1999 — 2000 |
Reynolds, Chandra A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cognitive Decline and the Role of Spicific Genes @ University of Southern California
DESCRIPTION (Adapted from the Applicant's Abstract): The proposed study will consider models and methods to examine the genetic and environmental influences on cognitive decline trajectories, including both estimates of total genetic influence and tests of the effects of specific genes. Because dementia may represent one extreme of cognitive changes seen with advancing age, methods are used that simultaneously consider normal aging and dementia and uncover tandem influences on both normative cognitive change and those effects specific to dementia. Cognitive measures from a unique population based sample of 788 same-sex twins from the Swedish/Adoption Twin Study of Aging and the Study of Dementia in Swedish Twins will be utilized; domain areas will include crystallized and fluid abilities, perceptual speed and memory. Cognitive decline trajectories will be estimated using longitudinal growth models where rate of change is quantified for each subjects' longitudinal profile of cognitive scores. We will examine the association of health traits, psychosocial traits, and measured susceptibility genotypes (e.g., APOE, LRP, HLA, other emerging loci) with cognitive decline trajectories, making use of current association and linkage methods utilized in twin and sib-pairs. Of principal interest are: (1) What amount of variation in cognitive decline trajectories is explained by significant risk genotypes? (2) What amount of variation in decline trajectories is explained by complex physical and psychosocial factors (e.g., educational attainment, serum lipoprotein levels, pulmonary function, smoking, head injury, self-efficacy)? Among significant factors, what are the shared genetic and environmental sources of covariance? (3) Are genotype-environment interactions present? For example, do identical (MZ) twins positive for environmental exposures (e.g., head injury) show greater decline than their co-twins without the environmental exposure? Is the interaction dependent on risk allele status (e.g., APOE 4)? The examination specific genetic and environmental influences on cognitive decline will lead to an increased understanding of factors that contribute to cognitive changes in late-life.
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0.958 |
2000 — 2001 |
Reynolds, Chandra A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Assortment and Transmission of Alcohol and Tobacco Use @ University of California Riverside
Studies of spouse similarity for alcohol and tobacco consumption find correlations that are moderate to strong in magnitude. The assessment of assortative mating for alcohol- and tobacco-related behaviors is critical for obtaining unbiased estimates of genetic and shared environmental effects in quantitative behavioral genetic studies; however, assortment effects have rarely been taken into account. Furthermore, many earlier studies of assortment lacked comprehensive testing of alternative explanations of spouse similarity to that of phenotypic assortment, including social homogamy. We propose to use a genetically informative twin-kinship design, including monozygotic and dizygotic twins, their spouses, and offspring, to resolve the mechanisms of assortment as well as models of parent-offspring transmission. The study will focus on data collected in 1977 from a population-based sample of 138 Swedish twin pairs and their spouses born between 1911 and 1935. The twin-kinship sample will be augmented with 745 same-sex twin pairs from the Swedish Adoption/Twin Study of Aging (SATSA). Assessments of tobacco and alcohol use were made by self-report questionnaire surveys. Information on other substance use (e.g., caffeine, tranquilizers) and socioeconomic indicators was also gathered. Behavioral genetic analyses will be utilized to address the following six questions: (1) What mechanisms of assortment account for spouse similarity for alcohol and smoking consumption? (2) What is the impact of assortment on estimates of genetic and environmental contributions to individual differences on alcohol and tobacco consumption under various models? (3) Is the assortment for alcohol and tobacco consumption primary or does it occur secondarily to assortment for education or other socioeconomic factors? (4) Is there a more complex phenotype of substance use on which assortment takes place? (5) What model of parent-offspring transmission accounts for familial similarity given an appropriate model of assortment? (6) To what relative extent do common genetic and environmental influences account for the bivariate relationship between alcohol and tobacco consumption? This study will also investigate potential generation and gender differences.
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0.958 |
2005 — 2008 |
Reynolds, Chandra A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Latent Growth Curve Paths to Longevity: the Terman Study @ University of California Riverside
DESCRIPTION (provided by applicant): Disparities in developmental biopsychosocial trajectories beginning in early childhood may distinguish those who reach advanced age exceptionally healthy from those who suffer an early death or chronic disease. Variations in longitudinal trajectories will be examined using a latent growth curve approach on 1,528 individuals from the Terman Life Cycle Study, a comprehensive 8-decade archive. Whilst individuals in the study were selected for childhood intelligence and promise, there was substantial variation in later success, longevity, and disease, including dementing illnesses. Life course trajectories have yet to be considered across the 8-decades of rich psychosocial, health and mortality information available. This project will use dynamical modeling approaches to examine patterns of stability and change for individual characteristics, including physical activity level, social support, and personality, and variations in growth curves as a function of cause-specific mortality (nosologist coded). Childhood data will be used as predictors of variations in growth trajectories, for example, birth weight, nursing, childhood illnesses, developmental milestones, gender, socioeconomic status, and parental age at participant's birth. Life events occurring in adulthood will also be examined as potential sources of turning points in health and psychosocial trajectories, for example, divorce or death of spouse. Sample and familial factors such as intelligence and parental longevity will be statistically accounted for in analyses. Consistent with the Request (RFA), the aim is to use new modeling techniques to expand use of and collaboration on an existing study to assess patterns of health and psychosocial trajectories as well as their dynamic interrelations across time in order to differentiate among those who reach old age and whether they reach it in good health.
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0.958 |
2007 — 2010 |
Reynolds, Chandra A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cholesterol Metabolism Pathway: Cognitive Change and Alzheimer's Disease Risk @ University of California Riverside
[unreadable] DESCRIPTION (provided by applicant): The etiologies of normative cognitive change and Alzheimer's disease (AD) in late adulthood are not fully understood. Outside of the gene encoding apoE, consistent candidate gene associations are relatively scant. Established effects of genetic variation in APOE, the primary cholesterol transporter in the brain, upon lipid levels, cognitive change, and AD risk suggest the cholesterol pathway may be centrally important. We propose to target genes integral to cholesterol homeostasis and perform multi-tiered association studies to investigate the possible existence and impact of functional genomic sequence variation on plasma lipid parameters, CSF Abeta and tau, measures of longitudinal cognitive performance, and Alzheimer's disease (AD). We have prioritized 502 genetic markers, focusing on HapMap based markers as well as potential functional polymorphisms within 20 cholesterol genes. We hypothesize that functional genetic polymorphism occurs in the selected candidate genes and will explain variance in a variety of cholesterol related phenotypes, with stronger effects upon proximal phenotypes (e.g. cholesterol and Abeta levels) than for cognitive phenotypes and AD risk. Several related longitudinal Swedish twin studies will be combined to test association with serum lipid biomarkers, cognitive decline, total dementia and AD risk. Additionally, we will use a large established Swedish AD case-control sample for testing additional biomarkers (CSF Abeta, tau) and AD risk. Across twin and case-control studies there are 3,858 of individuals (59 percent female) available for analysis of DMA markers, 1,227 with AD diagnoses. Of those with DNA, there are 676 twin pairs with available lipid biomarkers and 729 twin pairs with available cognitive data. Our goals are to move stepwise from anonymous variance components to measured genes in the cholesterol pathway, intermediate biomarkers, and ultimate behavioral and clinical phenotypes. Of principal interest is to: (1) test the association of cholesterol gene markers with serum lipid and CSF biomarkers; (2) test the association of lipid biomarkers and cholesterol gene markers with cognitive decline across verbal, spatial, memory and perceptual speed domains, using longitudinal growth models to quantify change; and (3) test Jhe association of cholesterol gene markers, total dementia and AD risk. We will apply haplotype and multi-locus regression approaches to determine association. Strengths of the study include multiple levels of replication and rich longitudinal data, both for lipid and cognitive traits. The examination of multiple candidate genes in the cholesterol pathway, using both twin-based and case-control methods, will lead to an increased understanding of factors that contribute to cognitive changes, total dementia and AD risk in late-life. [unreadable] [unreadable] [unreadable] [unreadable]
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0.958 |
2015 — 2019 |
Reynolds, Chandra A Wadsworth, Sally J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Colorado Adoption/Twin Study of Lifespan Behavioral Development & Cognitive Aging (Catslife) @ University of California Riverside
DESCRIPTION (provided by applicant): Early influences may accumulate over the life course to impact how well we age. However, relatively little is known about the developmental etiologies of individual differences in age- related cognitive change. Thus, the primary objective of the proposed research is to assess the unique saliency of early childhood factors to adult cognitive maintenance and change versus proximal influences and innovations (genetic and environmental) that emerge across development. We will leverage the strengths of two internationally renowned studies of behavioral development, the Colorado Adoption Project (CAP) and the Longitudinal Twin Study (LTS), each with decades of previously collected cognitive and behavioral data spanning infancy to early adulthood, and conduct a new assessment of 776 adoptive and non-adoptive probands and siblings and 824 twins, ranging in age from 28-38 years. The resulting Colorado Adoption/Twin Study of Lifespan behavioral development and cognitive aging (CATSLife) will be the first prospective longitudinal study of the etiologies of behavioral and cognitive changes during the transition to middle adulthood. The aims are to: conduct a genetically sensitive study of individual differences in behavioral and cognitive change at the cusp of middle adulthood, in 1600 participants studied almost yearly from birth to early adulthood; map individual differences in growth and maintenance of cognitive abilities; evaluate and trace measured physical factors and health behaviors, biochemical markers and measured genetic pathways important to sustaining cognitive performance; and track measured environmental factors that might decrease, sustain or boost cognitive performance. The CATSLife will include expanded assessment of cognitive performance, physical functioning and health behaviors, gene pathways, including measured genetic variation in lipid, synaptic plasticity and cell-signaling paths (based on chip array variants), biochemical markers (e.g., serum lipids), and environmental measures (e.g., engagement in leisure activities). We will assess etiologies of changes in physical health and cognitive functioning, and test whether associations across domains change with age due to changes in genetic variation or self-selection of environments. Measured gene pathway sets, and environmental measures, including engagement in leisure activities and neighborhood-level variables, will be evaluated as potential factors underlying dynamics of genetic variation or environmental selection. Thus, the CATSLife will provide an unparalleled opportunity to assess prospectively the etiologies of cognitive change, and test the saliency of early childhood versus proximal influences on the genesis of cognitive decline.
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0.958 |
2021 |
Reynolds, Chandra A Wadsworth, Sally J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Colorado Adoption/Twin Study of Lifespan Behavioral Development & Cognitive Aging (Catslife2) @ University of California Riverside
Emerging evidence suggests that individual differences in cognitive aging unfold across a lifetime; however, relatively little is known as to how early life versus proximal influences accumulate to impact cognitive functioning across midlife. The Colorado Adoption/Twin Study of Lifespan behavioral development and cognitive aging (CATSLife) seeks a greater understanding of the environmental and genetic factors that drive increasing divergence in cognitive maintenance. CATSLife comprises the prospective Colorado Adoption Project (CAP) and parallel Longitudinal Twin Study (LTS), now tested at ages 28-45 years (CATSLife1). We propose a 5-year follow-up of 1400 adoptive and nonadoptive probands, siblings, and twins as they navigate the transition to midlife at ages 33-50 years (CATSLife2). Whereas CATSLife1 established baseline performance as participants prepare for transitions to midlife, CATSLife2 proposes to evaluate stability and change across the midlife transition. Further, we propose to integrate the prospective Twins Early Development Study (TEDS) with a new assessment of 5000 twins at age 28 years, allowing us to build on over 20 years of prior data collection, including genome-wide genotyping, to explore similar predictors of cognitive maintenance. As participants transition to midlife, we will leverage powerful design features and a wealth of prospective data collected from infancy through adulthood, including a full adoption design, to examine causal implications of early environmental risk and protective factors, and a twin design to examine environmental factors that may have causal influence on cognition, controlling for familial confounds. As we leverage data from prior assessments with CATSLife1, the opportunity to investigate the transition across midlife with CATSLife2 is ideal. We will use our twin/adoption design with polygenic score data (PGS), detailed cognitive batteries, physical health, proposed biomarkers of accelerated aging that may participate in immune- inflammatory and neurotransmitter pathways, and neighborhood features to shed light on risk-resilience factors that account for midlife cognitive stability and change. This integrated follow-up study of CATSLife and TEDS aims to: 1) Evaluate individual differences in stability and change of cognitive abilities in midlife, considering cognitive reserve pathways vis-a-vis genetic and genetically mediated environmental influences; 2) Evaluate genetic factors with lifestyle and health behaviors that predict cognitive stability and change, considering early life reserve and genetic moderation; 3) Evaluate biomarkers of accelerated aging as predictors and mediators of cognitive stability and change, uniquely characterizing biomarker patterns and change at the midlife transition; and 4) Evaluate stressful and buffering contextual factors that predict cognitive stability and change, addressing individual socio-demographics and neighborhood features, accounting for active (rGE) selection. The findings from this proposed CATSLife/TEDS follow-up study could substantially increase our understanding of the genetic and environmental etiologies of individual differences in cognitive aging.
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0.958 |