Amanda M. Simanek

Seropositivity to Cytomegalovirus, Inflammation, All-Cause and Cardiovascular Disease-Related Mortality in the United States

Background Studies have suggested that CMV infection may influence cardiovascular disease (CVD) risk and mortality. However, there have been no large-scale examinations of these relationships among demographically diverse populations. The inflammatory marker C-reactive protein (CRP) is also linked with CVD outcomes and mortality and may play an important role in the pathway between CMV and mortality. We utilized a U.S. nationally representative study to examine whether CMV infection is associated with all-cause and CVD-related mortality. We also assessed whether CRP level mediated or modified these relationships. Methodology/Principal Findings Data come from subjects ≥25 years of age who were tested for CMV and CRP level and were eligible for mortality follow-up on December 31st, 2006 (N = 14153) in the National Health and Nutrition Examination Survey (NHANES) III (1988–1994). Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for all-cause and CVD-related mortality by CMV serostatus. After adjusting for multiple confounders, CMV seropositivity remained statistically significantly associated with all-cause mortality (HR 1.19, 95% CI: 1.01, 1.41). The association between CMV and CVD-related mortality did not achieve statistical significance after confounder adjustment. CRP did not mediate these associations. However, CMV seropositive individuals with high CRP levels showed a 30.1% higher risk for all-cause mortality and 29.5% higher risk for CVD-related mortality compared to CMV seropositive individuals with low CRP levels. Conclusions/Significance CMV was associated with a significant increased risk for all-cause mortality and CMV seropositive subjects who also had high CRP levels were at substantially higher risk for both for all-cause and CVD-related mortality than subjects with low CRP levels. Future work should target the mechanisms by which CMV infection and low-level inflammation interact to yield significant impact on mortality.

Socio-economic status, cortisol and allostatic load: a review of the literature

BACKGROUND The notion that chronic stress contributes to health inequalities by socio-economic status (SES) through physiological wear and tear has received widespread attention. This article reviews the literature testing associations between SES and cortisol, an important biomarker of stress, as well as the summary index of allostatic load (AL). METHODS A search of all published literature on the PubMed and ISI Web of Knowledge literature search engines was conducted using broad search terms. The authors reviewed abstracts and selected articles that met the inclusion criteria. A total of 26 published studies were included in the review. RESULTS Overall, SES was not consistently related to cortisol. Although several studies found an association between lower SES and higher levels of cortisol, many found no association, with some finding the opposite relationship. Lower SES was more consistently related to a blunted pattern of diurnal cortisol secretion, but whether this corresponded to higher or lower overall cortisol exposure varied by study. Approaches to collecting and analysing cortisol varied widely, likely contributing to inconsistent results. Lower SES was more consistently related to higher levels of AL, but primarily via the cardiovascular and metabolic components of AL rather than the neuroendocrine markers. CONCLUSIONS Current empirical evidence linking SES to cortisol and AL is weak. Future work should standardize approaches to measuring SES, chronic stress and cortisol to better understand these relationships.

Persistent pathogens linking socioeconomic position and cardiovascular disease in the US

BACKGROUND Numerous studies have documented a strong inverse association between cardiovascular disease and socioeconomic position (SEP). Several infections are associated with both cardiovascular disease and SEP; hence infection may form an important link between SEP and cardiovascular disease. This study examines whether seropositivity to cytomegalovirus (CMV), to herpes simplex virus type-1 (HSV-1), and/or to both pathogens mediates the relationship between SEP and cardiovascular disease history in a nationally representative sample of the United States. METHODS We conducted a cross-sectional study of subjects > or =45 years of age, who were tested for seropositivity to CMV, HSV-1 or both pathogens and assessed for cardiovascular disease history in the National Health and Nutrition Examination Survey III. Cardiovascular disease history was defined as history of stroke, heart attack and/or congestive heart failure and SEP as education level. RESULTS SEP was associated with CMV, HSV-1 and seropositivity to both pathogens. CMV seropositivity was associated with cardiovascular disease history even after adjusting for confounders as well as SEP. The odds of reporting a history of cardiovascular disease for those with less than a high school education compared with those with more than a high school education decreased by 7.7% after adjusting for CMV (Sobel mediation test for CMV, P = 0.0006). In contrast, neither seropositivity to HSV-1 nor to both pathogens was associated with cardiovascular disease history after adjusting for SEP. CONCLUSIONS Persistent pathogens such as CMV infection may explain a portion of the relationship between SEP and cardiovascular disease in the United States. Further studies examining additional pathogens and sociobiological mechanisms are warranted.

Persistent Viral Pathogens and Cognitive Impairment Across the Life Course in the Third National Health and Nutrition Examination Survey

BACKGROUND Herpesviruses have been linked to cognitive impairment in older individuals but little is known about the association in the general US population. METHODS We determined whether cytomegalovirus (CMV) and herpes simplex virus 1 (HSV-1) seropositivity were associated with cognitive impairment among children (aged 6-16 years) and adults aged 20-59 or ≥60 years, using data from the National Health and Nutrition Examination Survey (NHANES) III. Linear and logistic regression models were used to examine the associations between pathogen seropositivity and cognitive impairment. RESULTS Among children, HSV-1 seropositivity was associated with lower reading and spatial reasoning test scores (β, -0.69; 95% confidence interval [CI], -1.18 to -.21 and β, -0.82; 95% CI, -1.29 to -.36, respectively). Among middle-aged adults, HSV-1 and CMV seropositivity were associated with impaired coding speed (odds ratio [OR], 1.54; 95% CI, 1.13-2.11, and OR, 1.41; 95% CI, 1.09-1.82, respectively). CMV seropositivity was also associated with impaired learning and recall (OR, 1.43; 95% CI, 1.14-1.80). Among older adults, HSV-1 seropositivity was associated with immediate memory impairment (OR, 3.26; 95% CI, 1.68-6.32). CONCLUSIONS Future studies examining the biological pathways by which herpesviruses influence cognitive impairment across the life course are warranted.

Toxoplasma gondii and anxiety disorders in a community-based sample

A growing body of literature suggests that exposure to the neurotropic parasite Toxoplasma gondii (T. gondii) is associated with increased risk of mental disorders, particularly schizophrenia. However, a potential association between T. gondii exposure and anxiety disorders has not been rigorously explored. Here, we examine the association of T. gondii infection with both anxiety and mood disorders. Participants (n=484) were drawn from the Detroit Neighborhood Health Study, a population-representative sample of Detroit residents. Logistic regression was used to examine the associations between T. gondii exposure (defined by seropositivity and IgG antibody levels) and three mental disorders: generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD) and depression. We found that T. gondii seropositivity was associated with a 2 times greater odds of GAD (odds ratio (OR), 2.25; 95% confidence interval (CI), 1.11-4.53) after adjusting for age, gender, race, income, marital status, and medication. Individuals in the highest antibody level category had more than 3 times higher odds of GAD (OR, 3.35; 95% CI, 1.41-7.97). Neither T. gondii seropositivity nor IgG antibody levels was significantly associated with PTSD or depression. Our findings indicate that T. gondii infection is strongly and significantly associated with GAD. While prospective confirmation is needed, T. gondii infection may play a role in the development of GAD.

Population Levels of Psychological Stress, Herpesvirus Reactivation and HIV

Nearly 40,000 Americans are newly infected with Human Immunodeficiency Virus (HIV) each year. Recently, studies have demonstrated associations between group-level characteristics and the prevalence and incidence of HIV/Acquired Immune Deficiency Syndrome (AIDS) and other sexually transmitted diseases. Two mechanisms previously posited to explain these associations are neighborhood effects on risk behaviors and social or institutional policies. In this paper, we hypothesize that adversity at the population level, such as neighborhood poverty, also influences HIV risk through stress-mediated aberrations in immunological susceptibility by reviewing existing data examining each of these pathways. In particular, we review the evidence showing that: (1) Neighborhood ecologic stressors influence neighborhood- and individual-levels of mental health, psychosocial stress, and HIV/AIDS risk, (2) Individual-level psychosocial stressors influence progression from HIV to AIDS through stress-related hormonal changes, and (3) Individual-level psychosocial stressors influence HIV acquisition via stress-related reactivation of latent herpesviruses, specifically EBV and HSV-2. Our review indicates that further studies are needed to examine the joint pathways linking neighborhood-level sources of psychosocial stress, stress-related reactivation of HSV-2 and EBV, and increased acquisition rates of HIV. We suggest using a multi-level framework for targeting HIV prevention efforts that address not only behavioral risk factors, but structural, political, and institutional factors associated with neighborhood disadvantage, levels of psychosocial stress, and prevention or treatment of HSV-2 and EBV.

Cytomegalovirus and Immunological Aging: The Real Driver of HIV and Heart Disease?

HIV Study, Parrinello et al. [7] found that higher CMV immunoglobulin G (IgG) levels were not associated with markers of subclinical atherosclerosis among HIV-uninfected women, suggesting that increased antibody levels did not increase the risk of atherosclerosis in their HIV-uninfected subsample. In contrast, HIV-positive women with increased CMV IgG levels were more likely to have carotid artery stiffness. These same individuals did not show greater intima-media thickness nor presence of carotid lesions, indicating that the relationship between CMV IgG levels and markers of cardiovascular disease was specific for carotid artery stiffness in HIV-positive subjects. The relation between increased CMV IgG levels and carotid artery stiffness was consistentacrosstreated/aviremic,treated/ viremic, and untreated HIV-infected groups. However, when examining the association between CMV IgG levels and presence of carotid lesions by treatment/ viremia status groups, Parrinello and colleagues found that CMV IgG levels were associated with presence of carotid artery lesions only among HIV-infected persons who were receiving antiretroviral treatment and were aviremic, after adjustment for age, race, and smoking history. These results suggest that treatment/viremia status modifies the impact of CMV IgG level on carotid lesions.

Association Between Prenatal Exposure to Maternal Infection and Offspring Mood Disorders: A Review of the Literature

The purpose of this article is to provide a systematic review of studies that have examined the association between prenatal exposure to maternal infection and development of mood disorders across the life course. Drawing from both human- and animal-based studies, we give an overview of hypothesized biological mechanisms by which exposure to maternal infection during critical periods of gestation may contribute to fetal programming of mood disorders in offspring. We discuss studies examining the association between prenatal exposure to maternal infection with pathogens including influenza as well as other respiratory viruses, herpesviruses, hepatitis viruses, and Toxoplasma gondii and mood disorders in human populations. Moreover, we outline strengths and limitations of the current body of evidence and make recommendations for future research. We also discuss findings in the context of well-documented gender and socioeconomic disparities in the prevalence and severity of mood disorders, particularly major depression, and the role that early exposure to infection may play in explaining the perpetuation of such disparities across generations. Overall, this review of the current knowledge on this topic has important implications for determining future research directions, designing interventions as well as prenatal care guidelines targeted at prevention or treatment of infection during pregnancy, and clinical practice for the identification of individuals that may be at increased risk for mood disorders beginning early in life. Importantly, such efforts may not only lower the overall burden of mood disorders but also serve to address social disparities in these adverse mental health conditions in the U.S.

Herpesviruses, inflammatory markers and incident depression in a longitudinal study of Detroit residents

BACKGROUND Depression is predicted to become the leading cause of disability worldwide by 2030 and moreover, socioeconomic inequalities in depression persist. Herpesviruses, which are more prevalent among socioeconomically disadvantaged populations, subject to stress-induced reactivation and are associated with increased levels of pro-inflammatory cytokines implicated in the etiology of depression, may serve as novel risk factors for depression onset. METHODS Data are from individuals in the Detroit Neighborhood Health Study tested for herpes simplex virus-1 (HSV-1) and cytomegalovirus (CMV) seropositivity/immunoglobulin G (IgG) antibody levels (N=263) as well as interleukin-6 (IL-6) (N=245) and C-reactive protein (CRP) (N=236) levels and assessed for incident depression via the Patient Health Questionnaire-9. Linear and logistic regression models were used to examine associations between pathogen seropositivity/IgG antibody levels, pro-inflammatory markers and incident depression over approximately one-year of follow-up. RESULTS For every one unit increase in CMV IgG antibody level, the odds of incident depression increased by 26% and individuals with IgG antibody levels in the highest quartile had over three times greater odds of incident depression (odds ratio 3.87, 95% confidence interval 1.47, 10.19), compared to those in the lower three quartiles. Neither CMV or HSV-1 seropositivity nor HSV-1 IgG antibody level were associated with IL-6 or CRP levels at Wave 1, nor were IL-6 or CRP levels associated with incident depression at Wave 2. CONCLUSIONS Further examination of the biological pathways linking CMV and depression are warranted.

PTSD is associated with an increase in aged T cell phenotypes in adults living in Detroit

BACKGROUND Psychosocial stress is thought to play a key role in the acceleration of immunological aging. This study investigated the relationship between lifetime and past-year history of post-traumatic stress disorder (PTSD) and the distribution of T cell phenotypes thought to be characteristic of immunological aging. METHODS Data were from 85 individuals who participated in the community-based Detroit Neighborhood Health Study. Immune markers assessed included the CD4:CD8 ratio, the ratio of late-differentiated effector (CCR7-CD45RA+CD27-CD28-) to naïve (CCR7+CD45RA+CD27+CD28+) T cells, the percentage of KLRG1-expressing cells, and the percentage of CD57-expressing cells. RESULTS In models adjusted for age, gender, race/ethnicity, education, smoking status, and medication use, we found that past-year PTSD was associated with statistically significant differences in the CD8+ T cell population, including a higher ratio of late-differentiated effector to naïve T cells, a higher percentage of KLRG1+ cells, and a higher percentage of CD57+ cells. The percentage of CD57+ cells in the CD4 subset was also significantly higher and the CD4:CD8 ratio significantly lower among individuals who had experienced past-year PTSD. Lifetime PTSD was also associated with differences in several parameters of immune aging. CONCLUSIONS PTSD is associated with an aged immune phenotype and should be evaluated as a potential catalyzer of accelerated immunological aging in future studies.