Understanding and predicting the longitudinal course of dementia.
ABSTRACT: PURPOSE OF REVIEW:To date, most research in dementia has focused either on the identification of dementia risk prediction or on understanding changes and predictors experienced by individuals before diagnosis. Despite little is known about how individuals change after dementia diagnosis, there is agreement that changes occur over different time scales and are multidomain. In this study, we present an overview of the literature regarding the longitudinal course of dementia. RECENT FINDINGS:Our review suggests the evidence is scarce and findings reported are often inconsistent. We identified large heterogeneity in dementia trajectories, risk factors considered and modelling approaches employed. The heterogeneity of dementia trajectories also varies across outcomes and domains investigated. SUMMARY:It became clear that dementia progresses very differently, both between and within individuals. This implies an average trajectory is not informative to individual persons and this needs to be taken into account when communicating prognosis in clinical care. As persons with dementia change in many more ways during their patient journey, heterogeneous disease progressions are the result of disease and patient characteristics. Prognostic models would benefit from including variables across a number of domains. International coordination of replication and standardization of the research approach is recommended.
Project description:To determine whether asymptomatic persons with Alzheimer disease (AD) neuropathologic change differ in the trajectory of their cognitive performance compared to asymptomatic persons without AD neuropathologic change.Longitudinal performance on standard neuropsychological tests was examined in participants who died within 2 years of their last cognitive assessment and who were never diagnosed with mild cognitive impairment or dementia (Clinical Dementia Rating global score of 0 at all assessments). Using cognitive and neuropathologic data collected between 2005 and 2013 from the 34 National Institute on Aging-sponsored Alzheimer's Disease Centers, cognitive trajectories were compared for persons with and without evidence of AD neuropathologic change. We evaluated rates of decline in 4 domains (episodic memory, language, attention/working memory, executive function). The significance of the differences (?) in rates of decline was tested using linear regression, adjusting for age, education, sex, and other neuropathologic lesions.Participants who had low to high levels of AD neuropathologic change (n = 131) showed a greater rate of decline on the attention/working memory domain score (? = -0.11; 95% confidence interval = -0.19, -0.02; p = 0.02) when compared to 80 participants who died without evidence of AD neuropathologic change.Clinically normal individuals who come to autopsy with AD neuropathologic change exhibit subtle evidence of declining cognitive trajectories for attention/working memory.
Project description:OBJECTIVES:To understand how bereaved spousal caregivers of persons with dementia perceive and respond to changes over the course of their spouse's disease, from diagnosis into bereavement. DESIGN:Qualitative interview study with convenience sampling and thematic analysis approach. PARTICIPANTS:Participants included eight women and two men (n=10) who had been spousal caregivers for a person with dementia prior to his/her death. Participants were older adults who self-reported good health and were bereaved longer than a year. SETTING:Data collected in a small Canadian prairie city between fall 2014 and winter 2015. FINDINGS:Two overarching themes were developed as important components of participants' caregiving journey: emotional reactions to change and variation in social connectedness throughout the caregiving and bereavement journey. Four key sub-themes developed through the analysis of emotional reactions to events: memorable grief overshadows persistent grief, a progressive feeling of hopelessness and overwhelmed, relief is common but hidden and gratitude is a milestone in a constructive bereavement. Three key variations of social connectedness throughout the caregiving and bereavement journey were developed: the importance of social inclusion throughout a caregiving and bereavement journey, the repeated loss of companionship and withdrawing from social interactions is contingent on needs. CONCLUSIONS:The findings suggest that emotional changes throughout caregiving and bereavement are not linear. The need for support from family, friends and new social supports is influential in enabling the caregiver to move forward during caregiving and bereavement.
Project description:Dementia is characterized by accelerated cognitive decline before and after diagnosis as compared to normal aging. It has been known that cognitive impairment occurs long before the diagnosis of dementia. For individuals who develop dementia, it is important to determine the time when the rate of cognitive decline begins to accelerate and the subsequent gap time to dementia diagnosis. For normal aging individuals, it is also useful to understand the trajectory of cognitive function until their death. A Bayesian change-point model is proposed to fit the trajectory of cognitive function for individuals who develop dementia. In real life, people in older ages are subject to two competing risks, e.g., dementia and dementia-free death. Because the majority of people do not develop dementia, a mixture model is used for survival data with competing risks, which consists of dementia onset time after the change point of cognitive function decline for demented individuals and death time for nondemented individuals. The cognitive trajectories and the survival process are modeled jointly and the parameters are estimated using the Markov chain Monte Carlo method. Using data from the Honolulu Asia Aging Study, we show the trajectories of cognitive function and the effect of education, apolipoprotein E 4 genotype, and hypertension on cognitive decline and the risk of dementia.
Project description:OBJECTIVES:To estimate the associations between diabetes, heart disease, and dementia, which may increase the difficulty of self-care; model functional disability trajectories jointly with attrition (death or dropout) over 5 years. DESIGN:Population-based complex survey design. SETTING:National Health and Aging Trends Study. PARTICIPANTS:Community-dwelling Medicare beneficiaries aged 65 and older (N=7,609). MEASUREMENTS:National estimates were generated using sampling weights. Sociodemographic characteristics, self-reported physician-diagnosed chronic conditions, six activities of daily living (ADL), and cognitive status were ascertained in annual in-person interviews. A joint model using group-based trajectory modeling was used to estimate the number of ADL disabilities and attrition probability. Multinomial logistic regression with survey weights was used to estimate the association between diabetes, heart disease, and dementia and resultant trajectories of disability, with the least disabled trajectory used as a reference. RESULTS:Three functional disability trajectories were identified: 26.9 million (76.3%) individuals with no disability and a constant study attrition of 14.3%, 4.9 million (13.9%) with mild and increasing disability and 12% attrition in 2012 and 27.2% in 2015, and 3.4 million (9.7%) with severe and increasing disability and 25.4% attrition in 2012 and 35% in 2015. Persons with possible dementia, possible dementia and diabetes, or possible dementia with diabetes and heart disease had significantly greater odds of being on the mild disability trajectory than those with no disability. Persons with probable dementia, representing more than 1.5 million persons, regardless of concurrent conditions, had significantly greater odds of being on the severe disability trajectory than on the no disability trajectory. CONCLUSIONS:Methods that generate national estimates and account for attrition and for multiple chronic conditions and cognitive status may be useful for health policy-makers to make decisions on care provisions and services.
Project description:To understand the neuropsychological basis of dementia risk among persons in the spectrum including cognitive normality and mild cognitive impairment.We quantitated risk of progression to dementia in elderly persons without dementia from 2 population-based studies, the Framingham Heart Study (FHS) and Mayo Clinic Study of Aging (MCSA), aged 70 to 89 years at enrollment. Baseline cognitive status was defined by performance in 4 domains derived from batteries of neuropsychological tests (that were similar but not identical for FHS and MCSA) at cut scores corresponding to SDs of ?-0.5, -1, -1.5, and -2 from normative means. Participants were characterized as having no cognitive impairment (reference group), or single or multiple amnestic or nonamnestic profiles at each cut score. Incident dementia over the following 6 years was determined by consensus committee at each study separately.The pattern of hazard ratios for incident dementia, rates of incident dementia and positive predictive values across cognitive test cut scores, and number of affected domains was similar although not identical across the FHS and MCSA. Dementia risks were higher for amnestic profiles than for nonamnestic profiles, and for multidomain compared with single-domain profiles.Cognitive domain subtypes, defined by neuropsychologically derived cut scores and number of low-performing domains, differ substantially in prognosis in a conceptually logical manner that was consistent between FHS and MCSA. Neuropsychological characterization of elderly persons without dementia provides valuable information about prognosis. The heterogeneity of risk of dementia cannot be captured concisely with one test or a single definition or cutpoint.
Project description:Neuropsychiatric symptoms, depressive symptoms in particular, are common in patients with dementia but whether depressive symptoms in adulthood increases the risk for dementia remains the subject of debate.To characterize the trajectory of depressive symptoms over 28 years prior to dementia diagnosis to determine whether depressive symptoms carry risk for dementia.Up to 10?308 persons, aged 35 to 55 years, were recruited to the Whitehall II cohort study in 1985, with the end of follow-up in 2015. Data analysis for this study in a UK general community was conducted from October to December 2016.Depressive symptoms assessed on 9 occasions between 1985 and 2012 using the General Health Questionnaire.Incidence of dementia (n?=?322) between 1985 and 2015.Of the 10?189 persons included in the study, 6838 were men (67%) and 3351 were women (33%). Those reporting depressive symptoms in 1985 (mean follow-up, 27 years) did not have significantly increased risk for dementia (hazard ratio [HR], 1.21; 95% CI, 0.95-1.54) in Cox regression adjusted for sociodemographic covariates, health behaviors, and chronic conditions. However, those with depressive symptoms in 2003 (mean follow-up, 11 years) had an increased risk (HR, 1.72; 95% CI, 1.21-2.44). Those with chronic/recurring depressive symptoms (?2 of 3 occasions) in the early study phase (mean follow-up, 22 years) did not have excess risk (HR, 1.02; 95% CI, 0.72-1.44) but those with chronic/recurring symptoms in the late phase (mean follow-up, 11 years) did have higher risk for dementia (HR, 1.67; 95% CI, 1.11-2.49). Analysis of retrospective depressive trajectories over 28 years, using mixed models and a backward time scale, shows that in those with dementia, differences in depressive symptoms compared with those without dementia became apparent 11 years (difference, 0.61; 95% CI, 0.09-1.13; P?=?.02) before dementia diagnosis and became more than 9 times larger at the year of diagnosis (difference, 5.81; 95% CI, 4.81-6.81; P?<?.001).Depressive symptoms in the early phase of the study corresponding to midlife, even when chronic/recurring, do not increase the risk for dementia. Along with our analysis of depressive trajectories over 28 years, these results suggest that depressive symptoms are a prodromal feature of dementia or that the 2 share common causes. The findings do not support the hypothesis that depressive symptoms increase the risk for dementia.
Project description:Importance:Cardiometabolic risk factors have been associated with an increased risk of dementia; yet, the optimal targets and time window for the management of cardiometabolic health to prevent dementia remain unknown. Objectives:To model concurrently and compare the trajectories of cardiometabolic risk factors up to 14 years preceding diagnosis in individuals with dementia and matched controls free of dementia. Design, Setting, and Participants:A case-control study nested within the Three-City study, a French population-based cohort of older persons (≥65 years), included 6 home visits with neuropsychological testing between 1999 and 2014. Data analysis was performed in September 2017. A total of 785 incident dementia cases and 3140 controls matched by sex, age, educational level, and cohort center at the time of diagnosis were evaluated. Exposures:Repeated measures of body mass index (BMI) and systolic (SBP) and diastolic (DBP) blood pressure, high-density lipoprotein (HDL-C) and low-density lipoprotein cholesterol (LDL-C), triglycerides, and glycemia levels between 1999 and 2014. Main Outcomes and Measures:Incidence of dementia based on systematic detection and validated diagnosis. Results:A total of 785 cases and 3140 controls (2530 [65%] women; mean [SD] age, 76  years) were included in the study. Cases presented a faster decline in BMI, slower increase of SBP and constantly lower DBP. Mean values (95% CI) 14 years before diagnosis (-14 years) and at diagnosis (year 0) for the most common profile were BMI, 26.1 (25.6-26.5) and 24.8 (24.5-25.1) for a case, and 25.7 (25.4-26.1) and 25.3 (25.0-25.5) for a control; for SBP, 135.2 (131.8-138.7) and 142.1 (140.3-143.9) mm Hg for a case, and 135.8 (132.9-138.6) and 144.9 (143.7-146.1) mm Hg for a control; for DBP, 76.5 (74.7-78.5) and 74.0 (73.1-74.9) mm Hg for a case, and 76.7 (75.1-78.3) and 75.0 (74.2-75.7) mm Hg for a control. In contrast, glycemia was higher among cases (mean fasting glucose values [95% CI] at -14 years and year 0: 89.4 [86.9-92.1] and 96.4 [93.7-99.3] mg/dL for a case, and 87.1 [85.1-89.2] and 95.3 [93.5-97.1] mg/dL for a control), with a significant case-control difference from -1.6 to -14 years prior to diagnosis. There were no significant case-control differences in trajectories of blood lipid levels (mean values [95% CI] at -14 years and year 0: for HDL-C, 70.6 [67.6-73.9] and 61.3 [58.9-63.8] mg/dL for a case, and 70.4 [67.5-73.3] and 62.3 [60.2-64.3] mg/dL for a control; for LDL-C: 147.2 [140.5-154.5] and 141.6 [136.6-146.7] mg/dL for a case, and 144.3 [138.7-150.4] and 141.2 [137.5-145.2] mg/dL for a control; for triglycerides: 115.5 [103.6-149.1] and 112.6 [104.8-120.9] mg/dL for a case, and 112.5 [103.8-144.4] and 109.7 [105.0-114.8] mg/dL for a control). Conclusions and Relevance:In this large cohort of older persons, BMI declined in prodromal dementia, possibly reflecting early preclinical changes. Lower BP prior to dementia may reflect both a consequence and a contributing factor for the disease, whereas higher blood glucose levels may constitute a risk factor for dementia in the older age range. Overall, these findings suggest that elevated glycemia, low BP, and weight loss may be primary targets for the management of cardiometabolic health for primary and secondary prevention of dementia in the older age range.
Project description:PURPOSE:For persons who are at risk for, or living with, dementia exercise is recommended, yet many become or remain inactive. Exercise providers play a vital role in promoting and facilitating exercise in these groups by recognizing and being responsive to the needs of persons with mild cognitive impairment (MCI) or dementia in exercise programming. The objective of this study was to explore the experiences, perceptions, and needs of community exercise providers regarding dementia. MATERIALS & METHODS:Five focus groups were held with community exercise providers (n = 30) who deliver exercise to older adults (?55 years) in municipal, non-profit, for profit, or academic settings. RESULTS:Three themes were developed: (1) Unique experiences and diverse perceptions: suggests unique personal experiences with MCI and dementia inform distinct perceptions of dementia; (2) Dementia-Inclusive Practices: learning as you go and adapting for the individual: reflects exercise providers' approaches to recognizing and accommodating individuals' unique abilities and preferences; (3) Training and Best Practices, with Flexibility: identifies exercise providers' desires for MCI- and dementia-specific knowledge and training strategies, which need to recognize dementia heterogeneity between and within persons over time. CONCLUSIONS:These findings highlight a willingness of exercise providers to support dementia-inclusive exercise, but recognize they have minimal training and lack educational resources to do so. Formal training resources may enhance exercise accessibility and participation for persons with MCI or dementia.
Project description:Alzheimer's disease (AD) is characterised by a dynamic process of neurocognitive changes from normal cognition to mild cognitive impairment (MCI) and progression to dementia. However, not all individuals with MCI develop dementia. Predicting whether individuals with MCI will decline (i.e. progressive MCI) or remain stable (i.e. stable MCI) is impeded by patient heterogeneity due to comorbidities that may lead to MCI diagnosis without progression to AD. Despite the importance of early diagnosis of AD for prognosis and personalised interventions, we still lack robust tools for predicting individual progression to dementia. Here, we propose a novel trajectory modelling approach based on metric learning (Generalised Metric Learning Vector Quantization) that mines multimodal data from MCI patients in the Alzheimer's disease Neuroimaging Initiative (ADNI) cohort to derive individualised prognostic scores of cognitive decline due to AD. We develop an integrated biomarker generation- using partial least squares regression- and classification methodology that extends beyond binary patient classification into discrete subgroups (i.e. stable vs. progressive MCI), determines individual profiles from baseline (i.e. cognitive or biological) data and predicts individual cognitive trajectories (i.e. change in memory scores from baseline). We demonstrate that a metric learning model trained on baseline cognitive data (memory, executive function, affective measurements) discriminates stable vs. progressive MCI individuals with high accuracy (81.4%), revealing an interaction between cognitive (memory, executive functions) and affective scores that may relate to MCI comorbidity (e.g. affective disturbance). Training the model to perform the same binary classification on biological data (mean cortical ?-amyloid burden, grey matter density, APOE 4) results in similar prediction accuracy (81.9%). Extending beyond binary classifications, we develop and implement a trajectory modelling approach that shows significantly better performance in predicting individualised rate of future cognitive decline (i.e. change in memory scores from baseline), when the metric learning model is trained with biological (r = -0.68) compared to cognitive (r = -0.4) data. Our trajectory modelling approach reveals interpretable and interoperable markers of progression to AD and has strong potential to guide effective stratification of individuals based on prognostic disease trajectories, reducing MCI patient misclassification, that is critical for clinical practice and discovery of personalised interventions.