Pilot Projects

Title: Measuring the Effects of an Experimental Social Security Program for Poor Older Adults using Biomarkers Data
Investigator: Hiram Beltran-Sanchez (UCLA)
Project Description: There is a large body of research on the effects of obesity on mortality. Although findings vary and sometimes significantly, there is consensus that obesity but not overweight produce excess adult mortality at adult ages. In some cases obesity appears to have beneficial effects particularly at very old ages. The mainstay model used in the literature is one where the researcher retrieves estimates of effects of a variable for obesity (or obesity and overweight) with no controls for antecedent illness (a two state model). This pilot project aims at showing that the conventional two state estimates of obesity effects on mortality do not, as a norm, have a clear interpretation. Under some conditions routinely found in limited panel studies, the two state estimates typically used in the literature are biased and that in all cases comparability of estimates of total effects is jeopardized since the two state estimates conflate different processes that may be very different in the populations being compared. This study shows that total effects advocated in this body of research conflate direct and indirect effects and tend to underplay the role that obesity may play as a factor that increases adult mortality. This project also aims at proposing a strategy to minimize the problems of interpretability and comparability of estimates under most conditions generating limited panel data. This study proposes a two-stage estimation procedure to empirically assess the impact of obesity on older adult mortality patterns in U.S., Costa Rica, Mexico and Puerto Rico using available panel data.


Title: Estimating the Impact of Obesity on Adult Mortality: Assessment of Errors with Applications to the U.S., Costa Rica, Mexico and Puerto Rico
Investigators: Emma Aguila and Arie Kapteyn (USC)
Project Description: The demographic transition in developing countries is occurring more rapidly than in developed countries. For example, while the old-age dependency ratio in the United States is expected to double in 2050, that in Mexico is expected to quadruple. By 2050, the elderly proportion of the population in the United States and Mexico will be similar. Higher rates of poverty among older persons can increase the urgency of policies to address these populations. In Mexico, 29 percent of persons at least 60 years of age live in poverty. To address high poverty in old age, more than 40 low-and-middle-income countries have introduced non-contributory pension programs or cash-transfer programs for the older population. Such programs can boost health as well. Drawing data from a unique randomized controlled trial (RCT) study of a non-contributory pension program for adults over 70 years in the State of Yucatan, Mexico (2008-2012), this project evaluates the impact of the program on glycosylated haemoglobin (HbA1c) and inflammation (CRP). This is a unique opportunity to analyze the effects of income on health using a RCT with biomarkers data. The results of the project will be used to submit an R01 describing the impact of this type of program on health and extend the analysis by linking to administrative records (e.g., on other biomarkers, hospitalizations, and emergency visits) of the health-care system.


Title:  System dynamics in aging physiological systems: Implications of burnout, reactivity, and recovery
Investigators: Arun S Karlamangla, PhD, MD (Principal Investigator), Geriatrics UCLA
Project Description: Using data from the Midlife in the United States (MIDUS) Biomarker and Daily Diary Projects, we propose to examine relationships between the dynamics of the hypothalamic pituitary adrenal (HPA) axis and the parasympathetic system, in order to identify common characteristics that are indicative of dysregulation and predictive of poor future health.  In particular, we will examine the HPA and parasympathetic systems’ capacity to react (or dynamic range), their actual reactivity to the standardized challenge, and their rate of recovery after the challenge is completed. Our objective is to identify the particular characteristics that are most predictive of altered resting states in regulatory physiological systems. The ultimate objective of this line of work will be to create and validate a comprehensive score for physiological dysregulation across multiple systems - allostatic load, which includes not only measures of altered resting levels (which have traditionally been the primary focus for scoring of allostatic load) but also measures of dysregulated system dynamics.


Title: Gene Transcription Profiling of Fatigue in Hispanic Colorectal Cancer Survivors: Targeting Residual Symptoms after Completion of Cancer Treatment in and Aging Probability Sample
Investigators: David S. Black, PhD, Preventive Medicine USC
Project Description: This is the first study we know of to examine inflammation and fatigue in Hispanic colorectal cancer surviving older adults, and also uses a novel genome-wide transcriptional profiling methodology. The objective of this study is to understand the dynamics of fatigue and inflammation (genomics-based strategy to identify genes that are differentially expressed in leukocytes) in Hispanic colorectal cancer survivors after their completion of cancer treatment.


Title: Launching a New Study of the Long-Term Health and Wellbeing Consequences of Malnutrition: A Feasibility Study and Rapid Assessment
Investigator: Patrick Heuveline, PhD, Sociology, UCLA
Project Description: Building on an existing longitudinal, social-science research project in Cambodia, this pilot project would lay the foundations for a new rider survey on the long-term consequences of nutritional deficiencies in the country in the late-1970s. The pilot project considers 4 tiers of additional data that would have to be collected to this end: text-based questions on personal experiences in the late 1970s, anthropometric data, and health measurements without and with biological samples. Based on the pilot data, we will analyze the cost-effectiveness of the different approaches, their potential impact on item-specific non-response rate, the individual loss-to-follow-up and overall refusal to participate, and data quality.


Title: Development and Validation of Self-Administered Tablet Computer Cognitive Assessment
Investigators: Carol Prescott, PhD, Psychology, USC; Tara Gruenewald, PhD, Gerontology, USC; Margaret Gatz, PhD, Psychology, USC; Jack McArdle, PhD, Psychology, USC
Project Description: Evaluating cognitive performance by computer, including over the internet, is becoming increasingly common in research with younger respondents but has experienced much more limited penetration in studies of elders. Our goal is to create a tablet-based assessment that can be used in future studies with Project Talent (PT) participants – a U.S. population based study of individuals born 1942-1946. However, if successful, the potential applications are much broader, within the U.S. for studies of all ages within the U.S. and internationally.


Title: Genome-wide Transcriptome Profiling in an HRS Pilot Sample
Investigator:  Steve Cole, Morgan Canon 
Project Description: Project will assess how adverse social environments affect gene expression in human leukocytes, helping to clarify the biological processes underlying social gradients in health risk. It will utilize microarray-based transcriptome profiling to examine differences in leukocyte RNA profiles as a function of education and childhood circumstances in a small pilot sample of 121 HRS respondents. A number of large population studies are now collecting RNA samples; this study will be a pilot for use of those data.  


Title: SES Gradients of Metabolic Syndrome in China and India
Investigator:  Peifeng Hu, Jinkook Lee 
Project Description: This pilot will examine the relationship between measured indicators of metabolic status and socioeconomic status (SES) among community-residing persons aged 45+ in two developing countries, China and India.  


Title: Economic Conditions & Social Disparities in Biological Risk among US Adults
Investigator: Jennifer Ailshire, Sharon Merkin, Brian Finch 
Project Description: This pilot will determine whether exposure to adverse local economic conditions, including economic decline, is related to biological risk in U.S. adults, and if differential exposures explain race/ethnic and socioeconomic disparities in cumulative biological risk. This project consists of both data construction from secondary data sources and analysis using two national surveys: the Health and Retirement Study (HRS) and the Study of Midlife in the United States (MIDUS).  


Title: Assessing Biological Mechanisms Underlying Psycho-social & Cognitive Benefits of a Multi-Factorial Inter-Generational Intervention for Older Adults
Investigator:  Keyonna King, Pinchas Cohen, Teresa Seeman 
Project Description: This pilot project will assess whether there are physiological benefits to older adults who participate in an inter-generational program designed to offer them opportunities for meaningful, socially-valued civic engagement while simultaneously embedding substantial doses of physical, cognitive, and social activity into program content as a vehicle for health promotion. The pilot builds on prior work documenting cognitive and psychosocial benefits to older adults from program participation. Leveraging the introduction of a program into a demonstration school in Los Angeles, we propose to evaluate hypothesized changes in biological mechanisms underlying expected physical, cognitive and psychosocial benefits.  


Title: Quantifying the Mediating Pathways of Cumulative Stressors on Allostatic Load among Midlife Women: A Longitudinal Analysis
Investigator:  Dawn M. Upchurch, Judith Stein, Mei Hua Huang 
Project Description: This pilot project is longitudinally investigating the impact of cumulative social stressors (perceived stress, stressful life events, lack of social support, perceived discrimination) on level and change in allostatic load (AL) over time among midlife women. Eight years of data from the Study of Women’s Health Across the Nation (SWAN), an ethnically diverse community-based sample of women ages 40-55 at baseline, will be analyzed using structural equation models (SEM) and latent growth curve (LGC) analysis (N=2,870). We are interested in identifying the predictive pathways of level and change of cumulative stressors on level and change in AL and in identifying and quantifying the mediating pathways that explain racial and SES differentials. We are also testing whether lower SES and higher cumulative stressors result in worsened AL profiles (‘moderated mediation’). Innovations of this application include: 1. The proposed analysis will be one of the first to test a key theoretical feature of AL, namely that accumulation is driven by exposure to greater social stressors or disadvantage. 2. Assessment of cumulative stressors may more accurately reflect the total burden (or benefits) women have available to them to cope with life stressors. Stressors may also interact in a non-linear fashion. 3. SWAN is one of the few data sets with up to 08 years of annual biomarker and anthropometric assessments which will allow for testing hypotheses pertaining to accumulation of biological risk over time. 4. SWAN biological data are collected over a critical period of women’s life course – as they transition through menopause and age from midlife to early old age – a time during which there are accelerated changes in physiological parameters as well as substantive alterations in social/role circumstances.  


Title: Change in Telomere Length during Mid- to Late-Life: The Multi-Ethnic Study of Atherosclerosis
Investigator:  Belinda Needham and Ana Diez-Roux
Project Description: Telomeres cap the ends of chromosomes and promote chromosomal stability. Telomere shortening, which tends to occur with advancing chronological age, causes cellular senescence in vitro. Furthermore, a number of studies have found that leukocyte telomere length (LTL) is associated with morbidity and mortality independent of chronological age. Thus, telomere length has been proposed as a biomarker of aging. Although epidemiologic studies of LTL have become increasingly common, few studies include longitudinal measurement of telomere length. Thus, we know very little about (1) the average rate of change in LTL over time, (2) the extent to which the rate of change in LTL varies across individuals, (3) what factors increase or decrease the rate of change in LTL, and (4) whether the rate of change in LTL predicts health-related outcomes. The proposed study will address the following specific aims: To determine the average rate of change in telomere length over a ten-year period among adults aged 45-84 at baseline; to identify sociodemographic, psychosocial, and behavioral predictors of the rate of change in telomere length; and to determine whether the rate of change in telomere length is associated with risk factors for cardiovascular disease. nbsp;


Title: Testing correspondence of health environment indicators to health outcomes in older population groups 
Investigator:  Donald A. Lloyd and William A. Vega
Project Description: Measures of community-level social, economic, and demographic characteristics are commonly employed in scientific as well as program planning research to characterize the health-relevant qualities of a place, and to compare these features across locales. Measures such as median income, educational attainment, race/ethnic composition, poverty and crime rates, as examples, are often incorporated in multi-level ecological models as environmental factors that contribute to prediction of individuals’ health outcomes. The conceptual basis for using these measures is the social determinants of health model. In practice, however, the measures selected as markers are commonly selected by custom, consensus, or the untested policy of an institution or agency. Indeed, some projects engage community stakeholders in the variable selection process. It is not certain whether markers that are chosen this way permit the most valid judgment of population health significance; capacity for markers to represent a community’s vulnerability or resilience is assumed to be the same across diverse social groups. Little evidence has been offered of their validity for use with specific populations such as the aged. This study will use a combination of official statistical sources including the US decennial census and American Community Survey, in conjunction with recent epidemiological survey data from several studies covering Los Angeles County, to scientifically test equality of relationships between community markers and health outcomes, measured at the individual level, in distinct population groups. The anticipated results would provide an evidence base to recommend measures that best predict population health among old-age community residents, and promote the measures associated most closely with health outcomes in population subgroups defined by age group, race/ethnicity, nativity, primary language, and socioeconomic level. Such findings would more confidently inform epidemiological studies as well as future needs assessment and “healthy community” monitoring. nbsp;


Title: Relationship and Timing of Advance Directives and Stated Care Preference on Frequency and Type of Care Setting Transitions in the Last Six Months of Life
Investigator:  Susan Enguidanos 
Project Description: There is a dearth of information about how the timing of the advance directive (i.e., when it is completed in proximity to death) is associated with the frequency and type of health care transitions. Additionally, little is known about the relationship of an AD to the frequency and types of care transitions. Better understanding can inform research and practice in improving end-of-life care and reducing care setting transitions. The purpose of this pilot study is to better understand the relationship between timing of Advance Directive (AD) completion, stated care preferences, and the frequency and type of transitions made in the last six months of life. We also aim to examine the impact of sociodemographic factors and chronic illness on timing of Advance Directive completion and type and frequency of care setting transitions before and after completion of the Advance Directive. nbsp;


Title: Electronic Monitoring of Daily Generative Activity Engagement and Cognitive and Affective Well-Being CorrelatesFocus on Inflammation 
Investigator:  Tara Gruenewald
Project Description: A growing body of evidence indicates that engagement in generative activity, that is activity designed to contribute to the well-being of others, predicts more favorable trajectories of mental and physical health in later life. These health benefits may accrue, in part, from individuals’ perceptions of playing valuable and useful roles in the lives of others. Such perceptions have been found to predict decreased likelihood of physical disability development, institutionalization and mortality, and better cognitive functioning, in older adulthood. However, to date, efforts to identify the psychosocial and behavioral pathways through which perceptions of generativity and social usefulness are linked to beneficial health outcomes have indicated only minor mediating roles of hypothesized pathways. One potential explanation for the inability to better identify mediating mechanisms may be the temporal characteristics of previous measurements. Previous research in this area has utilized longitudinal survey data to explore associations between generativity perceptions, health outcomes, and potential psychosocial and behavioral mediators that asked participants to recall characteristics of these factors over considerable lengths of time (e.g., last month, last year) and often for variable recall lengths across measurements of different constructs. It may be that more fine-grained temporal measurements can better elucidate the associations between generative activity, generative perceptions, and the cognitive, affective, and behavioral processes that may lead to more favorable health states among the more generative. The proposed pilot study is designed to evaluate an electronic measurement system for capturing multiple daily assessments of generative activity, generative perceptions, and psychosocial and behavioral correlates. Specifically, the pilot study will examine the feasibility of implementing an experience sampling measurement protocol via the use of wireless tablet computers with cellular data connections (for real-time data transfer) in a sample of older adults age 60 years and over. Pilot study objectives are to examine implementation feasibility (e.g., recruitment success, measurement adherence), to use research team and user-participant data to fine-tune the assessment protocol, and to explore whether the length of the measurement period and the number of measurements is sufficient to capture intraindividual and interindividual variation in generative activity, generative perceptions, and cognitive, affective and behavioral factors. 


Title: Effects of Early Life Stress and Depression on Gene Expression in a Community Sample:Focus on Inflammation 
Investigator:  Julienne Bower
Project Description: Inflammation plays a pathogenic role in a number of serious illnesses, including many disorders of aging.  However, risk factors for chronic inflammation are still under investigation.  There is growing interest in the role of stress, particularly stress occurring in early life, as a predictor of inflammation and chronic disease later in adulthood, although longitudinal research in this area is extremely limited (1).  Moreover, despite intense interest in the impact of genetic factors on psychological responses to stress (e.g., depression; 2), there has been minimal investigation of how genetic and other factors shape inflammatory stress responses.  This longitudinal study will examine the impact of early stress exposure on genetic markers of inflammation, as well as genetic and psychosocial moderators of these effects, in a community sample of 500 young adults in Australia who have completed detailed stress assessments and provided blood for genetic and immune analysis.  Identification of early life predictors of lifespan health trajectories will enhance our understanding of risk factors for inflammation-related disorders in older age. 


Title: Lifecourse Socioeconomic Status and Cumulative Allostatic Load
Investigator: Sharon Stein Merkin
Project Description: Researchers have proposed multiple biological pathways by which socioeconomic status (SES) might influence health. We propose to examine the associations of childhood SES, socioeconomic intergenerational mobility (comparing childhood SES and adult SES) and cumulative SES over the lifecourse, and cumulative biological risk. Moreover, we plan to examine cumulative biological risk over time, the first study to consider a longitudinal assessment of allostatic load. The data will include 6,814 men and women in the Multi-Ethnic Study of Atherosclerosis, a longitudinal population-based study on cardiovascular disease sampled from 6 sites in the United States.  The main outcome, a cumulative measure of biological risk, or “allostatic load,” includes a summary score of high risk indicators representing metabolic, cardiovascular and inflammatory systems (and where available neuroendocrine data on cortisol, norepinephrine and epinephrine). Socioeconomic measures will include childhood SES (parental education) and adult SES (income, education and wealth). Childhood and adult SES measures will be considered simultaneously to assess their independent associations with AL. Moreover, the combination of these levels (i.e., social mobility) will be assessed as well. These models will be repeated with change in AL as the outcome to examine how lifecourse SES may be association with change in AL over time.


Title: Healthy Community Neighborhood Initiative (HCNI) Phase I
Investigator: Arleen Brown
Project Description: The proposed pilot will collect biomarker data to better quantify health risks in an area of Los Angeles characterized by high rates and early morbidity and mortality.Park Mesa Heights (PMH) is a largely African American and Latino community in South Los Angeles, an area characterized by high rates and early morbidity and mortality from obesity, diabetes, hypertension, congestive heart failure, stroke and other chronic conditions.  To understand and address these health disparities, we formed a community-academic partnership, the Healthy Community Neighborhood Initiative (HCNI), which is composed of the Los Angeles Urban League (LAUL), Healthy African American Families (HAAF), Charles Drew University (CDU), and the UCLA Clinical and Translational Science Institute (UCLA, LA Biomedical Institute/Harbor-UCLA Medical Center, Cedars Sinai Medical Center, and CDU).  The study overall has the following specific aims: (1) to design and conduct a household survey and clinical assessment, neighborhood observations, and neighborhood asset map to better understand factors that can be intervened upon to influence health and health outcomes in the Park Mesa Heights community; (2) to develop a chronic condition registry in the community that will be monitored to identify trends in chronic disease incidence, prevalence, and control over time and to develop a registry of biomarkers of stress and inflammation in a community cohort and to link biomarker levels to baseline and longitudinal clinical outcomes; and (3) to engage the community in data analysis, understanding and interpreting and disseminating the results of data collection, and prioritizing issues identified as most important to address with interventions.  The USC-UCLA Biodemography Center pilot study leverages the HCNI infrastructure by building upon and extending the household data collection to support the development of protocols and materials that are specific to the health of middle-aged and older PMH residents.  We propose to include survey and clinical measurements of geriatric syndromes, functional status, and cumulative measures of biologic risk among residents 50 years and older.  In recognition of prior evidence of earlier health deterioration among African Americans and Latinos, measuring these conditions in middle age will allow us to detect earlier onset of biologic “wear and tear” through cumulative measures such as allostatic load, and the implications for functional decline and disability in this community. 


Title: Measuring Cognitive Function in Developing Countries
Investigator: John Strauss
Project Description: Measurement of multiple dimensions of cognitive functioning is now done in the Health and Retirement Study (HRS) as well as other surveys in developed countries.  A number of studies in developing countries are attempting to harmonize with the HRS and related studies but it is not clear that it is possible to export cognitive scales to low education countries without appropriate adaptation. This project will develop scales of cognitive functioning for use in developing countries that are comparable to those in the U.S.  In this pilot, the cognitive scales will be added to the Indonesia Family Life Survey (IFLS). This will be similar to one done in Mexico by Rebecca Wong.  Approaches to measuring cognition will be developed in conjunction with Bob Willis and Jack McArdle.


Title: Estimating Genotypic Resemblance of Spouses and Assortative Mating for Alcohol Use in the HRS
Investigators: Carol Prescott and Jinkook Lee
Project Description: This project aims to analyze a set of over 2 million genotypes of approximately 4,350 spouse pairs from the Health and Retirement Study (HRS), a representative sample of aging adults in the U.S. Study aims include: (1) Estimating genotypic resemblance in a large sample of spouses to investigate sources of spousal selection; and (2) Estimating the degree to which genotypic resemblance mediates phenotypic resemblance between spouses for alcohol-related measures. The HRS couple data have not been widely used, but provide a unique opportunity to estimate overall genotypic resemblance, study mechanisms of assortment, and estimate the degree to which genotypic resemblance mediates phenotypic resemblance for alcohol use in the U.S. The results will inform other genetic studies by investigating the degree of spousal assortment in the U.S. They can also be applied to a wide variety of traits measured in the HRS.


Title: Long Term Sympathetic Nervous System Activity Assessed Through Analysis of Catecholamines In Hair-Shaft Samples In Healthy Subjects    
Investigator: Paul Foley
Project Description: The human stress response is transduced through two endocrinological pathways: The hypothalamic pituitary adrenal (HPA) axis and the sympathetic adrenal medullary (SAM) axis. The systemic effector of the HPA axis is the steroid hormone cortisol while the systemic effector of the SAM is epinephrine. The peripheral sympathetic nervous system (SNS) predominantly uses norepinephrine as its fast neurotransmitter. The stable end-metabolites of both epinephrine and norepinephrine are 3‑methoxy‑4‑hydroxyphenylglycol (MHPG) and vanillyl mandelic acid (VMA). These are used as indices of NE and E release.

We have established the measurement of cortisol concentrations in hair-shaft samples as retrospective measures of integral secretion of this hormone over the period of hair growth. Thus cortisol secretion can be assessed retrospectively over a period of up to six months. This measure has profound implications for biological psychology research and is providing an empirical measure of allostatic load. The latter is implicated in a number of pathologies including affective disorders, dementia and the metabolic syndrome.

A feature of a number of stress-related diseases is an imbalance between measures of sympathetic activation and measures of HPA function. To assess this we propose retrospectively measuring SNS-activity by assaying the levels of markers of catecholamine release by liquid chromatography coupled to mass spectroscopy in hair samples analogously to the method developed for steroid hormones. These values will be related to measures to long-term cortisol release in a healthy population. The development of such a measure will provide a method of wide applicability to research into long-term stress-responses and their dysregulation in disease.


Title:  Dried Blood Spot Methods for Evaluating the Regulation of Inflammation
Investigator: Thomas McDade

Project Description: We are requesting funds to develop new methods for assessing the regulation of inflammation in dried blood spot (DBS) samples.  DBS sampling represents a minimally-invasive alternative to venipuncture that has been recently incorporated into a large number of population- and community-based surveys.  The validation of new laboratory methods for DBS samples will expand the analytic options for the large number of NIA investigators who are collecting DBS samples, and who are interested in inflammation as a mediator of diseases of aging.  The aims of this project are to: develop and validate immunoassay protocols for quantifying IL-6, TNFa, and IL-10 at low concentrations in DBS samples; and to investigate the feasibility of quantifying glucocorticoid receptor in DBS samples.


Title: Social and Behavioral Risk for Late-Life Immunosenescence
Investigators: Judith Carroll
Project Description: This project will clarify the biological mechanisms linking late life social isolation and poor sleep to increased risk for morbidity and mortality. One potential mechanistic pathway through which both social isolation and sleep disturbances in late life contribute to disease vulnerability and mortality is through accelerated aging and immunosenescence. The present project aims to address this hypothesis by adding to an ongoing project examining the effects of late life social isolation and sleep deprivation on telomere length and inflammation, an assessment of telomerase (a novel biomarker of telomere maintenance) within peripheral blood mononuclear cells. More specifically, as CD8 T cells and CD14+ monocytes may play a pivotal role in immunosenescence and inflammation, our aim includes assessment of telomerase in these subsets. Aims include: (1) to determine whether telomerase activity will be decreased in the socially isolated older adults compared to the age and gender matched socially integrated adults; (2) to determine whether a brief controlled sleep deprivation experiment alters telomerase activity, providing new insight into how sleep loss may contribute to the functioning of the telomere maintenance system and (3) to undertake a more critical examination of immune cell subsets to establish that differences in telomerase activity are not driven by sleep deprivation induced cell redistribution and also shed light on the degree to which sleep loss influences telomerase activity within cells highly relevant to immunosenescence. This pilot project is designed to support a proposed K01 application in the coming year.


Title:Gender Differences in Biomarkers in China, Taiwan and Indonesia
Investigators: Jung Ki Kim
Project Description: This pilot project will evaluate evidence of sex differences in biomarkers in three Asian countries: China, Taiwan and Indonesia. The objectives are: (1) to examine sex differences in a set of cardiovascular and metabolic, and inflammatory biomarkers and markers of organ damage; (2) to examine the age pattern of sex differences in biomarkers in these countries; and (3) to develop preliminary evidence to support an application for NIH support to compare how behavioral, socioeconomic, and psychological factors are related to sex differences in biomarkers in Asian countries and the U.S. We expect this pilot to result in a submission for an R03.


Title:Genetic Studies of Inflammation in Indigenous Amazonians
Investigators: Hooman Allayee
Project Description: The overall goals of this pilot project are to use two complementary approaches to explore the genetic determinants of inflammatory pathways in the Tsimane, an indigenous group of Bolivian Amazonian forager-horticulturalists. The first aim is to determine whether single nucleotide polymorphisms (SNPs) that have been previously associated with blood leukocyte counts in Caucasian populations also demonstrate such effects in the Tsimane. The second goal is to carry out large-scale sequencing of inflammatory candidate genes toidentify rare genetic variants that may either occur at higher frequency in older Tsimane subjects compared to younger individuals or be unique to this indigenous Bolivian population compared to other populations. In the first set of analyses, nine SNPs previously identified in Caucasian populations were selected and analyzed in ~900 Tsimane individuals for association with eosinophil and neutrophil number. Of these variants, two were not polymorphic in the Tsimane and we obtained high quality genotypes for six others. None of these six variants exhibited significant association with either eosinophil or neutrophil counts.  There are several possibilities for these observations. First, the study may have been underpowered since phenotypic data were only available in ~700 subjects and all of these variants were initially identified in genome-wide association studies with large sample sizes (n>7000). Moreover, the minor allele frequencies of some of these SNPs are low in the Tsimane compared to other populations, which would further reduce power to detect association in our dataset. Alternatively, the Tsimane are chronically exposed to highly infectious/inflammatory conditions and have markedly elevated eosinophil and neutrophil counts compared to individuals living in industrialized countries. As a result, the genetic effects these variants have on leukocyte number in the Tsimane could be masked by such environmental effects. With respect to Aim 2 of the project, the deep sequencing of the interleukin 10 gene will be analyses completed over the remaining months of this pilot project. During this period, data generated from these experiments are being incorporated into manuscripts that will be submitted for publication.


Title:The Influence of Air Pollution Exposure on Cognitive Performances in the US Population
Investigators: Kelly M. Kadlec, John J. McArdle, Jiu-Chiuan Chen, and Frederick W. Lurmann
Project Description: Cross-sectional epidemiologic studies and neurotoxicological data have shown that exposure to air pollution may have deleterious effects on the brain and its functions, but convincing longitudinal studies linking air pollution exposure to cognitive decline in humans are still lacking. The purpose of this research is to link air pollution exposure estimates to two pre-existing datasets (CogNGCS and CogUSA) containing measurements of cognitive performance and demographics, and subsequently explore the adverse neurocognitive effects of air pollution. In CogNGCS (N=1,193), cognitive performance was assessed at two occasions by Woodcock-Johnson (WJ) tests measuring eight of the  broad cognitive abilities from the extended theory of fluid and crystallized intelligence. In CogUSA (N=1,434), a wide variety of cognitive performances were assessed at one time point by WJ tests measuring the same broad cognitive abilities as in CogNGCS, the Wechsler Abbreviated Scale of Intelligence (WASI), and the Health and Retirement Study (HRS) cognitive measures. Air pollution exposure models will be developed for ozone, NO2, PM2.5, PM10, and proximity to traffic. Adding air pollution exposure estimates to these national datasets will allow us to examine the longitudinal intra-individual changes and cross-sectional inter-individual differences in cognitive performances associated with exposure to ambient air pollutants, providing the preliminary data needed to seek R01 funding for future cohort studies.


Title: Long-run Trends in Cardiovascular Morbidity and Mortality 
Investigators: Dora Costa
Project Description: This pilot involved preparing several datasets for an investigation of the role of life-cycle environmental conditions (such as infectious disease, social network availability, and occupational factors) in long-term trends in cardiovascular disease (CVD) across different cohorts.  While prior work has documented the rapidly increasing epidemic of CVD, particularly from the 1950’s through the 1970’s, trends over the entire century have not been the focus of prior research. Data to be examined include the first cohort to reach age 65 in the twentieth century. Such data offer the first opportunity to examine these longer-run trends in what has been (and continues to be) the major cause of disease and mortality. The project is important for shedding light on changes in heart disease across cohorts and on the etiology of heart disease in different cohorts. The use of this historical data has entailed the classification of 19th and early 20th century descriptions of heart conditions into modern equivalents and this has been completed by an MD experienced in 19th century medical terminology. Hand coding of the data is still underway. The initial data work has been an input into a working paper which investigates the effects of severe prisoner of war stress on cardiac sequelae. This work has found increased mortality from valvular heart disease and stroke but little effects on cardiac morbidity. The work on POW status provides evidence that debilitating events could leave either frailer or more robust survivors, depending on the extent of insults and mortality selection. It is expected that the disease classification scheme will be usable later on. 


Title: Neurocognitive Test Battery for the Multi-Ethnic Study of Atherosclerosis (MESA) II
Investigators: Teresa Seeman
Project Description: Seeman took advantage of an opportunity to introduce cognitive assessment into a major national study which has collected significant information on cognitive risk factors but has ignored this outcomes.  The pilot was successful in getting needed materials to implement cognitive assessments which are now on-going in full MESA data collection -- data collection is scheduled to go through next November (2011). At that point proposals will be developed and papers written.


Title: Genetic and Social Environment Interactions
Investigators: Steven Cole
Project Description: This integrative article provides a unique combination of information from basic cell-based experimental studies and linked population-based data from the MacArthur Study of Successful Aging to illustrate the pathways through which individual psychosocial experience (e.g., depression) may trigger sympathetic activity which in turn can interact at the cellular-level with differences in genotype to produce differences in inflammatory responses which are in turn related to differences in mortality risks. 
Cole, S, Arevalo, J, Takahaski, R, Sloan, E, Sood, A, Lutgendorf, S, Sheridan, J, Seeman, T. Compuational identification of gene-social environment interaction at the human IL6 locus. Proceedings of the National Academy of Sciences. 2010; 107:5681-5686.
Related Grants: Work on this project has contributed to an R01 (currently in preparation) focusing on investigation of gene-by-environment interactions relating to inflammatory pathways using the Mid-Life in the US (MIDUS) cohort. 


Title: Validation of Blood Pressure, Lipid Profiles, and C-Reactive Protein Protocols for Population Surveys
Investigators: Heather McCreath
Project Description: This study aims to evaluate the comparability of blood pressure assessed using an Omron automatic device (used in HRS and NSHAP) with that obtained by standard sphygmomanometer, and to evaluate the comparability of lipid and C-reactive protein measurements assessed using a Cholestech (proposed for use in Costa Rica) device with that obtained from venous sample. Recruitment was stratified by gender and disease status (hypertensive versus not), with 93 participants recruited. For blood pressure, participants were randomized to complete either Omron or traditional sphygmomanometer first. Three measurements from the first device were taken, with a one-minute rest in between measurements. Three measurements with the other device were then taken. Analyses were conducted on the average of the second and third readings from both devices. Distributions from the two devices were similar, but the Omron was more similar to the sphygmomanometer for systolic blood pressure (r=0.89) than with diastolic blood pressure (r=0.67). Of the 93 participants, 49 also participated in the evaluation of the point-of-service equipment manufactured by Cholestech for cholesterol assays. First, blood was collected via capillary puncture for the Cholestech measurement and then a venous sample was drawn for comparison. Comparability of the Cholestech with venous results was quite good (total cholesterol: r=0.82, HDL: r=0.72, LDL: r=0.88, triglycerides: r=0.87, CRP: r=0.92 (analyzed only for samples with detectable venous values). While the results are quite comparable, several features of the Cholestech equipment limit its feasibility for community-based population studies. Manufacturer operating instructions require running control samples each day the unit is used. Both costs for the sample cartridges and the failure of initial control samples on a portion of the days result in high costs. Also, we did not assess the ability of the equipment to withstand high temperatures and humidity. As a result the CRELES study did not pursue their original idea of using the Cholestech and is going with more well-established venous protocols. Findings from this pilot will be incorporated into current work developing web-based materials for investigators interested in making informed decisions regarding protocols for biomarker data collection (e.g., pros and cons of Cholestech equipment will be outlined based on pilot findings).  


Title: Integrating Biological Risks into Models of Cognitive Aging: The Long Beach Longitudinal Study (LBLS)
Investigators: Elizabeth Zelinski
Project Description: This pilot is collecting saliva and blood samples for later assays of DNA, RNA, cardiovascular, metabolic and inflammatory risk factors in this long running study of cognitive aging. The resulting data set will be available to researchers. The blood samples are now being collected by the CTSI at the University of California, Irvine. This pilot laid the ground work for a project award as part of the USC Alzheimer Disease Research Center.


Title: Inflammation, Hemostasis and Acculturation in the Multiethnic Study of Atherosclerosis (MESA)
Investigators: Leo Morales
Project Description: What effects acculturation processes have on cardiovascular risk factors in the foreign-born over time spent living in the United States and over generations is unclear and an area of ongoing research. This study investigates the relationship of acculturation to two novel cardiovascular disease risk factors, inflammation and hemostasis,  among Latino and Asian immigrants. Baseline data from the Multiethnic Study of Atherosclerosis (MESA), a rich new data source on older Latinos and Asians, were analyzed using multivariate methods. MESA is unique in having detailed biometric, social and behavioral data on a large number of older Latino and Asian immigrants making this research possible. Analyses for this pilot project are complete and a manuscript is in preparation reporting on major findings – that native-born Hispanics and those who have lived in the US longer exhibit significantly greater burdens of inflammation. 


Title: Migrant-Nonmigrant Differentials in Cardiovascular Risk Factors in China
Investigators: Peifeng Hu and William M. Mason (with Thomas McDade)
Project Description: The primary aims of this project are to examine migrant-nonmigrant differentials in cardiovascular risk factors and explore the extent to which these differentials might be associated with differences in psychosocial stress, health behaviors, and access to health care. In this study, data from a 2007 national probability sample of migrants and nonmigrants in China was analyzed.  This project is the first study to integrate psychosocial and biological information in the explorations of potential differentials in cardiovascular risk factors across migrant and non-migrant populations in China. Findings from the study is expected to lead to new RO1 funding to measure biomarkers on stored specimens and to further examine longitudinal relations between migration and health in China. This project is developing the capability of assaying dried blood spots in a lab in Beijing, China, which should be useful infrastructure for later students.
Publications: The pre-test data from 197 participants in 10 different townships throughout China have been used to compare migrants to permanent urban residents. Both rural-to-urban migrants and rural non-migrants in China have higher risk of recent respiratory infections, after adjustment for age, sex, education, smoking, health insurance, number of chronic medical conditions, hazardous working environment, and housing characteristics. Hu also found an association between migration status and self-rated health. Using permanent urban residents as the reference group, the multiply-adjusted odd ratios of having fair or poor self-rated health were 3.18 (95% CI: 1.17  8.70) for rural non-migrants and 2.21 (95% CI: 0.81  6.25)for rural-to-urban migrants. 

Title: The effect of childhood experience on adult height differences in identical twins: implications for aging
: Wendy Cozen, Thomas M. Mack 
Project Description: This study investigates the relationship between adult height and health using data from twins in order to control for genetic and nutritional factors. In this pilot study questions on early childhood exposure to infections are linked to adult height. Further it tests the hypothesis that height is related to childhood experience, in a case-control study of healthy identical twins discordant for height by at least 1 inch. The data are based on both members of 213 healthy identical twin pairs born from 1968 to 1982 from the population-based California Twin Program (CTS) who reported a difference of at least 1 inch in height. The answers are validated by interviewing their mother, asking similar questions about their early experience. Questions include information on childhood infections, contact with pets, fecal-oral exposures, day care and school attendance, growth, diet, exercise, and onset of puberty. This project provides another approach to the issue of the effect of inflammation on lifetime health. The analysis of early childhood risk factors for adult height is in progress. The preliminary analysis found that mothers of twins are more consistently reliable historians regarding illness, but their twins know more about each other's physical development, especially as they approach puberty. Questions comparing members of the twin pair with regard to illness (e.g. Who missed more elementary school, you or your twin?), diet, growth, development and exercise often produce more information than absolute questions (How much elementary school did you miss on average due to illness? How much elementary school did your twin miss on average due to illness?). These data are being used to generate algorithms for using the questionnaire response data from twins and their mothers for the analysis of the main research question.


Title:  Antioxidant and Inflammatory Mechanisms Affecting Cognitive and Physical Functioning
Investigator: Peifeng Hu
Project Description: This pilot examined simultaneously the effects of serum beta-carotene level and inflammation burden on subsequent mortality. It also examined the role of beta-carotene and APOE in affecting cognitive functioning. The hypothesis was that there would be a link between adverse levels of serum beta-carotene level and inflammation factors and deterioration in physical and cognitive functioning among older persons. We also hypothesized that low beta-carotene level and high inflammation burden would independently predict functioning change and there will be a synergistic effect between the two in their association with higher subsequent overall mortality. An additional hypothesis is that the presence of APOE4 alleles would interact with the level of antioxidant status to affect cognitive functioning. The primary finding was that among high functioning older persons, the effect of low serum beta-carotene level on cognitive decline is confined to those who have APOE 4 alleles, suggesting a genetic influence on the effect of low antioxidant status.
Hu P, Bretsky P, Crimmins EM, Guralnik JM, Reuben DB, Seeman TE. The effects of serum beta-carotene levels on decline of cognitive function in high-functioning older persons with or without apolipoprotein E 4 alleles. MacArthur Studies of Successful Aging: Journal of Gerontol: Mel Sci. 2006; 61:616-620.

Hu P, Reuben DB, Crimmins EM, Harris TB, Huang MH, Seeman TE. The 
effects of serum beta-carotene concentration and burden of inflammation on all-cause mortality risk in high-functioning older persons: MacArthur studies of successful aging. J Gerontol:Med Sci. 2004; 59:849-54.
Related Grants: Based on the results of the pilot project Hu received grant K32 AG021029.


Title: Education as a Modifier of Rate of Change among Those with Memory Complaints and Mild Cognitive Dysfunction
Investigator:  Wendy Mack  
Project Description: The long run purpose of this study was to evaluate the protective effect of education and other indicators of mental ability or "mental exercise" against cognitive decline. The pilot research examined whether education relates to the timing of shifts from nondemented to mild cognitive impairment and from mild cognitive impairment to dementia, and from diagnosed dementia to death. The hypothesis is that people with higher education will drop faster once they start to decline, because their education protected them from crossing a diagnostic threshold for longer than would be the case for someone less endowed. Thus we would expect that having greater cognitive reserve will protect against onset of clinically diagnosed dementia, while decline after diagnosis will be more abrupt. The work of the pilot project was to develop the data from the ADRC files for such examination and test our ability to use the latent growth curve method with these data. This project will help us evaluate the role of changing educational levels in producing trends in population cognitive ability. This project was the basis of a section of a P01 project.
Andel R, Vigen C, Mack WJ, Clark LJ, Gatz M. The effect of education and occupational complexity on rate of cognitive decline in Alzheimer's patients. J Int Neuropsychol Soc. 2006; 12:147-52.
Related Grants:  A major sub-project of the new ADRC grant came out of this pilot work (P50 AG 05142).


Title: Cardiovascular Risk Assessment using Multiple Risk Factors in Older Adults
Investigator: Arun Karlamangla 
Project Description: Data for this project came from the MacArthur Study of Successful Aging, a longitudinal cohort of relatively high-functioning women and men aged 70-79 years at baseline in 1988. All standard cardiovascular risk factors including CRP were measured at baseline. Repeat measurements were obtained on all risk factors except for HDL cholesterol and CRP in 1991. Cardiovascular events and cardiovascular mortality information till 1998 has been collected. The baseline measurements of risk factors among the participants without history of previous diabetes, stroke, or heart attacks, were used to construct a composite risk score. This score was internally validated using bootstrapping to compare its risk discrimination ability with the Framingham score. The pilot project used stored plasma samples from the 1991 blood draw to measure 1991 values of CRP and HDL cholesterol. These were used to create change scores reflecting change in the new risk scores between 1988 and 1991, and study the association of these change scores with risk of cardiovascular events and/or cardiovascular mortality between 1991 and 1998.
Karlamangla A, Singer BS, Reuben D, Seeman TE. Increase in serum non-High-Density Lipoprotein Cholesterol may be beneficial in some high-functioning older adults: MacArthur Studies of Successful Aging. J Am Geriatr Soc. 2004; 52:487-494.
Related Grants: Building on his pilot work, Karlamangla has received R01 AG026108 to create cardiovascular risk scores from multiple risk factors tailored to older adults.


Title: Predicting Dementia Risk in Elderly Twins from Indicators of Early Life Infection
Investigators: Margaret Gatz
Project Description: This project explores the role of early life conditions in increasing risk of dementia and Alzheimer’s disease (AD). It builds on a study showing tooth loss before age 35 was a significant risk factor for AD, even controlling for socioeconomic status of the rearing household. We use a different data set, the National Academy of Sciences-National Research Council (NAS-NRC) Twin Registry of World War II veterans/Duke Twins Study database, to further test the hypothesis. We propose to augment the Duke Twins Study database with medical information from 1940s military records, including dental records. That information is archived on microfiche film. The pilot project allows us to contract with the Institute of Medicine (IOM) to extract a portion of these data and transfer them to a usable format that permits merging with the Duke Twins database. The first specific aim is to determine whether tooth loss, as a marker of early life infection, is associated with risk of cognitive decline and dementia. The second specific aim is to determine whether the association between tooth loss, cognitive decline and dementia is primarily due to its role as an indicator of low socioeconomic status. 
Watts, A, Crimmins, EM, Gatz, M. Inflammation as a potential mediator for the association between periodontal disease and Alzheimer’s disease. Neuropsychiatric Disease and Treatment. 2008; 4:865-876.


Title: Examination of the Relationship Between Allostatic Load and Geriatric Frailty across Demographic Subgroups of the Older Adult Population: The MacArthur Study of Successful Aging
Investigators: Catherine A. Sarkisian and Tara Gruenewald 
Project Description: A greater proportion of adults reach old age without disability than ever before, yet clinicians continue to struggle with how to approach the substantial proportion (over 10%) of the older population who develop what is increasingly referred to as the geriatric syndrome of “frailty”: a constellation of problems such as weight loss, muscle wasting, and cessation of physical activity, that cannot be explained by identifiable medical or psychiatric diseases. This investigative team proposes to use data from the MacArthur Study of Successful Aging (MSSA), a longitudinal cohort of 1189 high-functioning Americans, to examine whether and to what extent “allostatic load” predicts geriatric frailty across demographic subgroups. Allostatic load explicitly considers the simultaneous and potentially cumulative impacts of physiological effects from multiple regulatory systems before they become clinically manifest as frailty, fitting very well with the theoretical framework of frailty as a cycle of declining reserves across physiologic systems. Proposed analyses offer the potential to identify dysregulatory pathways across one or multiple physiological systems preceding onset of geriatric frailty, thus suggesting possible opportunities to intervene to prevent frailty across the population. This exploratory investigation would provide preliminary data laying the groundwork for an RO1 application to NIA to extend these findings in larger more diverse samples of older adults including the Health ABC study and Hispanic EPESE. 
Gruenewald, TL, Seeman, TE, Karlamangla, AS, Sarkisian, CA. Allostatic load and frailty in older adults. J Am Geriatr Soc. 2009; 57:1525-1531.

Sarkisian, CA, Gruenewald, TL, Boscardin, WJ, Seeman, TE. Preliminary evidence for subgroups of the geriatric frailty: the MacArthur Study of Successful Aging. J Am Geriatr Soc. 2008; 56:2292-2297.


Title: Comparison of Different Methods for Measuring HbA1c in Epidemiologic Studies 
Investigators: Orpheu Buxton 
Project Description: This project combines the assessment of three methods for determining HbA1c levels as used in clinical trials currently conducted by the PI of this proposal, ongoing epidemiologic studies using a portable device that gives rapid feedback, and dried blood spots appropriate for large-scale studies. The results are expected to provide a ‘Rosetta Stone’ for comparing the three methods and for interpretation of results across different studies. Finally, the proposed pilot will provide additional pilot data for the PI to submit a K award to the NIA and other federal and foundation grants that should facilitate the entry of the PI to the field of Aging research and the study of the social determinants of health.
Buxton, OM, Malarick, K, Wang, W, Seeman, TE. Changes in dried blood spot HbA1c with varied postcollection conditions. Clinical Chem.2009; 55:1034-1036.


Title: Neighborhood Context and Mortality in Late Life 
Investigators: Richard G. Wight and Carol S. Aneshensel
Project Description: Investigate contextual effects of neighborhood socioeconomic status (SES) on mortality among older adults using the Asset and Health Dynamics Among Older Adults (AHEAD) study of 1993 and 1995. This is done by estimating the magnitude of between-neighborhood variation in mortality, and the extent of which this variation persists net of differences in the social status of the people who live in these different neighborhoods.
Wight, RG, Cumming, JR, Karlamangla, AS, Aneshensel, CA. Urban neighborhood context and mortality in late life. J Aging Health. 2010; 22:197-218.

Title: Evaluating Fast Decay of Iconic Memory as an Early Sign for Alzheimer Disease
Investigators: Zhong-Lin Lu and Linda Clark 
Project Description: This study will follow subjects longitudinally to determine whether rapid decay of iconic memory predicts later development of AD by comparing iconic (visual) sensory memory and attention in older adults with normal cognition to those with mild cognitive impairment (MCI). The hypothesis is that the difference in iconic memory can accurately predict cognitive status. These psychophysical measures will be compared to standard neuropsychological cognitive assessments scores and to changes in those scores over the previous year, to determine whether iconic memory correlates with lower current scores, and declines in scores, on standard cognitive tests.

Title: Feelings of Usefulness and Disability and Mortality Outcomesin the MacArthur Study of Successful Aging: Psychosocial, Behavioral and Physiological Pathways
Investigators: Tara L. Gruenewald 
Project Description: This project is investigating whether feelings of usefulness to others is associated with the likelihood of disability development and mortality using the MacArthur Study of Successful Aging (MSSA). This study examines depression, physical and social activity, and indicators of low-grade inflammation (IL6 and CRP) as mediators associated with feeling useful.

Title: New Longitudinal Analyses of the Hawaii Family Study of Cognition
Investigators: John J. McArdle
Project Description: The purpose of this research is to recover and organize the database from the Hawaii Family Study of Cognition (HFSC) so that these classical data can be used in new longitudinal research to study a variety of contemporary dynamic propositions about aging, health and cognitive abilities. 

Title: Longitudinal Analysis of Race/Ethnic and SES Differences in Allostatic Load among Midlife Women
Investigators: Dawn M. Upchurch and Gail A. Greendale
Project Description: This project will characterize the distribution of allostatic load (AL) and its consequences for important health markers (vascular stiffness and bone density) among a longitudinal sample of midlife women as well as the impact of demographic factors, personal coping strategies, spirituality, and social support of the accumulation of AL and its consequences on vascular stiffness and bone density using the data from the Study of Women’s Health Across the Nation (SWAN).

Title: C-Reactive Protein and Blood Spots in Indonesia
Investigators: Elizabeth Frankenberg, Duncan Thomas, and Thomas McDade 
Project Description: The first goal of this pilot project was to provide new evidence on the feasibility of using DBS to measure C-Reactive Protein (CRP), an indicator of acute inflammation and possibly a risk factor for coronary artery disease. The second goal of the project was to provide a careful and comprehensive characterization of the socio-demographic and health factors that are correlated with CRP. The analyses will combine detailed SES and health information in the WISE study, a random assignment treatment-control intervention study in Indonesia, and identify those characteristics of individuals and their families that are predictive of elevated CRP. The results of this pilot study have been the foundation for a research application that included measurement of CRP using the DBS collected from all adult respondents in WISE as well as follow-up interviews three years after the DBS were collected. These measures of CRP will be used to predict subsequent heart disease, other health problems and mortality and will thereby provide unparalleled opportunities to more fully interpret the information contained in CRP in low income settings.

Title: Inflammation and Metabolic Risk and the Aging Process: Diet, Disease, and Development
Investigators: Hillard Kaplan 
Project Description: This project has obtained and prepared a number of existing data sets that have information on markers of inflammation and cardiovascular and metabolic risk factors as well as indicators of physiological capacity such as height and weight, grip strength, stunting, etc. We are investigating these factors across the age range for populations living under very different conditions. We include populations from the United States, Mexico, and the Tsimane of Bolivia. Such populations have very different disease structures, economic status, expenditures of energy, nutritional status, and medical treatment. They have very different levels of both childhood and adult mortality and causes of morbidity. The aim of this project is to develop pilot data that will be used to prepare a program project. The use of physiological indicators from this variety of environments will provide the basis for groundbreaking work in biodemography. This project tests the hypothesis that disease exposure, diet, and intervention experienced in childhood have a lasting effect on the aging process. The effect of the increasing societal development including better public health, diet, and health care has been to delay the aging process. Reductions in exposure to infections and noxious environments in childhood have left cohorts of older persons progressively healthier because they have been exposed to lower lifetime levels of inflammation. Improvements in sanitation and public health have resulted in more resistant hosts through decreases in exposure to bacteria and parasites.

Title: Education as a Modifier of Rate of Change among those with Memory Complaints and Mild Cognitive Dysfunction 
Investigators: Margaret Gatz, Wendy Mack, Helena Chui, Carol McCleary, Caleb Finch, and Eileen Crimmins
Project Description: The long run purpose of this study is to evaluate the protective effect of education and other indicators of mental ability or "mental exercise" against cognitive decline. The pilot research examined whether education relates to the timing of shifts from non-demented to mild cognitive impairment and from mild cognitive impairment to dementia, and from diagnosed dementia to death. The hypothesis is that people with higher education will drop faster once they start to decline, because their education protected them from crossing a diagnostic threshold for longer than would be the case for someone less endowed. Thus we would expect that having greater cognitive reserve will protect against onset of clinically diagnosed dementia, while decline after diagnosis will be more abrupt. The work of the pilot project is to develop the data from the ADRC files for such examination and test our ability to use the latent growth curve method with these data. This project will help us evaluate the role of changing educational levels in producing trends in population cognitive ability. This project was the basis of a section of a P01 project.

Title: Allostatic load, and telomere length, an index of cell aging
Principal Investigator: Teresa Seeman, Elissa Epel, and Richard Cawthon
Project Description: The aim of this project is to determine whether there is a link between telomere length and morbidity among a sample of older persons and to link psychosocial and demographic variables to telomere length. This pilot will provide unique longitudinal data on telomere length (and changes therein over time) for an older cohort, allowing for evaluation of hypothesized relationships between changes in TL and subsequent health outcomes. This study is measuring telomere length of white blood cells for the 900 subjects in the MacArthur Study who have blood samples archived from baseline, around 7.5 years earlier. It examines whether telomere length predicts cardiovascular related diseases and morbidity (from death certificates) and possible relations with allostatic load, which is already linked to cognitive decline, morbidity, or mortality, in the MacArthur Aging Study. As a secondary aim, we will explore how antioxidants and psychosocial factors linked to neuroendocrine reactivity or morbidity, including socio-economic status, depression, and social support, are linked to telomere length. Currently, final DNA samples have been extracted. Samples will be shipped to Dr. Cawthon’s laboratory once funding for laboratory assays and planned analyses of resulting data is available.

Title: Race/Ethnic Differences in Years of Potential Life Lost
Project Investigator: Susan Ettner and Mitchell Wong
Project Description: This study analyzed data from the National Health Interview Survey (NHIS) with linked vital statistics data to build a descriptive simulation model of mortality among Black, Latino, Asian and White adults. We first calculated all-cause and cause-specific mortality rates. We then examined mortality among Asians for only the more common causes of death given the more limited sample size of this ethnic group in the NHIS dataset. These rates were then used in a simlulation model to estimate racial/ethnic differences in years of potential life lost (YPLL). The specific aims of this study were to, 1) Estimate all-cause and cause-specific mortality rates for Whites, Blacks, Hispanics and Asians, standardized to the age and sex distribution of the U.S. population, 2) Conduct a simulation model using the mortality rate estimates in order to project the racial/ethnic differences in YPLL, 3) Calculate mortality rates adjusted for education, years lived in the U.S., obesity and smoking and incorporate these estimates into the simulation model to predict the impact of these variables on racial/ethnic differences in YPLL.
Results: In this study, we found that African-Americans have higher mortality rates from a wide range of causes, however, the disparity is concentrated in a few areas. HIV contributed most to the difference in YPLL (20.0%), followed by homicide (6.9%), hypertension (5.8%) and ischemic heart disease (4.8%). In fact, HIV accounted for a greater proportion of the racial disparity in YPLL than ischemic heart disease, cerebrovascular stroke, hypertension and congestive heart failure combined. Dr. Wong has submitted a proposal for a K award to extend this work in several ways. First, the previous study examined years of life lost over an average follow-up period of 7.4 years. The proposed work will use a simulation model to estimate the life years lost over a lifetime. The simulation model will also allow the estimation the racial disparity in years of life lost due to differences in incidence vs. fatality from specific diseases. Thirdly, the simulation model would serve as a policy tool to estimate the impact of future interventions targeting the elimination of racial disparities in health. Finally, the proposed project will estimate the difference in cause-specific mortality for Latinos and Asians compared to Whites. 
Wong, MD, Chung, AK, Boscardin, WJ, Li, M, Hsieh, H, Ettner, SL, Shapiro, MF. The contribution of specific causes of death to sex differences in mortality. Public Health Rep. 2006; 121:746-754.

Wong, MD, Tomoko, T, Hsieh, H, Shapiro, MF, Boscardin, WJ, Ettner, SL. Differences in cause-specific mortality between Latino and White adults.Medical Care. 2005; 43:1058-1062.

Wong, MD, Shapiro, MF, Boscardin, WJ, Ettner, SL. Contribution of major diseases to disparities in mortality. N Engl J Med. 2002; 347:1585-1592.


Title: The Genetics of Aging and Mortality of the Yeast S. Cerevisiae
Investigator: Valter Longo
Specific Aims: Analysis of age-specific mortality rates can provide a measure of the rate of aging and can enhance our understanding of the mechanisms underlying aging and death. The goal of this research is to study the age-specific mortality of populations of billions of long-lived and control yeast. These studies will be performed in parallel with measurements to assess age-dependent deteriorative physiological changes that lead to loss of function and death. 
Findings: This study found that long-term, multiphasic mortality rates in yeast populations are highly reproducible, both within and across genotypes. Replicate cohorts show striking consistency throughout the lifespan, which reached over 120 days in some instances. The complicated dynamics are not a result of random variation (P<0.0001, P<0.005 for the null hypotheses that the log-mortality patterns are flat or linearly increasing, respectively). The multiphasic mortality patterns may be truly reflective of the underlying biology of the organism, such that physiological changes over time cause the risk of death in individual yeast to fluctuate. Observed mortality patterns might be due to a changing frailty of the individual organisms caused by the byproducts of respiration (e.g., oxidative damage) or by other physiological effects of aging. This hypothesis predicts that other physiological characters, such as stress resistance, would also exhibit multiphasic behavior. The mutations that extend life in a variety of species appear to cause the organisms to be resistant to damage from heat and the corrosive effects of antioxidants. Extended longevity of these simple organisms appears to be associated with increased investment in maintenance and repair, sometimes at the expense of the growth rate. These findings could have important implications for the treatment of diseases. If drugs can be developed that make human cells younger and more resistant to multiple stresses, as in the long-lived organisms, then longevity would be extended and human cells would be protected against a variety of diseases.

Title: Ethnic/Education Differences in Cognitive Performance among Women in Five Ethnic Groups
Investigators: Galen Buckwalter, Gail Greendale, and Teresa Seeman 
Project Description: This project funded initial analyses of cognitive data from the multi-site, multi-ethnic Study of Women's Health Across the Nation (SWAN). This is a study of menopause, focusing on ethnic variations through inclusion of cohorts of Hispanic, African American, Japanese American and Chinese American women, in addition to Caucasians. The pilot analyses explored ethnic variation in cognitive performance and its relationship to differences in educational attainment. These analyses are designed to provide some preliminary, cross-sectional data on which an R01 application was based for additional funding to obtain longitudinal cognitive data for the SWAN cohort (something that was not included in the original planned SWAN data collections). This project provides the basis for requesting longitudinal data on cognition in future waves of SWAN. 

Title: Education/Cognition and APOE
Investigators: Philip Bretsky, Teresa Seeman, and Eileen Crimmins
Specific Aims: While perhaps the most general genetic risk factor currently described for the development of late-onset Alzheimer Disease, the effects of e4 allele of the Apolipoprotein E (APOE) gene on cognitive functioning more generally remain unclear. Cognitive decline in elderly persons is an early predictor of dementia and risks may be modified by a genetic predisposition. Multiple measures of cognitive function were assessed longitudinally in the MacArthur Successful Aging Study, a population-based cohort free of frank impairment at baseline. Subjects were 965 Caucasian and African-American men and women from Durham NC, East Boston MA, and New Haven CT, aged 70-79, and recruited in 1988-1989. Two follow-up evaluations were completed, one at 3 years and another at 7 years.
Results: At the first follow-up, modest but significant declines in naming and spatial ability were associated with APOE-e4 genotype. By the second follow-up, more pronounced and significant associations were noted between APOE-e4 genotype and cognitive decline from six of the eight cognitive outcomes. After 7 years, APOE-e4 allele carriers were twice as likely to have declined on a global cognitive score (OR=2.0; 95%CI: 1.1, 3.6) as compared to non-carriers. This study shows that the APOE-e4 is associated with cognitive decline among a high-functioning elderly cohort with effects most pronounced after 7 years of follow-up. Hence, the e4 allele either may function as a risk factor for cognitive impairment in normal aging across a broad spectrum of domains or, alternatively, may exert detectable effects early in a long prodromal AD trajectory.
Bretsky P, Guralnik JM, Launer L, Albert M, Seeman TE. The role of APOE-epsilon4 in longitudinal cognitive decline: MacArthur Studies of Successful Aging. Neurology. 2003; 60(7):1077-81.

Title: Measurement of Cognition 
Investigators: Elizabeth Zelinski and Michael Gilewski
Specific Aims: To determine whether demographic and health variables differentially interact to predict cognitive scores in Asset and Health Dynamics of the Oldest-old (AHEAD), a nationally representative survey of older Americans to test the developmental discontinuity hypothesis. This research examined cognition in older adults across a variety of measures and used modern scaling methods to identify patterns of cross-sectional decline across measures, to evaluate the role of educational attainment in cross-sectional age differences and in longitudinal decline across cognitive abilities, and to determine whether change in some abilities is more differentially affected by educational attainment than in other abilities. This work used both the Long Beach longitudinal Study and the AHEAD data sets. 
Methods: Rasch modeling procedures were used to rescale cognitive measures in AHEAD to calibrate interval scores from raw scores, equating scales across measures, making it possible to compare directly effects of predictors. It also reduces the likelihood of obtaining spurious interactions. Tasks included combined immediate and delayed recall, the Telephone Interview for Cognitive Status (TICS), Series 7, and an overall cognitive score. 
Results: Direct comparisons of predictors across Rasch scales showed that demographic variables most strongly predicted performance on all scores, with health variables having smaller effects. Age interacted with both demographic and health variables, but patterns varied across variables. Demographic variables have strong effects on cognition. The developmental discontinuity hypothesis that health variables have stronger effects than demographic ones in cognition in the oldest-old was not supported. 
Zelinski EM, Gilewski MJ. Effects of demographic and health variables on Rasch scaled cognitive scores. J Aging Health. 2003;15(3):435-64.


Title: Education, Occupation, and Cognitive Impairment: The Study of Dementia in Swedish Twins
Investigators: Margaret Gatz, Nancy Pedersen, and Boo Johansson
Specific Aims: The purpose of this study was to examine whether education and intellectual engagement earlier in life are associated with cognitive impairment later. A co-twin control design was used in order to control for genetic and other familial influences. 167 twin pairs were included in the study in which one member was clinically demented while the twin partner was cognitively intact. These discordant pairs were identified from the Study of Dementia in Swedish Twins and the OCTO-Twin Study, subsamples from the population-based Swedish Twin Registry.
Results: Results from this research have been reported in two articles. The first is an analysis of education. The association between dementia and education was studied in 143 twin pairs discordant for dementia, using a matched pair design, and in 221 dementia cases and 442 unrelated controls from the same twin registry, using a case control design. Low education was defined as 6 years or less of schooling. Case control analyses with prevalent cases showed low education to be a risk for Alzheimer's disease but not dementia in general. Low education did not significantly predict incident cases. In the matched pairs analysis, which controls for genetic and other familial influences, differences in education between demented twins and twin partners were not statistically significant. However, for Alzheimer's disease, odds ratios resulting from matched pairs and case control analyses were similar. Twins' comparative reports about intellectual involvement earlier in their lives suggest a longstanding difference on this dimension, with less involvement by the twin who will become demented. The second study examined whether an active lifestyle affects risk of Alzheimer’s disease: specifically, whether participation in leisure activities during early and middle adulthood was associated with reduced subsequent risk of Alzheimer’s disease and dementia in general. The study sample consisted of 107 same-sex twin pairs discordant for dementia for whom information on leisure activities was self-reported more than 20 years prior to clinical evaluation. A factor analysis of these activities yielded three activity factors: intellectual-cultural, self-improvement and domestic activity. Matched pair analyses compared activities within the discordant twin pairs while controlling for level of education. Odds ratios adjusted for level of education revealed that, within twin pairs, participation in a greater overall number of leisure activities was associated with lower risk of both Alzheimer’s disease (OR=.5, 95% CI=0.3-1.0) and dementia in general (OR=0.6, 95% CI=0.4-1.0). The association between overall activity level and Alzheimer’s disease was significant for women (OR=0.4, 95% CI=0.2-0.8) but not for men (OR=1/1, 95% CI=0.4-3.4). In addition, greater engagement in intellectual –cultural activities was associated with lower risk of Alzheimer’s disease for women (OR=0.4, 95% CI=0.2-1.0), although not for men (OR=0.9, 95% CI=0.3-2.6). Thus, within twin pairs, those who reported participating in more leisure activities than their siblings were less likely to develop Alzheimer’s disease or any type of dementia. Social and intellectual activities may be more important for dementia. 
Andel, R, Crowe, M, Pedersen, NL, Mortimer, J, Crimmins, E, Johansson, B, Gatz, M. Complexity of work and risk of Alzheimer’s disease: A population-based study of Swedish twins. J Gerontol B Psychol Sci Soc Sci. 2005; 60:P251-P258.

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