Search

Much of the heterogeneity in the rate of cognitive decline and the age of dementia onset remains unexplained, and there is compelling data supporting psychosocial stressors as important risk factors. However, the literature has yet to come to a consensus on whether there is a causal relationship and, if there is, its direction and strength. This study estimates the relationship between lifecourse traumatic events and cognitive trajectories and predicted dementia incidence.Using data on 7,785 participants aged ≥65 years from the Health and Retirement Study, this study estimated the association between lifecourse experience of 10 traumatic events (e.g., losing a child) and trajectories of Telephone Interview for Cognitive Status from 2006 to 2016 using linear mixed-effects models and predicted incident dementia from 2006 to 2014 using cumulative incidence functions (data analysis was in 2020-2022). Inverse probability weights accounted for loss to follow-up and confounding by sex, education, race/ethnicity, and age.Experiencing 1 or more traumatic events over the lifecourse was associated with accelerated decline compared with experiencing no events (e.g., β= -0.05 [95% CI= -0.07, -0.02] Health and Retirement Study-Telephone Interview for Cognitive Status units/year; 1 vs 0 events). In contrast, experiencing traumatic events was associated with better cognitive function cross-sectionally. Furthermore, the impact of trauma on cognitive decline was of greater magnitude when it occurred after the age of 64 years. However, the magnitude and direction of association varied by the specific traumatic event. There were no associations with predicted incident dementia.These results suggest that researchers and clinicians should not aggregate traumatic events for understanding the risk of accelerated cognitive decline.

Chronic infections and the subsequent immune response have recently been shown to be risk factors for cognitive decline and Alzheimer disease and related dementias (ADRD). While some studies have shown an association between cytomegalovirus (CMV), a chronic and highly prevalent infection, and cognition and/or ADRD, these studies have been limited by nonrepresentative and small samples. Using 2016 data on 5,617 adults aged 65 years or more from the Health and Retirement Study, we investigated the cross-sectional associations of both CMV serostatus and immunoglobulin G (IgG) antibody response with cognitive function using linear regression models adjusting for age, sex, race/ethnicity, and educational attainment. We further investigated potential effect-measure modification by educational attainment. Overall, both CMV seropositivity and higher IgG antibody response were associated with lower cognitive function, though the relationship was not statistically significant in adjusted models. Among participants with less than a high school diploma, CMV seropositivity and being in the first tertile of IgG response, relative to seronegative persons, were associated with lower scores on the Telephone Interview for Cognitive Status (−0.56 points (95% confidence interval: −1.63, 0.52) and −0.89 points (95% confidence interval: −2.07, 0.29), respectively), and the relationship was attenuated among those with higher education. Our results suggest that CMV may be a risk factor for cognitive impairment, particularly among persons with fewer educational resources.

Objectives Previous research has documented a consistent association between current socioeconomic status (SES) and cytomegalovirus (CMV). Early life is likely a critical period for CMV exposure and immune development, but less is known about early-life socioeconomic factors and CMV, particularly in older age populations. Using data from the Health and Retirement Study, we investigated the association between life course socioeconomic disadvantage and immune response to CMV among older adults. Methods Using ordered logit models, we estimated associations between several measures of socioeconomic disadvantage and the odds of being in a higher CMV Immunoglobulin G (IgG) response category in a sample of 8,168 respondents aged older than 50 years. Results We found a significant association between educational attainment and CMV IgG response. Those with less than a high school education had 2.00 (95% confidence interval [CI]: 1.67–2.40) times the odds of being in a higher CMV category compared to those with a college degree or greater. In addition, we also observed a significant association with parental education and CMV response. Individuals with parents having 8 years or less of schooling had 2.32 (95% CI: 2.00–2.70) times the odds of higher CMV response compared to those whose parents had greater than high school education. Discussion CMV IgG levels in older adults are associated with both early-life and adult SES. Life course socioeconomic disadvantage may contribute to disparities in immunological aging.

BackgroundThere is growing body of literature on the long-term cardiac symptoms following COVID-19. We conducted a systematic review and meta-analysis to synthesize and evaluate related evidence to inform clinical management and future studies.MethodsWe searched two preprint and seven peer-reviewed article databases from January 1, 2020 to January 8, 2022 for studies investigating cardiac symptoms that persisted for at least 4 weeks among individuals who survived COVID-19. A customized Newcastle–Ottawa scale was used to evaluate the quality of included studies. Random-effects meta-analyses were performed to estimate the proportion of symptoms with 95% confidence intervals (CI), and stratified analyses were conducted to quantify the proportion of symptoms by study characteristics and quality.ResultsA total of 101 studies describing 49 unique long-term cardiac symptoms met the inclusion criteria. Based on quality assessment, only 15.8% of the studies (n=16) were of high quality, and most studies scored poorly on sampling representativeness. The two most examined symptoms were chest pain and arrhythmia. Meta-analysis showed that the proportion of chest pain was 10.1% (95% CI: 6.4-15.5) and arrhythmia was 9.8% (95% CI: 5.4-17.2). Stratified analyses showed that studies with low-quality score, small sample size, unsystematic sampling method, and cross-sectional design were most likely to report high proportions of symptoms. For example, the proportion of chest pain was 21.3% (95% CI: 10.5-38.5), 9.3% (95% CI: 6.0-14.0), and 4.0% (95% CI: 1.3-12.0) in studies with low, medium, and high-quality scores, respectively. Similar patterns were observed for other cardiac symptoms including hypertension, cardiac abnormalities, myocardial injury, thromboembolism, stroke, heart failure, coronary disease, and myocarditis.DiscussionThere is a wide spectrum of long-term cardiac symptoms following COVID-19. Findings of existing studies are strongly related to study quality, size and design, underscoring the need for high-quality epidemiologic studies to characterize these symptoms and understand their etiology.Research in contextEvidence before this studyAccumulating evidence shows long-term cardiac symptoms following COVID-19. However, no previous reviews systematically evaluated and synthesized findings from studies on long-term cardiac symptoms.Added value of this studyThis is the first systematic review and meta-analysis that focused on studies of long-term cardiac symptoms of COVID-19. We included 101 studies and identified 49 cardiac symptoms that are indicative of cardiac abnormalities. We scored their quality based on epidemiologic principles and identified domains of study design that need improvements. We quantified proportions of multiple long-term cardiac symptoms including chest pain, arrhythmia, and others. We also observed systematic differences in reported proportions of these symptoms by selected study characteristics, including total quality assessment score, sample size, sampling representativeness, and study design. High-quality studies identified here can provide important guidelines for future studies of long-term symptoms following COVID-19.Implications of all the available evidenceMultiple domains of study design, especially sampling representativeness, need to be improved in future studies on long-term cardiac symptoms following COVID-19. Notably, low-quality and smaller studies tend to report a larger proportion of symptoms, are more likely to be subject to greater sampling variation, and hence are less precise. These studies should be revisited with the emergence of large studies with rigriours study designs. This systematic review and meta-analysis highlight the scope of persistent cardiac symptoms among those who survived the acute phase of COVID-19, and the importance of synthesizing rigorous evidence to inform post-COVID surveillance and management plans.

Background Dysregulation of some metabolic factors increases the risk of dementia. It remains unclear if overall metabolic dysregulation, or only certain components, contribute to cognitive aging and if these associations are sex specific. Methods Data from the 2006–2016 waves of the Health and Retirement Study (HRS) was used to analyze 7 103 participants aged 65 and older at baseline (58% women). We created a metabolic-dysregulation risk score (MDRS) composed of blood pressure/hypertension status, glycosylated hemoglobin (HbA1c)/diabetes status, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and waist circumference, and assessed cognitive trajectories from repeated measures of the HRS-Telephone Interview for Cognitive Status (HRS-TICS) over 10 years of follow-up. Linear mixed-effects models estimated associations between MDRS or individual metabolic factors (biomarkers) with mean and change in HRS-TICS scores and assessed sex-modification of these associations. Results Participants with higher MDRSs had lower mean HRS-TICS scores, but there were no statistically significant differences in rate of decline. Sex stratification showed this association was present for women only. MDRS biomarkers revealed heterogeneity in the strength and direction of associations with HRS-TICS. Lower HRS-TICS levels were associated with hypertension, higher HbA1c/diabetes, and lower HDL-C and TC, whereas faster rate of cognitive decline was associated with hypertension, higher HbA1c/diabetes, and higher TC. Participants with higher HbA1c/diabetes presented worse cognitive trajectories. Sex differences indicated that women with higher HbA1c/diabetes to have lower HRS-TICS levels, whereas hypertensive males presented better cognitive trajectory. Conclusions Our results demonstrate that metabolic dysregulation is more strongly associated with cognition in women compared with men, though sex differences vary by individual biomarker.

BackgroundThe COVID-19 pandemic has highlighted the urgent need to understand variation in immunosenescence at the population-level. Thus far, population patterns of immunosenescence are not well described.MethodsWe characterized measures of immunosenescence from newly released venous blood data from the nationally representative U.S Health and Retirement Study (HRS) of individuals ages 56 years and older.FindingsMedian values of the CD8+:CD4+, EMRA:Naïve CD4+ and EMRA:Naïve CD8+ ratios were higher among older participants and were lower in those with additional educational attainment. Generally, minoritized race and ethnic groups had immune markers suggestive of a more aged immune profile: Hispanics had a CD8+:CD4+ median value of 0.37 (95% CI: 0.35, 0.39) compared to 0.30 in Whites (95% CI: 0.29, 0.31). Blacks had the highest median value of the EMRA:Naïve CD4+ ratio (0.08; 95% CI: 0.07, 0.09) compared to Whites (0.03; 95% CI: 0.028, 0.033). In regression analyses, race/ethnicity and education were associated with large differences in the immune ratio measures after adjustment for age and sex. For example, each additional level of education was associated with roughly an additional decade of immunological age, and the racial/ethnic differences were associated with two to four decades of additional immunological age.InterpretationOur study provides novel insights into population variation in immunosenescence. This has implications for both risk of age-related disease and vulnerability to novel pathogens (e.g., SARS-CoV-2).FundingThis study was partially funded by the U.S. National Institutes of Health, National Institute on Aging R00AG062749. AEA and GAN acknowledge support from the National Institutes of Health, National Institute on Aging R01AG075719. JBD acknowledges support from the Leverhulme Trust (Centre Grant) and the European Research Council grant ERC-2021-CoG-101002587Research in contextEvidence before this studyAlterations in immunity with chronological aging have been consistently demonstrated across human populations. Some of the hallmark changes in adaptive immunity associated with aging, termed immunosenescence, include a decrease in naïve T-cells, an increase in terminal effector memory cells, and an inverted CD8:CD4 T cell ratio. Several studies have shown that social and psychosocial exposures can alter aspects of immunity and lead to increased susceptibility to infectious diseases.Add value of this studyWhile chronological age is known to impact immunosenescence, there are no studies examining whether social and demographic factors independently impact immunosenescence. This is important because immunosenescence has been associated with greater susceptibility to disease and lower immune response to vaccination. Identifying social and demographic variability in immunosenescence could help inform risk and surveillance efforts for preventing disease in older age. To our knowledge, we present one of the first large-scale population-based investigations of the social and demographic patterns of immunosenescence among individuals ages 50 and older living in the US. We found differences in the measures of immunosenescence by age, sex, race/ethnicity, and education, though the magnitude of these differences varied across immune measures and sociodemographic subgroup. Those occupying more disadvantaged societal positions (i.e., minoritized race and ethnic groups and individuals with lower educational attainment) experience greater levels of immunosenescence compared to those in less disadvantaged positions. Of note, the magnitude of effect of sociodemographic factors was larger than chronological age for many of the associations.Implications for practice or policy and future researchThe COVID-19 pandemic has highlighted the need to better understand variation in adaptive and innate immunity at the population-level. While chronological age has traditionally been thought of as the primary driver of immunological aging, the magnitude of differences we observed by sociodemographic factors suggests an important role for the social environment in the aging human immune system.

Background Prior studies in humans have suggested that telomere shortening may be accelerated by infection, but research on multiple pathogens and use of large population-based study samples has been limited. We estimated cross-sectional associations between seropositivity to five persistent pathogens (Herpes Simplex Virus Type-1 (HSV-1), Herpes Simplex Virus Type-2 (HSV-2), cytomegalovirus (CMV), Helicobacter pylori (H.pylori), and Hepatitis B) as well as total pathogen burden and leukocyte telomere length. Data were derived from the National Health and Nutrition Examination Survey (1999–2000) for individuals 20–49 years of age, N = 1708. We analyzed the influence of each pathogen separately, a pathogen count score and a latent class model of pathogen burden on log telomere length using linear regression models, adjusted for covariates. Results Individuals in a latent pathogen burden class characterized by high probabilities of infection with HSV-1, CMV, and H. pylori, had significantly decreased log telomere length (− 0.30 [95% CI: − 0.36, − 0.24]) compared to those in a latent class characterized by low probabilities of all five infections. There were limited significant associations using other pathogen measures. Conclusions These results suggest that infection with specific combinations of pathogens may be one mechanism contributing to accelerated cellular senescence with possible origins early in the life course.

In 2013, the under-5 mortality rate in Liberia was 71 deaths per 1,000 live births, with malaria responsible for 22% of those deaths. One of the primary existing control tools, long-lasting insecticide-treated bed nets (LLINs), is thought to be dually effective, acting as a physical barrier but also decreasing the mosquito population in communities. However, there has been little investigation into the protective effects of community-wide bed net use above and beyond the individual level. Using data from the population-representative 2011 Liberia Malaria Indicator Survey, we estimated the association between proportion of a community using LLINs and malaria in children using multi-level logistic regression. To investigate the potential effect measure modification of the relationship by urbanicity, we included an interaction term and calculated stratum-specific prevalence odds ratios (PORs) for rural and urban communities. We calculated a POR of malaria for an absolute 10% increase in community bed net use of 1.13 (95% confidence interval [CI]: 0.91, 1.41) and 0.35 (95% CI: 0.13, 0.92) for rural and urban communities, respectively, indicating a strong, though imprecise, protective effect within urban communities only. Our results indicate that bed net use has an indirect protective effect in urban areas, above and beyond individual use. Little or no such effect of community-wide use is seen in rural areas, likely because of population density factors. Therefore, although all control efforts should be multifaceted, promotion of bed net use in urban areas in particular will likely be a highly effective tool for control.

Background The etiology of dementias and cognitive decline remain largely unknown. It is widely accepted that inflammation in the central nervous system plays a critical role in the pathogenesis of dementia. However, less is known about the role of the peripheral immune system and interactions with cortisol, though evidence suggests that these, too, may play a role. Methods Using data from 1337 participants aged 60+ years from the Sacramento Area Latino Study of Aging (observational cohort) we investigated variation in trajectories of cognitive decline by pathogen IgG and cytokine levels. Linear mixed effects models were used to examine the association between baseline Interleukin (IL)−6, C-reactive protein, tumor necrosis factor (TNF)- α , and five persistent pathogens’ IgG response and trajectories of cognition over 10 years, and to examine interactions between immune biomarkers and cortisol. Stratified cumulative incidence functions were used to assess the relation between biomarkers and incident dementia. Inverse probability weights accounted for loss-to-follow-up and confounding. Results IL-6, TNF- α , and CMV IgG were statistically significantly associated with a higher log of Modified Mini-Mental State Examination errors (IL-6, β = 0.0935 (95%CI: 0.055, 0.13), TNF-alpha β = 0.0944 (95%CI: 0.032, 0.157), and CMV, β = 0.0409 (95%CI: 0.013, 0.069)). Furthermore, cortisol interacted with HSV-1 and IL-6, and CRP for both cross-sectional cognitive function and rate of decline. No statistically significant relationship was detected between biomarkers and incidence of dementia. Conclusions These findings support the theory that the peripheral immune system may play a role in cognitive decline but not incident dementia. Furthermore, they identify specific markers amenable for intervention for slowing decline.

Background A substantial proportion of infants born with tetralogy of Fallot (TOF) die in infancy. A better understanding of the heterogeneity associated with TOF, including extracardiac malformations and chromosomal anomalies is vital to stratifying risk and optimizing outcomes during infancy. Methods Using the North Carolina Birth Defects Monitoring Program, infants diagnosed with TOF and born between 2003 and 2012 were included. Kaplan-Meier survival curves were used to estimate cumulative 1-year mortality, stratified by the presence of concomitant birth defects (BDs) and chromosomal anomalies. Multivariable logistic regression was used to estimate the direct effect of each concomitant BD, after adjusting for all others. Results A total of 496 infants with TOF were included, and 15% (n = 76) died. The number of concomitant BD systems was significantly associated with the risk of death at 1-year, p

Background Geographic variation in congenital heart disease is not well-described. This study uses geographic information systems (GIS) to describe the spatial epidemiology of tetralogy of Fallot (TOF), in North Carolina (NC) and to compare travel time for cases to congenital heart centers in NC. Methods Using the NC Birth Defects Monitoring Program database, live births with TOF born between 2003 and 2012 were identified. Birth certificates provided demographic variables. A denominator of live births/zip code was obtained from the NC live births database. ArcGIS® software was used to illustrate TOF prevalence by zip code, and SatScanTM was used to identify spatial clusters of TOF cases and to identify changes in cluster location over time. Driving time to each of five NC congenital heart centers was predicted based on road systems information. Results A total of 496 infants were born with TOF between 2003 and 2012. The prevalence was 4.2/10,000 live births. A large cluster (330 zip codes, 306 cases) was identified in northeastern NC. Average driving time for each case to closest congenital heart center was: University of North Carolina 37 min, Vident Medical Center 64 min, Duke University 58 min, Carolina's Medical Center 89 min, and Wake Forest Baptist Health 57 min. Overall, average predicted driving time to the nearest congenital heart center was 61 min. Conclusion Approximately 50 infants/year were born with TOF in NC. One cluster was identified. Further study is necessary to explore potential explanations for the observed case cluster. As interest in regionalization of congenital heart surgery grows, GIS and spatial analysis can become increasingly useful tools for health care planning. Birth Defects Research (Part A) 106:881-887, 2016. © 2016 Wiley Periodicals, Inc.

While approximately 5.2 million people over 65 years old in the U.S. suffer from Alzheimer’s Disease, the etiology of dementias and cognitive decline are still largely unknown. A growing body of literature suggests that highly prevalent persistent pathogens may be associated with faster decline and higher risk of dementia. One hypothesized mechanism for this relationship is that chronic inflammation induced by latent infections accelerates neurodegeneration. Using data of over 900 participants 60+ years old from the Sacramento Area Latino Study of Aging, we investigated variation in cognitive decline trajectories by infection status over 10 years of follow-up. Linear mixed effects models accounting for repeated outcome measurements were used to examine the association between baseline seropositivity to HSV-1, CMV, VZV, T. gondii, and H. pylori and 3MSE scores, and to examine interactions between seropositivity and cortisol. We found that seropositivity to CMV and H. pylori were significantly associated with cognitive decline (p=0.0002 and p=0.019, respectively). Among seropositive patients, we found associations between higher quartiles of IgG response and cognitive decline compared to the lowest quartile, indicating that intensity of immune response plays a role in observed decline. Furthermore, CMV and H. pylori interacted with baseline cortisol to affect the trajectory of cognitive decline (p=0.0016 and p=0.0014, respectively). These findings support the theory that persistent pathogens may be risk factors for neurodegeneration. Furthermore, they identify specific infection markers in that process, as well as interactions with hormonal pathways, and suggest novel points of intervention for slowing decline and reducing disparities.

A substantial proportion of infants born with tetralogy of Fallot (TOF) die in infancy. A better understanding of the heterogeneity associated with TOF, including extracardiac malformations and chromosomal anomalies is vital to stratifying risk and optimizing outcomes during infancy.Using the North Carolina Birth Defects Monitoring Program, infants diagnosed with TOF and born between 2003 and 2012 were included. Kaplan-Meier survival curves were used to estimate cumulative 1-year mortality, stratified by the presence of concomitant birth defects (BDs) and chromosomal anomalies. Multivariable logistic regression was used to estimate the direct effect of each concomitant BD, after adjusting for all others.A total of 496 infants with TOF were included, and 15% (n = 76) died. The number of concomitant BD systems was significantly associated with the risk of death at 1-year, p 0.0001. Specifically, the risk of mortality was 8% among infants with TOF with or without additional cardiac defects, 16% among infants with TOF and 1 extracardiac BD system, 19% among infants with 2 extracardiac BD systems, and 39% among infants with ≥ 3 extracardiac BD systems. After adjustment, concomitant eye and gastrointestinal defects were significantly associated increased with 1-year mortality, odds ratio 2.83 (95% confidence interval, 1.08-7.32) and odds ratio 4.43 (95% confidence interval, 1.57, 12.45), respectively. Infants with trisomy 13 or trisomy 18 were also significantly more likely to die, p 0.0001.Both concomitant BDs and genetic anomalies increase the risk of mortality among infants with TOF. Future studies are needed to identify the underlying genetic and socioeconomic risk factors for high-risk TOF infants. Birth Defects Research 109:1154-1165, 2017. © 2017 Wiley Periodicals, Inc.

The social patterning of cytomegalovirus (CMV) and its implication in aging suggest that the virus may partially contribute to socioeconomic disparities in mortality. We used Cox regression and inverse odds ratio weighting to quantify the proportion of the association between socioeconomic status (SES) and all-cause mortality that was attributable to mediation by CMV seropositivity. Data were from the National Health and Nutrition Examination Survey (NHANES) III (1988–1994), with mortality follow-up through December 2011. SES was assessed as household income (income-to-poverty ratio ≤1.30; >1.30 to ≤1.85; >1.85 to ≤3.50; >3.50) and education (high school). We found strong associations between low SES and increased mortality: hazard ratio (HR) 1.80; 95% confidence interval (CI): 1.57, 2.06 comparing the lowest versus highest income groups and HR 1.29; 95% CI: 1.13, 1.48 comparing high school education. 65% of individuals were CMV seropositive, accounting for 6–15% of the SES-mortality associations. Age modified the associations between SES, CMV, and mortality, with CMV more strongly associated with mortality in older individuals. Our findings suggest that cytomegalovirus may partially contribute to persistent socioeconomic disparities in mortality, particularly among older individuals.

Geographic variation in congenital heart disease is not well-described. This study uses geographic information systems (GIS) to describe the spatial epidemiology of tetralogy of Fallot (TOF), in North Carolina (NC) and to compare travel time for cases to congenital heart centers in NC.Using the NC Birth Defects Monitoring Program database, live births with TOF born between 2003 and 2012 were identified. Birth certificates provided demographic variables. A denominator of live births/zip code was obtained from the NC live births database. ArcGIS® software was used to illustrate TOF prevalence by zip code, and SatScanTM was used to identify spatial clusters of TOF cases and to identify changes in cluster location over time. Driving time to each of five NC congenital heart centers was predicted based on road systems information.A total of 496 infants were born with TOF between 2003 and 2012. The prevalence was 4.2/10,000 live births. A large cluster (330 zip codes, 306 cases) was identified in northeastern NC. Average driving time for each case to closest congenital heart center was: University of North Carolina 37 min, Vident Medical Center 64 min, Duke University 58 min, Carolina's Medical Center 89 min, and Wake Forest Baptist Health 57 min. Overall, average predicted driving time to the nearest congenital heart center was 61 min.Approximately 50 infants/year were born with TOF in NC. One cluster was identified. Further study is necessary to explore potential explanations for the observed case cluster. As interest in regionalization of congenital heart surgery grows, GIS and spatial analysis can become increasingly useful tools for health care planning. Birth Defects Research (Part A) 106:881-887, 2016. © 2016 Wiley Periodicals, Inc.

NAD(+) is both a co-enzyme for hydride transfer enzymes and a substrate of sirtuins and other NAD(+) consuming enzymes. NAD(+) biosynthesis is required for two different regimens that extend lifespan in yeast. NAD(+) is synthesized from tryptophan and the three vitamin precursors of NAD(+): nicotinic acid, nicotinamide and nicotinamide riboside. Supplementation of yeast cells with NAD(+) precursors increases intracellular NAD(+) levels and extends replicative lifespan. Here we show that both nicotinamide riboside and nicotinic acid are not only vitamins but are also exported metabolites. We found that the deletion of the nicotinamide riboside transporter, Nrt1, leads to increased export of nicotinamide riboside. This discovery was exploited to engineer a strain to produce high levels of extracellular nicotinamide riboside, which was recovered in purified form. We further demonstrate that extracellular nicotinamide is readily converted to extracellular nicotinic acid in a manner that requires intracellular nicotinamidase activity. Like nicotinamide riboside, export of nicotinic acid is elevated by the deletion of the nicotinic acid transporter, Tna1. The data indicate that NAD(+) metabolism has a critical extracellular element in the yeast system and suggest that cells regulate intracellular NAD(+) metabolism by balancing import and export of NAD(+) precursor vitamins.