Consistency and timing of marital transitions and survival during midlife: the role of personality and health risk behaviors.

BACKGROUND: Marital status is associated with survival. PURPOSE: The aims of this study are to evaluate marital history and timing on mortality during midlife, test the role of pre-marital personality, and quantify the role of health risk behaviors. METHODS: Cox proportional hazard models were run with varying classifications of marital history and sets of covariates. RESULTS: In fully adjusted models compared to the currently married, lifetime marital history predicts premature mortality with never married at 2.33 times risk of death and ever married at 1.64 risk of death. Midlife marital history shows that not having a partner during midlife (hazard ratio (HR) = 3.10 formerly married; HR = 2.59 remaining single) has the highest risk of death. Controlling for personality and health risk behaviors reduces but does not eliminate the impact of marital status. CONCLUSION: Consistency of marital status during midlife suggests that lack of a partner is associated with midlife mortality.

Hyperreactive platelet phenotypes: relationship to altered serotonin transporter number, transport kinetics and intrinsic response to adrenergic co-stimulation.

The mechanism underlying a hyperreactive platelet phenotype remains unknown. Since serotonin has been shown to influence platelet biology and atherothrombosis, we sought to investigate the association of platelet serotonin transporter number, binding affinity, and uptake kinetics with platelet aggregation. A total of 542 healthy volunteers had light transmittance platelet aggregometry measured in response to varying concentrations of epinephrine, serotonin, epinephrine plus serotonin, ADP and collagen. Transporter-dependent serotonin uptake rate was determined (Vmax), as were serotonin transporter number (Bmax) and binding affinity (Kd) using 3H paroxetine binding in a homologous displacement assay, nonlinear regression and validated algorithms for kinetic modelling. Stimulation with submaximal (2µM) epinephrine concentration elicited a distinct, bimodal pattern of platelet aggregation in this population. In contrast, subjects exhibited minimal aggregation in response to serotonin alone. Co-stimulation with submaximal epinephrine and serotonin induced platelet aggregation to a level beyond that observed with either agonist alone and maintained a bimodal response distribution. Subjects with heightened (>60%) platelet aggregation to both epinephrine alone and epinephrine plus serotonin exhibited increased platelet serotonin uptake, and transporter number and affinity. In a population of healthy subjects, co-stimulation with submaximal concentrations of epinephrine and serotonin identifies a subset of individuals with a hyperreactive platelet aggregation profile that is associated with changes in platelet serotonin function.

Recovery expectations and long-term prognosis of patients with coronary heart disease.

BACKGROUND: Expectations of patients regarding their prospects for recovery have been shown to predict subsequent physical and social functioning. Evidence regarding the impact of expectations on clinical outcomes is limited. METHODS: At the inpatient service of a tertiary care hospital, we evaluated beliefs of patients undergoing coronary angiography about their prognosis as predictors of long-term survival and 1-year functional status. Baseline assessments, including a measure of expectations for recovery, were obtained during hospitalization with mortality follow-up for approximately 15 years. Patients with significant obstructive coronary artery disease were interviewed while in the hospital and enrolled in follow-up. Functional status was assessed at baseline and 1 year later with questionnaires reflecting physical capabilities. Analyses controlled for age, sex, disease severity, comorbidities, treatments, demographics, depressive symptoms, social support, and functional status. There were 1637 total deaths, 885 from cardiovascular causes, in the 2818 patients in these analyses. The outcomes were total mortality, cardiovascular mortality, and 1-year functional status. RESULTS: Expectations were positively associated with survival after controlling for background and clinical disease indicators. For a difference equivalent to an interquartile range of expectations, the hazard ratio (HR) for total mortality was 0.76 (95% confidence interval [CI], 0.71-0.82) and 0.76 (95% CI, 0.69-0.83) for cardiovascular mortality. The HRs were 0.83 (95% CI, 0.76-0.91) and 0.79 (95% CI, 0.70-0.89) with further adjustments for demographic and psychosocial covariates. Similar associations (P < .001) were observed for functional status. CONCLUSION: Recovery expectations at baseline were positively associated with long-term survival and functioning in patients with coronary artery disease.

Central nervous system serotonin and clustering of hostility, psychosocial, metabolic, and cardiovascular endophenotypes in men.

OBJECTIVE: To use measures of cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5HIAA) and genotype of a functional polymorphism of the monoamine oxidase A gene promoter (MAOA-uVNTR) to study the role of central nervous system (CNS) serotonin in clustering of hostility, other psychosocial, metabolic and cardiovascular endophenotypes. METHODS: In 86 healthy male volunteers, we evaluated CSF levels of the primary serotonin metabolite 5HIAA and MAOA-uVNTR genotype for association with a panel of 29 variables assessing hostility, other psychosocial, metabolic, and cardiovascular endophenotypes. RESULTS: The correlations of 5HIAA with these endophenotypes in men with more active MAOA-uVNTR alleles were significantly different from those of men with less active alleles for 15 of the 29 endophenotypes. MAOA-uVNTR genotype and CSF 5HIAA interacted to explain 20% and 22% of the variance, respectively, in scores on one factor wherein high scores reflected a less healthy psychosocial profile and a second factor wherein high score reflected increased insulin resistance, body mass index, blood pressure and hostility. In men with less active alleles, higher 5HIAA was associated with more favorable profiles of hostility, other psychosocial, metabolic and cardiovascular endophenotypes; in men with more active alleles, higher 5HIAA was associated with less favorable profiles. CONCLUSIONS: These findings indicate that, in men, indices of CNS serotonin function influence the expression and clustering of hostility, other psychosocial, metabolic and cardiovascular endophenotypes that have been shown to increase risk of developing cardiovascular disease. The findings are consistent with the hypothesis that increased CNS serotonin is associated with a more favorable psychosocial/metabolic/cardiovascular profile, whereas decreased CNS serotonin function is associated with a less favorable profile.

Coping skills training to reduce psychosocial risk factors for medical disorders: a field trial evaluating effectiveness in multiple worksites.

OBJECTIVE: To determine whether a commercial coping skills training program shown to reduce psychosocial risk factors in randomized clinical trials of patients with coronary heart disease is also effective in achieving similar improvements among stressed workers in a real world corporate setting. METHODS: Conduct an observational trial to evaluate the impact of the Williams LifeSkills Workshop on depression, social support, anxiety, and hostility in a sample of 110 employees working at multiple U.S. sites of a client of Williams LifeSkills, Inc. RESULTS: All psychosocial risk factors showed highly significant improvements from pre- to post-training. Except for social support, these improvements were maintained at six months follow-up. CONCLUSIONS: These findings provide support for the effectiveness of the Williams LifeSkills Workshop by suggesting that its efficacy, as demonstrated in randomized clinical trials, generalizes to real world settings like the multiple U.S. work sites of a corporate client.

Midlife activity predicts risk of dementia in older male twin pairs.

BACKGROUND: This was a prospective study of dementia to elucidate mechanisms of disease risk factors amenable to modification and specifically to determine whether midlife cognitive and physical leisure activities are associated with delayed onset or reduced risk of dementia within older male twin pairs. METHODS: The co-twin control design used prospectively collected exposure information to predict risk of dementia 20 to 40 years later. The subjects were community-dwelling and nursing home residents living throughout the continental United States. We studied 147 male twin-pairs who were discordant for dementia or age of dementia onset and were members of the National Academy of Sciences-National Research Council Twin Registry of World War II veterans and participants in the Duke Twins Study of Memory in Aging. The main outcome measure was diagnosed dementia by using a two-stage screen and full clinical evaluation. Conditional odds ratios were estimated for the association between midlife leisure activities and late-life dementia. RESULTS: Greater midlife cognitive activity was associated with a 26% risk reduction for dementia onset. Protective effects were most robust in monozygotic twin pairs, where genetic and early-life influences were most tightly controlled, and for activities that were often cognitive and social in nature. Cognitive activity was particularly protective among monozygotic twin pairs carrying the apolipoprotein E epsilon4 allele, with a 30% risk reduction. Midlife physical activity did not modify dementia risk. CONCLUSIONS: Participation in a range of cognitively and socially engaging activities in midlife reduced risk for dementia and AD in twins discordant for onset, particularly among twin pairs at elevated genetic risk, and might be indicative of an enriched environment.

Childhood socioeconomic status and serotonin transporter gene polymorphism enhance cardiovascular reactivity to mental stress.

OBJECTIVE: To test the hypothesis that low socioeconomic status (SES) and the 5HTTLPR L allele are associated with increased cardiovascular reactivity (CVR) to stress in a larger sample and that SES and 5HTTLPR genotypes interact to enhance CVR to stress. CVR to mental stress has been proposed as one mechanism linking stress to the pathogenesis of cardiovascular disease. The more transcriptionally efficient long (L) allele of a polymorphism of the serotonin transporter gene promoter (5HTTLPR) has been found associated with increased risk of myocardial infarction. We found the long allele associated with larger CVR to mental stress in a preliminary study of 54 normal volunteers. METHODS: Subjects included 165 normal community volunteers stratified for race, gender, and SES, who underwent mental stress testing. RESULTS: Childhood SES as indexed by Father's Education Level was associated with larger systolic blood pressure (SBP) (p < .05) and diastolic blood pressure (DBP) (p = .01) responses to mental stress. The L allele was associated with larger SBP (p = .04), DBP (p < .0001), and heart rate (p = .04) responses to mental stress compared with the short (S) allele. Subjects with the SS genotype and high Father's Education exhibited smaller SBP (5.2 mm Hg) and DBP (2.9 mm Hg) responses than subjects with LL genotype and low Father's Education (SBP = 13.3 mm Hg, p = .002; DBP = 9.7 mm Hg, p < .0001). CONCLUSIONS: Both the 5HTTLPR long allele and low SES, particularly during childhood, are associated with increased CVR to mental stress, which could account, at least in part, for the increased cardiovascular disease risk associated with these characteristics. If confirmed in further research, these characteristics could be used to identify persons who might benefit from preventive interventions.

Associations of job demands and intelligence with cognitive performance among men in late life.

OBJECTIVE: To examine the association of job characteristics and intelligence to cognitive status in members of the National Academy of Sciences-National Research Council Twins Registry of World War II veterans. METHODS: Participants (n = 1,036) included individuals with an assessment of intelligence based on Armed Services testing in early adulthood. In late adulthood, these individuals completed the modified Telephone Interview for Cognitive Status (TICS-m) and occupational history as part of an epidemiologic study of aging and dementia. Occupational history was coded to produce a matrix of job characteristics. Based on factor analysis, job characteristics were interpreted as reflecting general intellectual demands (GI), human interaction and communication (HC), physical activity (PA), and visual attention (VA). RESULTS: Based on regression analysis of TICS-m score covarying for age, intelligence, and years of education, higher levels of GI and HC were independently associated with higher TICS-m performance, whereas higher PA was independently associated with lower performance. There was an interaction of GI and intelligence, indicating that individuals at the lower range of intellectual aptitude in early adulthood derived greater cognitive benefit from intellectually demanding work. CONCLUSIONS: Intellectually demanding work was associated with greater benefit to cognitive performance in later life independent of related factors like education and intelligence. The fact that individuals with lower intellectual aptitude demonstrated a stronger positive association between work and higher cognitive performance during retirement suggests that behavior may enhance intellectual reserve, perhaps even years after peak intellectual activity.

Depressive symptoms, race, and glucose concentrations: the role of cortisol as mediator.

OBJECTIVE: This study examined the associations of depressive symptoms with glucose concentrations and morning cortisol levels in 665 African-American and 4,216 Caucasian Vietnam-era veterans. RESEARCH DESIGN AND METHODS: Glucose level was measured as a three-level variable (diabetes, impaired glucose, and normal). Depressive symptoms were measured by the Obvious Depression Scale (OBD) from the Minnesota Multiphasic Personality Inventory. RESULTS: Regression models showed significant race x OBD interactions in relation to glucose concentration (P < 0.0001) and cortisol (P < 0.0001). The OBD was positively associated with glucose concentration and cortisol in both racial groups. However, the magnitude of those associations was larger for African Americans. Further analyses suggested that cortisol partially mediated the race difference in the relation of depressive symptoms to glucose concentrations. CONCLUSIONS: These results suggest that enhanced hypothalamic pituitary adrenal activity plays an important role in the relation of depressive symptoms to dysregulated glucose metabolism and may partially explain the differential effects of depressive symptoms on glucose levels in African-American and Caucasian male subjects.

Job demands and dementia risk among male twin pairs.

BACKGROUND: Job characteristics may influence dementia risk, but some types of job complexity remain to be examined. Twin studies provide a useful methodology to examine job differences between pairs who share many environmental and genetic influences. METHODS: Members of the NAS-NRC Twins Registry of World War II Veterans received a clinical evaluation for dementia and had job ratings from the Dictionary of Occupational Titles. RESULTS: Cotwin-control models (n = 220 pairs) indicated lower dementia risk with greater job demands of reasoning, mathematics, language, and vocational training, with comparable results in case-control models (n=425 cases). These effects were significant among twin pairs discordant for 6 or more years, but not among those discordant between 3-5 years. Results were similar for Alzheimer's disease, and main effects were not further explained by zygosity or apolipoprotein E genotype. CONCLUSIONS: Jobs that utilize data, academic skills, and extensive vocational training may protect against dementia; however, in twin pairs these effects only emerged among individuals who remained free of dementia several years after onset in their sibling.

Prediction of all-cause mortality by the Minnesota Multiphasic Personality Inventory Optimism-Pessimism Scale scores: study of a college sample during a 40-year follow-up period.

OBJECTIVE: To examine a measure of explanatory style, the Optimism-Pessimism (PSM) scale derived from college-entry Minnesota Multiphasic Personality Inventory scores, as a predictor of all-cause mortality. SUBJECTS AND METHODS: A total of 7007 students entering the University of North Carolina at Chapel Hill completed the Minnesota Multiphasic Personality Inventory during the mid-1960s. Of those students, 6958 had scores on the PSM scale and data for all-cause mortality through 2006. Scores on the PSM scale were evaluated as predictors of mortality using the Cox proportional hazards regression model, adjusted for sex. During the 40-year follow-up period, 476 deaths occurred. RESULTS: Pessimistic individuals who scored in the upper tertile of the distribution had decreased rates of longevity (hazard ratio, 1.42; 95% confidence Interval, 1.13-1.77) compared with optimistic individuals who scored in the bottom tertile of the distribution. CONCLUSION: In a model that adjusted only for sex, a measure of optimistic vs pessimistic explanatory style was a significant predictor of survival during a 40-year follow-up period such that optimists had Increased longevity.

Vascular risk factors and cognitive decline among elderly male twins.

BACKGROUND: Studies investigating the association between cardiovascular risk factors and cognitive decline report discrepant outcomes. The co-twin control method improves on traditional case-control approaches by controlling for within-twin pair similarities of genetic and early environmental influences. OBJECTIVE: To examine the association of diabetes, hypertension, hypercholesterolemia, and elevated body mass index (BMI) (>30 kg/m(2)), individually and combined, with cognitive decline over a 12-year period in members of the National Academy of Sciences-National Research Council Twin Registry of World War II male veterans. METHODS: Modified Telephone Interview for Cognitive Status (TICS-m) was administered four times at approximately 4-year intervals from 1990 to 2002 as part of an epidemiologic study of dementia. Self-report medical information was collected from 1996 to 2002. We examined the difference in cognitive decline within twin pairs discordant for the vascular risk factors while controlling for baseline TICS-m, education, smoking, and alcohol history. RESULTS: Among twin pairs discordant for diabetes (n = 177), the diabetic twins declined an average of almost 1 point more than their nondiabetic co-twins (p = 0.018) at the last screening time point. Further analyses showed that this was in large part due to greater decline among older men (age 76 to 84 years). Cognitive change was not significantly different between members of pairs discordant for hypertension (n = 326), hypercholesterolemia (n = 282), or elevated BMI (n = 166). CONCLUSION: Based on this study of twin pairs who share similar genetic and early environmental risks for cardiovascular risk factors, diabetes is associated with greater cognitive decline, particularly among the oldest individuals.

Duke Twins Study of Memory in Aging in the NAS-NRC Twin Registry.

The Duke Twins Study of Memory in Aging is an ongoing, longitudinal study of cognitive change and dementia in the population-based National Academy of Sciences-National Research Council (NAS-NRC) Twin Registry of World War II Male Veterans. The primary goal of this study has been to estimate the overall genetic and environmental contributions to dementia with a specific focus on Alzheimer's disease. An additional goal has been to examine specific genetic and environmental antecedents of cognitive decline and dementia. Since 1989, we have completed 4 waves of data collection. Each wave included a 2-phase telephone cognitive screening protocol, followed by an in-home standardized clinical assessment for those with suspected dementia. For many participants, we have obtained postmortem neuropathological confirmation of the diagnosis of dementia. In addition to data on cognition, we have also collected information on occupational history, medical history, medications and other lifetime experiences that may influence cognitive function in late life. We provide an overview of the study's methodology and describe the focus of recent research.

Prevalence and clinical correlates of neuropsychiatric symptoms in dementia.

The purpose of this research was to assess the frequency and severity of neuropsychiatric and behavioral symptoms and to examine the association between preexisting medical conditions and specific neuropsychiatric symptoms in demented individuals. We studied 211 demented subjects (87.7 percent male) who were participants in epidemiological studies of dementia. Using the Neuropsychiatric Inventory (NPI), we assessed the frequency and severity of neuropsychiatric symptoms. We collected medical history information during a structured telephone interview. Our analyses focused on determining prevalence of neuropsychiatric symptoms by dementia diagnosis and severity. We also examined the association of history of head injury, alcohol abuse, and stroke with development of neuropsychiatric symptoms. We found that neuropsychiatric symptoms were common, with approximately three-fourths of the subjects exhibiting at least one symptom during the preceding month. Apathy (39.3 percent), agitation (31.8 percent), and aberrant motor behavior (31.1 percent) were the most frequent symptoms. Frequency and severity of symptoms were similar for the all-dementia and Alzheimer's disease-only groups, neuropsychiatric symptoms varied by severity of dementia, but generally not in a consistent ordinal pattern. History of alcohol abuse, head injury, or stroke was associated with presence of specific neuropsychiatric symptoms in dementia. While psychiatric symptoms are common in dementia, they also vary by type and severity of dementia. The finding that certain medical conditions may increase risk for specific types of neuropsychiatric symptoms expands our knowledge of the natural history of dementia and should improve management of dementia in medically ill patients. Our results may also shed light on mechanisms that underlie neuropsychiatric symptoms.

Hostility as a predictor of survival in patients with coronary artery disease.

OBJECTIVE: This article presents a reanalysis of an earlier study that reported a nonsignificant relation between the 50-item Cook-Medley Hostility Scale (CMHS) and survival in a sample of coronary patients. Since publication of those results, there have been significant developments in the measurement of hostility that suggest that an abbreviated scale may be a better predictor of health outcomes. This study examined the ability of the total CMHS and an abbreviated form of the CMHS (ACM) to predict survival in a sample of patients with documented coronary artery disease (CAD) with increased statistical power. METHODS: Nine hundred thirty-six patients (83% were male; mean age = 51.48) with CAD who were followed for an average of 14.9 years. The ACM consisted of the combination of the cynicism, hostile attribution, hostile affect, and aggressive responding subscales that were identified in an earlier study (Barefoot et al. [1989]) by a rational analysis of the item content. The relation between hostility and survival was examined with Cox proportional hazard models (hazard ratios [HRs] based on a two standard deviation difference). RESULTS: Controlling for disease severity, the ACM was a significant predictor for both CHD mortality (HR = 1.33, p <.009) and total mortality (HR = 1.28, p <.02). The total CMHS was only a marginally significant predictor of either outcome (p values < 0.06). CONCLUSION: The results of this study suggest that hostility is associated with poorer survival in CAD patients, and it may be possible to refine measures of hostility in order to improve prediction of health outcomes.

Patterns of change in hostility from college to midlife in the UNC Alumni Heart Study predict high-risk status.

OBJECTIVE: To examine hostility measured in college and patterns of change in hostility from college to midlife as predictors of high health-related risk later in midlife. METHODS: Logistic regression models were used to test hostility/risk associations. RESULTS: College hostility predicted being a current smoker, consuming more than two drinks of alcohol, low social support, achieving less than expected in career and in relationships, risk for depression, and appraisal of life changing for the worse in terms of family events at midlife. Change in hostility did not predict smoking and drinking; however, it did significantly predict social isolation, lower income (only for women), obesity, avoidance of exercise, high-fat diet, and negative changes in economic life, work life, and physical health events-all risk indicators measured during the next decade. Appraisals of social support, lowered expectations, risk for depression, and reports of family life changing for the worse were predicted at both time periods. When change in hostility was modeled with college hostility, all risk indicators were significantly predicted by college hostility. CONCLUSIONS: High hostility in college and change in hostility from college to midlife predicts a full range of health risk indicators. When compared with the average population decline in hostility, gains in hostility at midlife are related to increased risk while declines in hostility are related to reduced risk. Higher midlife hostility is associated with increased odds of being in the higher risk group. Future research should focus on developing interventions to reduce hostility.

Serotonin-related gene polymorphisms and central nervous system serotonin function.

Central nervous system (CNS) serotonergic function affects a wide range of biological and behavioral functions affecting health and disease. Our objective in this study was to determine whether functional polymorphisms of the genes that encode for the serotonin transporter promoter (5HTTLPR) and monoamine oxidase A (MAOA-uVNTR) are associated with CNS serotonin turnover-indexed by cerebrospinal fluid levels of 5-hydroxyindoleacetic acid (5-HIAA)-in a community sample of healthy adults. Subjects were 165 community volunteers without current medical or psychiatric illness, stratified with respect to ethnicity, gender, and socioeconomic status who underwent inpatient evaluation in the General Clinical Research Center of a university medical center. A significant ethnicity x genotype interaction (P=0.008) indicated that, compared to the long/long and long/short genotypes, the 5HTTLPR short/short genotype was associated with higher CSF 5-HIAA levels in African Americans, but with lower levels in Caucasians. A gender x genotype interaction (P=0.04) indicated that 5HTTLPR short/short genotype was associated with higher 5-HIAA levels in women but with lower levels in men. MAOA-uVNTR 3.5 and 4 repeat alleles were associated with higher 5-HIAA (P=0.03) levels in men, but were unrelated to 5-HIAA levels in women. These findings suggest that effects of serotonin-related gene polymorphisms on CNS serotonergic function vary as a function of both ethnicity and gender. Further research will be required to determine the mechanism(s) underlying these differential effects. In the meanwhile, both ethnicity and gender should be taken into account in research evaluating effects of these and related polymorphisms on CNS serotonergic function, as well as the broad range of biological and behavioral functions that are regulated by CNS serotonergic function.

Head injury in early adulthood and the lifetime risk of depression.

BACKGROUND: Depressive symptoms are common and can be debilitating in the months after head injury. Head injury can also have long-term cognitive effects, but little is known about the long-term risk of depression associated with head injury. We investigated the lifetime rates of depressive illness 50 years after closed head injury. METHODS: Participants were male World War II veterans who served during 1944-1945 and were hospitalized at that time for a head injury, pneumonia, or laceration, puncture, or incision wounds. We used military medical records to establish the presence and severity of closed head injuries. Veterans with (n = 520) and without (n = 1198) head injuries were interviewed in 1996-1997 for their lifetime history of depressive illness. Men with dementia were excluded. RESULTS: Veterans with head injury were more likely to report major depression in subsequent years and were more often currently depressed. Using logistic regression and controlling for age and education, the lifetime prevalence of major depression in the head injured group was 18.5% vs 13.4% in those with no head injury (odds ratio = 1.54, 95% confidence interval = 1.17-2.04). Current major depression was detected in 11.2% of the veterans with head injuries vs 8.5% of those without head injury (odds ratio = 1.63, 95% confidence interval = 1.07-2.50). This increase in depression could not be explained by a history of myocardial infarction, a history of cerebrovascular accident, or history of alcohol abuse. The lifetime risk of depression increased with severity of the head injury. CONCLUSION: The risk of depression remains elevated for decades following head injury and seems to be highest in those who have had a severe head injury.