Protocol for the Brain Health Support Program Study of the Canadian Therapeutic Platform Trial for Multidomain Interventions to Prevent Dementia (CAN-THUMBS UP): A Prospective 12-Month Intervention Study.

BACKGROUND/OBJECTIVES: CAN-THUMBS UP is designed as a comprehensive and innovative fully remote program to 1) develop an interactive and compelling online Brain Health Support Program intervention, with potential to positively influence dementia literacy, self-efficacy and lifestyle risk factors; 2) enroll and retain a community-dwelling Platform Trial Cohort of individuals at risk of dementia who will participate in the intervention; 3) support an open platform trial to test a variety of multidomain interventions that might further benefit individuals at risk of dementia. This manuscript presents the Brain Health Support Program Study protocol. DESIGN/SETTING: Twelve-month prospective multi-center longitudinal study to evaluate a fully remote web-based educational intervention. Participants will subsequently be part of a Platform Trial Cohort and may be eligible to participate in further dementia prevention clinical trials. PARTICIPANTS: Three hundred fifty older adults who are cognitively unimpaired or have mild cognitive impairment, with at least 1 well established dementia risk factor. INTERVENTION: Participants engage in the Brain Health Support Program intervention for 45-weeks and complete pre/post intervention measures. This intervention is designed to convey best available evidence for dementia prevention, consists of 181 chapters within 8 modules that are progressively delivered, and is available online in English and French. The program has been developed as a collaborative effort by investigators with recognized expertise in the program's content areas, along with input from older-adult citizen advisors. MEASUREMENTS: This study utilizes adapted remote assessments with accessible technologies (e.g. videoconferencing, cognitive testing via computer and mobile phone, wearable devices to track physical activity and sleep, self-administered saliva sample collection). The primary outcome is change in dementia literacy, as measured by the Alzheimer's Disease Knowledge Scale. Secondary outcomes include change in self-efficacy; engagement using the online program; user satisfaction ratings; and evaluation of usability and acceptance. Exploratory outcomes include changes in attitudes toward dementia, modifiable risk factors, performance on the Neuropsychological Test Battery, performance on self-administered online cognitive assessments, and levels of physical activity and sleep; success of the national recruitment plan; and the distribution of age adjusted polygenic hazard scores. CONCLUSIONS: This fully remote study provides an accessible approach to research with all study activities being completed in the participants' home environment. This approach may reduce barriers to participation, provide an easier and less demanding participant experience, and reach a broader geography with recruitment from all regions of Canada. CAN-THUMBS UP represents a Canadian contribution to the global World-Wide FINGERS program (alz.org/wwfingers).

Decline in Memory, Visuospatial Ability, and Crystalized Cognitive Abilities in Older Adults: Normative Aging or Terminal Decline?

The aim of this study is to explore the pattern of change in multiple measures of cognitive abilities in a sample of oldest-old adults, comparing two different time metrics (chronological age and time to death) and therefore examining both underlying conceptual assumptions (age-related change and terminal decline). Moreover, the association with individual characteristics as sex, education, and dementia diagnosis was also examined. Measures of cognitive status (Mini-Mental State Examination and the Swedish Clock Test) and tests of crystallized (knowledge and synonyms), memory (verbal memory, nonverbal long-term memory, recognition and correspondence, and short-term memory), and visuospatial ability were included. The sample consisted of 671 older Swedish adult participants of the OCTO Twin Study. Linear mixed models with random coefficients were used to analyse change patterns and BIC indexes were used to compare models. Results showed that the time to death model was the best option in analyses of change in all the cognitive measures considered (except for the Information Test). A significant cognitive decline over time was found for all variables. Individuals diagnosed with dementia had lower scores at the study entrance and a faster decline. More educated individuals performed better in all the measures of cognition at study entry than those with poorer education, but no differences were found in the rate of change. Differences were found in age, sex, or time to death at baseline across the different measures. These results support the terminal decline hypothesis when compared to models assuming that cognitive changes are driven by normative aging processes.

Genetic architecture for hole-board behaviors across substantial time intervals in young, middle-aged and old mice.

A quantitative trait locus (QTL) analysis of behaviors across the life span was conducted in F(2) mice from a C57BL/6J x DBA/2J cross and 22 BXD recombinant inbred (RI) strains. Mice of three age groups were tested in a hole-board apparatus for 3 min on three occasions approximately 1 month apart (average age at test 150, 450 and 750 days, approximately 400 mice per group, divided equally by sex). Quantitative trait loci with small effect size were found on 11 chromosomes for hole-board activity (Hbact) and hole-board rearing (Hbrear). Analysis of 22 RI strains tested at 150 and 450 days of age found only suggestive linkage, with four QTL for Hbact overlapping with those from the F(2) analysis. There was a significant phenotypic correlation between Hbact and Hbrear (approximately 0.55-0.69) and substantial commonality among QTL for the two behaviors. QTL analyses of head-pokes (HP) and fecal boli (FB) only identified QTL at the suggestive level of significance. Age accounted for approximately 15% of the phenotypic variance (sex approximately 3%), and there were genotype by age interactions at approximately 25% of the Hbact and Hbrear QTL. Quantitative trait loci for Hbrear were relatively stable across the three measurement occasions (those for Hbact somewhat less so), although mean levels of each index declined markedly comparing the first to subsequent trials. Considered as a whole, the polygenic system influencing exploratory behaviors accounts for approximately the same amount of phenotypic variance as age (within the range studied), is stable across substantial periods of time, and acts, for the most part, independently of age and sex.

Onset of terminal decline in cognitive abilities in individuals without dementia.

OBJECTIVE: To identify time of onset and rate of mortality-related change (terminal decline) in cognitive abilities in later life. METHOD: The sample consisted of 288 individuals without dementia (born 1901-1902) drawn from the population of Göteborg, Sweden. Participants were followed from age 70 until death, with up to 12 measurement occasions on three cognitive abilities. Change-point analysis was performed using an automated piecewise linear mixed modeling approach to identify the inflection point indicating accelerated within-person change related to mortality. A profile likelihood method was used to identify the change point that best fit the data for each of three cognitive abilities. RESULTS: Onset of terminal decline was identified 6.6 years prior to death for verbal ability, 7.8 years for spatial ability, and 14.8 years for perceptual speed. CONCLUSIONS: There is substantial acceleration in cognitive decline many years prior to death among individuals without dementia. Time of onset and rate of terminal decline vary considerably across cognitive abilities.

Behavioral and psychological symptoms of dementia and caregivers' stress appraisals: intra-individual stability and change over short-term observations.

Dementia is commonly associated with memory loss, but Behavioral and Psychological Symptoms of Dementia (BPSD) such as disruptive behaviors, agitation, and problems with mood, usually have a more significant impact on caregivers' stress. It is known that BPSD and caregivers' stress reactions vary in frequency over the long-term course of dementia, however little is known about the variability over the short-term. The current study included 85 people with dementia and their primary caregivers assessed over three months. Caregivers used a 24-hour log on multiple, consecutive days to report behavioral symptoms of dementia on seven domains of behavior, as well as their stress reactions for each domain. Using latent growth curve analysis, most BPSD and caregiver stress appraisals were found to be, on average, stable over the three-month time frame. For many BPSD and stress appraisal models, however, intra-individual differences in rate of change were significantly different from the mean trend, indicating behaviors and stress are not stable over three months when assessed at the level of the individual. Covariates were used to explain individual differences in rates of change; however few variables were significantly associated with intra-individual short-term change over time.

Genetic and environmental influences on age at sexual initiation in the Colorado Adoption Project.

Whereas the majority of research on adolescent sexual initiation has focused solely on environmental factors, the present study used behavioral genetic analyses to investigate the relative contributions of genetic and environmental influences. Structural equation models were fitted to data from adoptive and non-adoptive sibling pairs (231 biologically related pairs and 169 unrelated pairs) from the Colorado Adoption Project. Information from censored individuals who had not yet experienced sexual initiation was maximized by adapting the twin survival analysis method of Pickles et al. (Behav Genet 24(5):457-468, 1994) to accommodate adoptive and non-adoptive siblings. Point estimates of variance components from an ACE model, including additive genetic (A), shared environmental (C), and non-shared environmental (E) influences were 28%, 24%, and 48%, respectively. Despite the lower point estimate for shared environmental effects than additive genetic effects, a CE model provided the best fit to the data. However, because adoptive siblings provide a direct estimate of shared environmental influences there is greater power to detect shared environmental effects in adoption designs. Evidence for genetic influences from our data were somewhat lower than those obtained in previous twin studies, possibly reflecting a return to more socially conservative sexual attitudes, changing sexual behaviors, or ambiguities in the wording of questions commonly used in research on adolescent sexuality.

Understanding Ageing. An evaluation of research designs for assessing the interdependence of ageing-related changes.

BACKGROUND: Cross-sectional studies of samples varying widely in age have found moderate to high levels of shared age-related variance among measures of cognitive and physiological capabilities, leading researchers to posit common factors or common causal influences for diverse age-related phenomenon. OBJECTIVE: The influence of population average changes with age on cross-sectional estimates of association has not been widely appreciated in developmental and ageing research. Covariances among age-related variables in cross-sectional studies are highly confounded in regards to inferences about associations among rates of change within individuals since covariances can result from a number of sources including average population age-related differences (fixed age effects) in addition to initial individual differences and individual differences in rates of ageing (random age effects). Analysis of narrow age-cohort samples may provide a superior analytical basis for testing hypotheses regarding associations between rates of change in cross-sectional studies. CONCLUSIONS: The use of age-heterogeneous cross-sectional designs for evaluating interdependence of ageing-related processes is discouraged since associations will not necessarily reflect individual-level correlated rates of change. Typical cross-sectional studies do not provide sufficient evidence for the interdependence of ageing-related changes and should not serve as the basis for theories and hypotheses of ageing. Reanalyzing existing cross-sectional studies using a sequential narrow-age cohort approach provides a useful alternative for evaluating associations between ageing-related changes. Longitudinal designs, however, provide a much stronger basis for inference regarding associations between rates of ageing within individuals.

Age is no kinder to the better educated: absence of an association investigated using latent growth techniques in a community sample.

BACKGROUND: Higher education has been posited to protect against cognitive decline, either because the rate of decline is slower in the more highly educated or the start of decline is delayed. Latent growth models provide improved methodology to examine this issue. METHODS: The sample consisted of 887 participants aged 70-93 years in 1991 and followed up in 1994 and 1998. Latent growth models and standard regression techniques were used to examine the rate of cognitive decline in four cognitive measures while controlling for health status and sex. A delayed start model was examined by incorporating interaction effects in a regression model. RESULTS: Neither the latent growth models nor the regression techniques revealed a slower rate of decline for the more highly educated. The proportion of the highly educated showing no change was no larger than the proportion of the less well educated. There were no significant age by education interaction effects, no chronologically later accelerations in the rate of change as a function of education, and no differences in rate of decline between the first measurement interval and the second. CONCLUSIONS: Education may not protect against cognitive decline although it is associated with long-term individual differences in level of functioning. The discrepancy between our study and others may be attributable to attrition effects, follow-up length, sample age, scaling artefacts and negative publication bias. Most importantly, practice effects may favour the better educated and hence account for the supposed protective effect in many longitudinal studies of cognitive change.

Predictors of maternal child-feeding style: maternal and child characteristics.

We investigated relationships among maternal and child characteristics, and two aspects of maternal child-feeding styles that may place daughters at risk for developing problems with energy balance. Participants included 104 overweight (BMI> or =25) and 92 non-overweight (BMI<25) mothers and their 5-year-old, non-Hispanic, White daughters. Child-feeding styles included (a) restriction of daughters' intake of energy-dense snack food, and (b) pressure to eat more food. Predictors of child-feeding styles included measures of (1) maternal investment in weight and eating issues, including dietary restraint and weight concern, (2) child adiposity, (3) maternal perceptions of the child as underweight or overweight, and (4) maternal concern for child weight. Mothers reported using more restrictive feeding practices when they were invested in weight and eating issues, when they perceived daughters as overweight, when they were concerned about daughters' weight, and when daughters were heavier. Mothers reported using more pressure in child feeding when daughters were thinner, and when mothers perceived daughters as underweight. Further analyses examined whether relationships among child-feeding styles were different for overweight and non-overweight mothers. Overweight mothers' child-feeding styles appeared to be influenced by observable child weight characteristics, concerns for the child's weight status, and mothers' own history of overweight. Non-overweight mothers' child-feeding styles appeared to be influenced by distorted perceptions of and concerns for children, as well as distorted self-perceptions.

Epistatic quantitative trait loci for alcohol preference in mice.

Alcohol consumption is a complex trait, responding to the influence of various genes and environmental influences acting in a quantitative fashion. Various studies in alcohol consumption processes have identified quantitative trait locus (QTL) regions across the mouse genome that appear to contribute to this phenotype. The purpose of this study was to examine the influence of interactions between alleles at different loci, a phenomenon known as epistasis, on previously identified QTLs for alcohol consumption in mice. A multiple regression model was developed and applied to test for the significance of the interaction between two QTLs and to quantify this interaction. Our results indicate the presence of epistasis between loci on mouse chromosomes 2 and 3 accounting for 7-8% of the variation in alcohol preference, respectively.

Genes as gerontological variables: uniform genotypes.

Genetic conceptualizations and procedures have become integral to the conduct of research across the spectrum of life sciences, including gerontology, even when genetics is not the focus of inquiry. Among the research tools thus provided, one of the most basic is that of inbred strains. A close approximation to genetic uniformity is achieved by a sufficient number of successive generations of matings of relatives, and, once this near-uniformity is attained, the members of an inbred strain constitute a reference group relatively stable over time and available to diverse investigators. Different inbred strains possess different genotypes, so that numerous distinctive reference groups are available. The stability of these groups enhances prospects of replication-testing, and makes possible the focused accumulation of pertinent data. Phenotypic differences among strains identify particular groups that can be most appropriate for particular subsequent research objectives (and also provide ipso facto evidence of genetic influence on the phenotype). The very substantial advantages of the uniform genotypes provided by inbred strains (and by their F1 offspring) are purchased at the cost of limited generalizability of results and constraints on assessment of co-variation among variables. Uniform genotypes are, thus, not a tool for all purposes but must be seen as a powerful basic tool within an abundant genetic tool-kit. Particular research purposes will require use of more than one tool from the kit.

Genes as gerontological variables: genetically heterogeneous stocks and complex systems.

In gerontological research utilizing animal models, a major general strategy has been the use of uniform genotypes of inbred strains or their F1 hybrids. These animal models provide standard reference groups that are of major importance in establishing a reliable data base on aging phenomena. There are limitations to their usage, however, particularly in respect to descriptions or evaluations of variances or of covariance relationships. For these purposes, genetically heterogeneous stocks have the advantage that phenotypic variance (and covariance) has a genetic as well as an environmental component. The advantages of genetic heterogeneity are best realized when the stock has been systematically derived (usually by intercrossing of inbred strains) and maintained by a mating scheme of sufficient size to minimize inbreeding. Genetically heterogeneous stocks are of particularly high potential value in the study of complex systems. Some examples of their use in a gerontological context are provided.

Origins of individual differences in episodic memory in the oldest-old: a population-based study of identical and same-sex fraternal twins aged 80 and older.

The relative importance of genetic and environmental influences on episodic memory in very late life was studied using a quantitative genetic approach. Identical (n = 125) and same-sex fraternal (n = 157) twin pairs, aged 80 and older (mean age = 83.3; SD = 3.1) and without a diagnosis of dementia were tested with seven memory measures: (1-2) Digit Span Forward and Backwards, (3) Prose Recall, (4) Thurstone's picture memory test, and the Memory in Reality (MIR) test, including the subtasks of (5) free recall, (6) recognition, and (7) relocation. Heritabilities, estimated by structural equation modeling, ranged from .04 to .49. The digit span backward test showed the highest heritability (h2 = .49), while heritabilities were typically lower for the long-term memory measures. The results demonstrate genetic influences on memory in the oldest-old, but suggest that the magnitude of these effects differs across memory measures.

Developmental loss of effect of a Chromosome 15 QTL on alcohol acceptance.

Human alcohol abuse and alcoholism have clear developmental features, suggesting the possibility of changes over time in heritability and in quantitative genetic architecture, and raising prospects of identifying individual genes or quantitative trait loci (QTLs) that display different influence on alcohol-related phenotypes at different ages. The identification of specific loci showing such age-related changes will open up opportunities of focused association studies and of genotype manipulation by various mating procedures. Most animal model research in alcohol assesses the phenotypes of the animals at an early age; developmental studies are rare. Here we report on a QTL on Chromosome (Chr) 15 of the mouse that has been shown in several populations, including BXD recombinant inbred strains, an F2, and genotypically selected lines, to affect a measure of alcohol consumption. In the present study, we measured alcohol acceptance in the genotypically selected animals and in an F4 sample at about 100 days and again at about 300 days of age. In both groups, and in both sexes, significant differences were observed at 100 days between animals that were homozygous for the "increasing" haplotype defining the QTL region and those homozygous for the "decreasing" haplotype. At 300 days of age, the effect is absent in females and has diminished or disappeared in males. The results provide a further confirmation of the Chr 15 QTL in young mice, offer a new perspective on the development of alcohol-related phenotypes, and have strong implications for research design.

A multivariate model for the analysis of sibship covariance structure using marker information and multiple quantitative traits.

A model was developed to detect effects of quantitative trait loci (QTLs) in sibships from simulated nuclear family data using the full covariance structure of the data and analyzing all five quantitative traits simultaneously in a multivariate model. Evidence of the presence of loci was detected on chromosomes 4, 8, 9, and 10. The method provided stable results and is worth further exploration for its performance and optimal sample size requirements under realistic conditions.

Analysis of structure and discriminative power of the Mattis Dementia Rating Scale.

The study examines the factor structure and provides test of the discriminative properties of the 38-item Mattis Dementia Rating Scale (MDRS). The MDRS was designed a priori to measure five broad domains of cognitive abilities: attention, initiation/perseveration, conceptualization, construction, and memory. Complete item level data were collected at the USC Alzheimer Disease Research Center from 19 probable Alzheimer's Disease (AD) patients, 17 cases with dementia of various etiologies (e.g., multiple infarct), and 49 contrast subjects. Factor analyses, with rotation to equamax criterion, were performed on education partialled data. Five and six factor solutions accounted for most of the reliable variance and permitted simple structure theoretical description for separate subscales. These factors, similar to Mattis' design, can be characterized as Memory (Recall)/Verbal Fluency, Construction, Memory (short-term), Initiation/Perseveration, and Simple Commands. Cross-validated discriminant analyses performed on five unit-weighted composite variables derived from factor analysis provided better classification (72% vs 62%) than the 38 Mattis items alone.

Maximizing the Usefulness of Data Obtained with Planned Missing Value Patterns: An Application of Maximum Likelihood Procedures.

Researchers often face a dilemma: Should they collect little data and emphasize quality, or much data at the expense of quality? The utility of the 3-form design coupled with maximum likelihood methods for estimation of missing values was evaluated. In 3-form design surveys, four sets of items. X, A, B, and C are administered: Each third of the subjects receives X and one combination of two other item sets - AB, BC, or AC. Variances and covariances were estimated with pairwise deletion, mean replacement, single imputation, multiple imputation, raw data maximum likelihood, multiple-group covariance structure modeling, and Expectation-Maximization (EM) algorithm estimation. The simulation demonstrated that maximum likelihood estimation and multiple imputation methods produce the most efficient and least biased estimates of variances and covariances for normally distributed and slightly skewed data when data are missing completely at random (MCAR). Pairwise deletion provided equally unbiased estimates but was less efficient than ML procedures. Further simulation results demonstrated that nun-maximum likelihood methods break down when data are not missing completely at random. Application of these methods with empirical drug use data resulted in similar covariance matrices for pairwise and EM estimation, however, ML estimation produced better and more efficient regression estimates. Maximum likelihood estimation or multiple imputation procedures. which are now becoming more readily available, are always recommended. In order to maximize the efficiency of the ML parameter estimates, it is recommended that scale items be split across forms rather than being left intact within forms.

Analysis with missing data in drug prevention research.

Missing data problems have been a thorn in the side of prevention researchers for years. Although some solutions for these problems have been available in the statistical literature, these solutions have not found their way into mainstream prevention research. This chapter is meant to serve as an introduction to the systematic application of the missing data analysis solutions presented recently by Little and Rubin (1987) and others. The chapter does not describe a complete strategy, but it is relevant for (1) missing data analysis with continuous (but not categorical) data, (2) data that are reasonably normally distributed, and (3) solutions for missing data problems for analyses related to the general linear model in particular, analyses that use (or can use) a covariance matrix as input. The examples in the chapter come from drug prevention research. The chapter discusses (1) the problem of wanting to ask respondents more questions than most individuals can answer; (2) the problem of attrition and some solutions; and (3) the problem of special measurement procedures that are too expensive or time consuming to obtain for all subjects. The authors end with several conclusions: Whenever possible, researchers should use the Expectation-Maximization (EM) algorithm (or other maximum likelihood procedure, including the multiple-group structural equation-modeling procedure or, where appropriate, multiple imputation, for analyses involving missing data [the chapter provides concrete examples]); If researchers must use other analyses, they should keep in mind that these others produce biased results and should not be relied upon for final analyses; When data are missing, the appropriate missing data analysis procedures do not generate something out of nothing but do make the most out of the data available; When data are missing, researchers should work hard (especially when planning a study) to find the cause of missingness and include the cause in the analysis models; and Researchers should sample the cases originally missing (whenever possible) and adjust EM algorithm parameter estimates accordingly.