Modeling Risk Factors for Intraindividual Variability: A Mixed-Effects Beta-Binomial Model Applied to Cognitive Function in Older People in the English Longitudinal Study of Ageing.

Cognitive functioning in older age profoundly impacts quality of life and health. While most research on cognition in older age has focused on mean levels, intraindividual variability (IIV) around this may have risk factors and outcomes independent of the mean value. Investigating risk factors associated with IIV has typically involved deriving a summary statistic for each person from residual error around a fitted mean. However, this ignores uncertainty in the estimates, prohibits exploring associations with time-varying factors, and is biased by floor/ceiling effects. To address this, we propose a mixed-effects location scale beta-binomial model for estimating average probability and IIV in a word recall test in the English Longitudinal Study of Ageing. After adjusting for mean performance, an analysis of 9,873 individuals across 7 (mean = 3.4) waves (2002-2015) found IIV to be greater at older ages, with lower education, in females, with more difficulties in activities of daily living, in later birth cohorts, and when interviewers recorded issues potentially affecting test performance. Our study introduces a novel method for identifying groups with greater IIV in bounded discrete outcomes. Our findings have implications for daily functioning and care, and further work is needed to identify the impact for future health outcomes.

Insulin resistance, age and depression's impact on cognition in middle-aged adults from the PREVENT cohort.

BACKGROUND: Alzheimer's disease (AD), type 2 diabetes mellitus (characterised by insulin resistance) and depression are significant challenges facing public health. Research has demonstrated common comorbidities among these three conditions, typically focusing on two of them at a time. OBJECTIVE: The goal of this study, however, was to assess the inter-relationships between the three conditions, focusing on mid-life (defined as age 40-59) risk before the emergence of dementia caused by AD. METHODS: In the current study, we used cross-sectional data from 665 participants from the cohort study, PREVENT. FINDINGS: Using structural equation modelling, we showed that (1) insulin resistance predicts executive dysfunction in older but not younger adults in mid-life, that (2) insulin resistance predicts self-reported depression in both older and younger middle-aged adults and that (3) depression predicts deficits in visuospatial memory in older but not younger adults in mid-life. CONCLUSIONS: Together, we demonstrate the inter-relations between three common non-communicable diseases in middle-aged adults. CLINICAL IMPLICATIONS: We emphasise the need for combined interventions and the use of resources to help adults in mid-life to modify risk factors for cognitive impairment, such as depression and diabetes.

Differences in the longitudinal change of behaviours related to dementia in long-term care: a growth mixture modelling approach.

BACKGROUND: There is still a need for more information about the different trajectories of responsive behaviours that people living with dementia present in long-term care homes (LTC). OBJECTIVE: This study identified subgroups of individuals with similar trajectories of responsive behaviours related to dementia in LTC and evaluated the role of demographic variables, depressive symptomatology, social engagement, cognitive functioning, and activities of daily living (ADL) on class membership. METHODS: Growth mixture models were run using data from the Continuing Care Reporting System. RESULTS: Results suggest that change in responsive behaviours is best represented by seven classes of trajectories. The largest class was composed of individuals who presented the lowest frequency of behaviours upon entry in LTC that increased at a slow linear rate. The other classes were composed of individuals who presented different frequencies of behaviours upon entry in LTC and varying rates of change (e.g., individuals who presented a low frequency of behaviours upon entry in LTC that increased at a linear rate followed by a decrease in the later months, individuals who presented a high frequency of responsive behaviours upon entry in LTC and that remained stable). Cognitive functioning, social engagement, depressive symptomatology, and ADL were markers of class membership. CONCLUSIONS: These findings can help identify individuals at increased risk of presenting a high frequency of responsive behaviours and highlight interventions that could decrease behaviours in LTC.

Extremes of baseline cognitive function determine the severity of delirium: a population study.

Although delirium is a significant clinical and public health problem, little is understood about how specific vulnerabilities underlie the severity of its presentation. Our objective was to quantify the relationship between baseline cognition and subsequent delirium severity. We prospectively investigated a population-representative sample of 1510 individuals aged ≥70 years, of whom 209 (13.6%) were hospitalized across 371 episodes (1999 person-days assessment). Baseline cognitive function was assessed using the modified Telephone Interview for Cognitive Status, supplemented by verbal fluency measures. We estimated the relationship between baseline cognition and delirium severity [Memorial Delirium Assessment Scale (MDAS)] and abnormal arousal (Observational Scale of Level of Arousal), adjusted by age, sex, frailty and illness severity. We conducted further analyses examining presentations to specific hospital settings and common precipitating aetiologies. The median time from baseline cognitive assessment to admission was 289 days (interquartile range 130 to 47 days). In admitted patients, delirium was present on at least 1 day in 45% of admission episodes. The average number of days with delirium (consecutively positive assessments) was 3.9 days. Elective admissions accounted for 88 bed days (4.4%). In emergency (but not elective) admissions, we found a non-linear U-shaped relationship between baseline global cognition and delirium severity using restricted cubic splines. Participants with baseline cognition 2 standard deviations below average (z-score = -2) had a mean MDAS score of 14 points (95% CI 10 to 19). Similarly, those with baseline cognition z-score = + 2 had a mean MDAS score of 7.9 points (95% CI 4.9 to 11). Individuals with average baseline cognition had the lowest MDAS scores. The association between baseline cognition and abnormal arousal followed a comparable pattern. C-reactive protein ≥20 mg/l and serum sodium <125 mM/l were associated with more severe delirium. Baseline cognition is a critical determinant of the severity of delirium and associated changes in arousal. Emergency admissions with lowest and highest baseline cognition who develop delirium should receive enhanced clinical attention.

The effect of baseline cognition and delirium on long-term cognitive impairment and mortality: a prospective population-based study.

Background: There is an unmet public health need to understand better the relationship between baseline cognitive function, the occurrence and severity of delirium, and subsequent cognitive decline. Our aim was to quantify the relationship between baseline cognition and delirium and follow-up cognitive impairment. Methods: We did a prospective longitudinal study in a stable representative community sample of adults aged 70 years or older who were registered with a Camden-based general practitioner in the London Borough of Camden (London, UK). Participants were recruited by invitation letters from general practice lists or by direct recruitment of patients from memory clinics or patients recently discharged from secondary care. We quantified baseline cognitive function with the modified Telephone Interview for Cognitive Status. In patients who were admitted to hospital, we undertook daily assessments of delirium using the Memorial Delirium Assessment Scale (MDAS). We estimated the association of pre-admission baseline cognitive function with delirium prevalence, severity, and duration. We assessed subsequent cognitive function 2 years after baseline recruitment using the Telephone Interview for Cognitive Status. Regression models were adjusted by age, sex, education, illness severity, and frailty. Findings: We recruited 1510 participants (median age 77 [IQR 73-82], 57% women) between March, 2017, and October, 2018. 209 participants were admitted to hospital across 371 episodes (1999 person-days of assessment). Better baseline cognition was associated with a lower risk of delirium (odds ratio 0·63, 95% CI 0·45 to 0·89) and with less severe delirium (-1·6 MDAS point, 95% CI -2·6 to -0·7). Individuals with high baseline cognition (baseline Z score +2·0 SD) had demonstrable decline even without delirium (follow-up Z score +1·2 SD). However, those with a high delirium burden had an even larger absolute decline of 2·2 SD in Z score (follow-up Z score -0·2). Once individuals had more than 2 days of moderate delirium, the rates of death over 2 years were similar regardless of baseline cognition; a better baseline cognition no longer conferred any mortality benefit. Interpretation: A higher baseline cognitive function is associated with a good prognosis with regard to likelihood and severity of delirium. However, those with a high baseline cognition and with delirium had the highest degree of cognitive decline, a change similar to the decline observed in individuals with a high amyloid burden in other cohorts. Older people with a healthy baseline cognitive function who develop delirium stand to lose the most after delirium. This group could benefit from targeted cognitive rehabilitation interventions after delirium.

Measuring axial length of the eye from magnetic resonance brain imaging.

BACKGROUND: Metrics derived from the human eye are increasingly used as biomarkers and endpoints in studies of cardiovascular, cerebrovascular and neurological disease. In this context, it is important to account for potential confounding that can arise from differences in ocular dimensions between individuals, for example, differences in globe size. METHODS: We measured axial length, a geometric parameter describing eye size from T2-weighted brain MRI scans using three different image analysis software packages (Mango, ITK and Carestream) and compared results to biometry measurements from a specialized ophthalmic instrument (IOLMaster 500) as the reference standard. RESULTS: Ninety-three healthy research participants of mean age 51.0 ± SD 5.4 years were analyzed. The level of agreement between the MRI-derived measurements and the reference standard was described by mean differences as follows, Mango - 0.8 mm; ITK - 0.5 mm; and Carestream - 0.1 mm (upper/lower 95% limits of agreement across the three tools ranged from 0.9 mm to - 2.6 mm). Inter-rater reproducibility was between - 0.03 mm and 0.45 mm (ICC 0.65 to 0.93). Intra-rater repeatability was between 0.0 mm and - 0.2 mm (ICC 0.90 to 0.95). CONCLUSIONS: We demonstrate that axial measurements of the eye derived from brain MRI are within 3.5% of the reference standard globe length of 24.1 mm. However, the limits of agreement could be considered clinically significant. Axial length of the eye obtained from MRI is not a replacement for the precision of biometry, but in the absence of biometry it could provide sufficient accuracy to act as a proxy. We recommend measuring eye axial length from MRI in studies that do not have biometry but use retinal imaging to study neurodegenerative changes so as to control for differing eye size across individuals.

Comparisons of disease cluster patterns, prevalence and health factors in the USA, Canada, England and Ireland.

BACKGROUND: Identification of those who are most at risk of developing specific patterns of disease across different populations is required for directing public health policy. Here, we contrast prevalence and patterns of cross-national disease incidence, co-occurrence and related risk factors across population samples from the U.S., Canada, England and Ireland. METHODS: Participants (n = 62,111) were drawn from the US Health and Retirement Study (n = 10,858); the Canadian Longitudinal Study on Ageing (n = 36,647); the English Longitudinal Study of Ageing (n = 7938) and The Irish Longitudinal Study on Ageing (n = 6668). Self-reported lifetime prevalence of 10 medical conditions, predominant clusters of multimorbidity and their specific risk factors were compared across countries using latent class analysis. RESULTS: The U.S. had significantly higher prevalence of multimorbid disease patterns and nearly all diseases when compared to the three other countries, even after adjusting for age, sex, BMI, income, employment status, education, alcohol consumption and smoking history. For the U.S. the most at-risk group were younger on average compared to Canada, England and Ireland. Socioeconomic gradients for specific disease combinations were more pronounced for the U.S., Canada and England than they were for Ireland. The rates of obesity trends over the last 50 years align with the prevalence of eight of the 10 diseases examined. While patterns of disease clusters and the risk factors related to each of the disease clusters were similar, the probabilities of the diseases within each cluster differed across countries. CONCLUSIONS: This information can be used to better understand the complex nature of multimorbidity and identify appropriate prevention and management strategies for treating multimorbidity across countries.

The association between anxiety disorders and hippocampal volume in older adults.

The hippocampus, through its mediation of fear responses is thought to play a central role in the onset and maintenance of anxiety disorders. Prevalence of anxiety disorders remains high in older populations; however, little is known about their association with hippocampal changes in this age group. Due to differing levels of cortisol as adults age, age-related decreases in hippocampal volume, and the suggestion that age-related loss of neurogenesis results in anxiety disorders, this area requires investigation. We examined the association between hippocampal volume and anxiety disorders (social anxiety disorder, generalized anxiety disorder, agoraphobia, panic disorder, obsessive compulsive disorder and posttraumatic stress disorder) in 534 older adults participating in the Enquête de Santé Psychologique-Risques, Incidence et Traitement (ESPRIT) study of late-life neuropsychiatric disorders. Anxiety disorders were diagnosed using the Mini International Neuropsychiatric Interview MINI, French version 5.00. Cross-sectional analyses adjusted for age, educational level, gender, Mini-Mental State Examination scores, National Adult Reading Test scores, whole brain volume and depression found that a diagnosis of generalized anxiety disorder was positively associated with larger hippocampal volume. No other anxiety disorder was significantly associated with hippocampal volume. The present study is the first to examine the association between several anxiety disorders and hippocampal volume in an older population and the results highlight the need for further research relating to the relationship between hippocampal volume and anxiety disorders in older adults. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Cognitive Functions as Predictors of Alzheimer's Disease Biomarker Status in the European Prevention of Alzheimer's Dementia Cohort.

Alterations in Alzheimer's disease (AD) biomarkers have been observed decades before the onset of dementia. Cognitive dysfunction, while central to the clinical diagnosis of AD, has long been considered as a late-stage phenomenon. This assumption is currently challenged and signals on some cognitive tests are now being observed within the preclinical stage. As part of the European Prevention of Alzheimer's Dementia (EPAD) project, a battery of cognitive tests has been proposed (the EPAD Neuropsychological Examination, ENE) which is designed to detect cognitive changes in persons without clinical signs of AD but who are at high risk. Analysis of results from the 361 participants with complete measures and without dementia recruited into the EPAD Longitudinal Cohort Study showed that the majority have elevated biomarker levels, with significant associations between an episodic verbal memory task and tau, while amyloid-ß (Aß) was associated with a central executive task. These preliminary findings suggest that profiles of cognitive performance may be specific to a given biomarker, with a primarily hippocampal task being associated with higher levels of tau and a frontal executive task being associated with higher levels of Aß. While previous research has focused on the relationship between cognition and levels of Aß, our findings suggest that p-tau may potentially be a more significant correlate.

Healthy ageing trajectories and lifestyle behaviour: the Mexican Health and Aging Study.

Projections show that the number of people above 60 years old will triple by 2050 in Mexico. Nevertheless, ageing is characterised by great variability in the health status. In this study, we aimed to identify trajectories of health and their associations with lifestyle factors in a national representative cohort study of older Mexicans. We used secondary data of 14,143 adults from the Mexican Health and Aging Study (MHAS). A metric of health, based on the conceptual framework of functional ability, was mapped onto four waves (2001, 2003, 2012, 2015) and created by applying Bayesian multilevel Item Response Theory (IRT). Conditional Growth Mixture Modelling (GMM) was used to identify latent classes of individuals with similar trajectories and examine the impact of physical activity, smoking and alcohol on those. Conditional on sociodemographic and lifestyle behaviour four latent classes were suggested: high-stable, moderate-stable, low-stable and decliners. Participants who did not engage in physical activity, were current or previous smokers and did not consume alcohol at baseline were more likely to be in the trajectory with the highest deterioration (i.e. decliners). This study confirms ageing heterogeneity and the positive influence of a healthy lifestyle. These results provide the ground for new policies.

A Multi-study Coordinated Meta-analysis of Pulmonary Function and Cognition in Aging.

BACKGROUND: Substantial research is dedicated to understanding the aging-related dynamics among individual differences in level, change, and variation across physical and cognitive abilities. Evaluating replicability and synthesizing these findings has been limited by differences in measurements and samples, and by study design and statistical analyses confounding between-person differences with within-person changes. In this article, we conducted a coordinated analysis and summary meta-analysis of new results on the aging-related dynamics linking pulmonary function and cognitive performance. METHODS: We performed coordinated analysis of bivariate growth models in data from 20,586 participants across eight longitudinal studies to examine individual differences in baseline level, rate of change, and occasion-specific variability in pulmonary and cognitive functioning. Results were summarized using meta-analysis. RESULTS: We found consistent but weak baseline and longitudinal associations in levels of pulmonary and cognitive functioning, but no associations in occasion-specific variability. CONCLUSIONS: Results provide limited evidence for a consistent link between simultaneous changes in pulmonary and cognitive function in a normal aging population. Further research is required to understand patterns of onset of decline and differences in rates of change within and across physical and cognitive functioning domains, both within-individuals and across countries and birth cohorts. Coordinated analysis provides an efficient and rigorous approach for replicating and comparing results across independent longitudinal studies.

Lifestyle and neurodegeneration in midlife as expressed on functional magnetic resonance imaging: A systematic review.

INTRODUCTION: Lifestyle factors may influence brain health in midlife. Functional magnetic resonance imaging is a widely used tool to investigate early changes in brain health, including neurodegeneration. In this systematic review, we evaluate the relationship between lifestyle factors and neurodegeneration in midlife, as expressed using functional magnetic resonance imaging. METHODS: We searched MEDLINE, EMBASE, and PsycINFO combining subject headings and free text terms adapted for each database. Articles were screened, and their quality was assessed independently by two reviewers before final inclusion in the review. RESULTS: We screened 4116 studies and included 29 in the review. Seven lifestyle factors, such as alcohol, cognitive training, excessive internet use, fasting, physical training, smoking, and substance misuse, were identified in this review. DISCUSSION: Cognitive and physical trainings appear to be associated with a neuroprotective effect, whereas alcohol misuse, smoking, and substance misuse appear to be associated with neurodegeneration. Further research is required into the effects of excessive internet use and fasting.

Methods for handling longitudinal outcome processes truncated by dropout and death.

Cohort data are often incomplete because some subjects drop out of the study, and inverse probability weighting (IPW), multiple imputation (MI), and linear increments (LI) are methods that deal with such missing data. In cohort studies of ageing, missing data can arise from dropout or death. Methods that do not distinguish between these reasons for missingness typically provide inference about a hypothetical cohort where no one can die (immortal cohort). It has been suggested that inference about the cohort composed of those who are still alive at any time point (partly conditional inference) may be more meaningful. MI, LI, and IPW can all be adapted to provide partly conditional inference. In this article, we clarify and compare the assumptions required by these MI, LI, and IPW methods for partly conditional inference on continuous outcomes. We also propose augmented IPW estimators for making partly conditional inference. These are more efficient than IPW estimators and more robust to model misspecification. Our simulation studies show that the methods give approximately unbiased estimates of partly conditional estimands when their assumptions are met, but may be biased otherwise. We illustrate the application of the missing data methods using data from the 'Origins of Variance in the Old-old' Twin study.

Verbal memory and search speed in early midlife are associated with mortality over 25 years' follow-up, independently of health status and early life factors: a British birth cohort study.

BACKGROUND: Cognitive capabilities in childhood and in late life are inversely associated with mortality rates. However, it is unclear if adult cognition, at a time still relatively free from comorbidity, is associated with subsequent mortality, and whether this explains the associations of early life factors with adult mortality. METHODS: We used data from the MRC National Survey of Health and Development, a birth cohort study prospectively assessing 5362 participants born in 1946. The present analysis includes participants followed up from age 43 and undergoing cognitive assessment (verbal memory and search speed). Mortality outcomes were notified through linkage with a national register. Cox regression was used to estimate mortality hazards in relation to cognitive performance at age 43, adjusting for early life factors, socioeconomic position and health status. RESULTS: Data were available on 3192 individuals. Univariable analyses indicated that adult verbal memory and search speed, parental factors, childhood cognition and educational attainment were associated with mortality. However, multivariable models showed that the mortality associations with earlier life factors were explained by adult cognitive capability. A standard deviation increase in verbal memory and search speed scores was associated with lower mortality rates [hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.77-0.97, P = 0.02; HR = 0.88, 95% CI 0.78-1.00, P = 0.05, respectively), after adjustment for adult health. CONCLUSIONS: Cognitive capability in early midlife was inversely associated with mortality rates over 25 years and accounted for the associations of family background, childhood cognitive ability and educational attainment with mortality. These findings, in a nationally representative cohort with long-term follow-up, suggest that building cognitive reserve may improve later life health and survival chances.

Independent and interactive impacts of hypertension and diabetes mellitus on verbal memory: A coordinated analysis of longitudinal data from England, Sweden, and the United States.

The importance of preventing and controlling hypertension (HTN) and diabetes mellitus (DM) to mitigate risks to physical health has long been understood by health care professionals. More recently, a growing body of evidence implicates HTN and DM in age-related cognitive decline and risk for dementia, though consensus has yet to be reached on whether older adults living with comorbid HTN and DM are at heightened risk for cognitive impairment. The present study sought to contribute to this topic through a coordinated analysis of 3 longitudinal studies of aging from England, Sweden, and the United States (total N = 12,513). Identical multilevel linear growth models were fit to each to estimate the impact of baseline disease status on initial level and change in verbal declarative memory performance. Overall, few associations between HTN, DM, and cognition were observed. Rate of decline was steeper for Swedish participants with independent HTN but attenuated for their American counterparts. Americans with comorbid HTN and DM showed attenuated decline. Treatment with medication was substantially less prevalent in the earlier-born and lower-educated Swedish sample, which may help to explain our pattern of results. In addition, those living with multiple conditions may be more likely to receive treatment, mitigating cognitive decline. Our results present a nuanced view of the interactions between HTN, DM, and cognition, and lead us to recommend consideration of treatment status or proxies such as birth cohort and education, in combination with age at assessment and specific measure used to interpret research in this area. (PsycINFO Database Record

Educational inequalities in aging-related declines in fluid cognition and the onset of cognitive pathology.

BACKGROUND: Education has been robustly associated with cognitive reserve and dementia, but not with the rate of cognitive aging, resulting in some confusion about the mechanisms of cognitive aging. This study uses longitudinal data to differentiate between trajectories indicative of healthy versus pathological cognitive aging. METHODS: Participants included 9,401 Health and Retirement Study respondents aged 55 and older who completed cognitive testing regularly over 17.3 years until most recently in 2012. Individual-specific random change-point modeling was used to identify age of incident pathological decline; acceleration is interpreted as indicating likely onset of pathological decline when it is significant and negative. RESULTS: These methods detect incident dementia diagnoses with specificity/sensitivity of 89.3%/44.3%, 5.6 years prior to diagnosis. Each year of education was associated with 0.09 (95% CI, 0.087-0.096; P<0.001) standard deviation higher baseline cognition and delayed onset of cognitive pathology (HR, 0.98; 95% CI, 0.96-0.99; P=0.006). CONCLUSION: Longitudinal random change-point modeling was able to reliably identify incident dementia. Accounting for incident cognitive pathology, we find that education predicts cognitive capability and delayed onset pathological declines.

Dementia trials and dementia tribulations: methodological and analytical challenges in dementia research.

Dementia is a substantial and increasing public health concern. Despite decades of research, a cure or effective preventative treatment for dementia remains elusive. We offer critical review of contemporary dementia research and discuss potential reasons why progress in the field has not been as rapid as in other disciplines. We adopt a broad approach in keeping with the broad nature of the topic. We cover the difficulties inherent in studying dementia from 'bench' to 'bedside' to 'population'. We make particular reference to issues of operationalisation of the dementia syndrome and our evolving understanding of dementia as a research 'outcome'. We discuss contemporary 'hot topics' in dementia research methodology focussing on dementia models, pre-dementia states and biomarkers. Recognising the importance of prospective epidemiological cohorts and large-scale clinical trials we pay particular attention to these approaches and the challenges of generating results that have 'real world' external validity. Based on our thoughts we end with suggestions for future dementia research. Our review is designed to be critical but not unnecessarily negative. There is reason for cautious optimism in dementia research. The recent G8 summit on dementia and subsequent establishment of the World Dementia Council are examples of initiatives that reflect societal and political will to increase research efforts in dementia.

Dementia prediction for people with stroke in populations: is mild cognitive impairment a useful concept?

BACKGROUND: criteria for mild cognitive impairment (MCI) capture an intermediate cognitive state between normal ageing and dementia, associated with increased dementia risk. Whether criteria for MCI are applicable in the context of stroke and can be used to predict dementia in stroke cases is not known. OBJECTIVES: to determine the prevalence of MCI in individuals with stroke and identify predictors of 2-year incident dementia in stroke cases. METHODS: individuals were from the Medical Research Council Cognitive Function and Ageing Study. MCI prevalence in individuals with stroke was determined. Logistic regression, with receiver operating characteristic curve analysis, was used to identify variables associated with risk of dementia in stroke cases including MCI criteria, demographic, health and lifestyle variables. FINDINGS: of 2,640 individuals seen at the first assessment, 199 reported stroke with no dementia. In individuals with stroke, criteria for MCI are not appropriate, with less than 1% of stroke cases being classified as having MCI. However, in individuals with stroke two components of the MCI definition, subjective memory complaint and cognitive function (memory and praxis scores) predicted 2-year incident dementia (area under the curve = 0.85, 95% CI: 0.77-0.94, n = 113). CONCLUSION: criteria for MCI do not appear to capture risk of dementia in the context of stroke in the population. In stroke cases, subjective and objective cognitive performance predicts dementia and these variables could possibly be incorporated into dementia risk models for stroke cases. Identifying individuals with stroke at greatest risk of dementia has important implications for treatment and intervention.