0·6-0·9, p=0·003). Sensitivity analyses suggest that these estimates are robust to the change in response. INTERPRETATION: This study provides further evidence that a cohort effect exists in dementia prevalence. Later-born populations have a lower risk of prevalent dementia than those born earlier in the past century. FUNDING: UK Medical Research Council.