Anemia, hemoglobin concentration and cognitive function in the Longitudinal Ageing Study in India-Harmonized Diagnostic Assessment of Dementia (LASI-DAD) and the Health and Retirement Study.

Background: In India, anemia is widely researched in children and women of reproductive age, however, studies in older populations are lacking. Given the adverse effect of anemia on cognitive function and dementia this older population group warrants further study. The Longitudinal Ageing Study in India - Harmonized Diagnostic Assessment of Dementia (LASI-DAD) dataset contains detailed measures to allow a better understanding of anaemia as a potential risk factor for dementia. Method: 2,758 respondents from the LASI-DAD cohort, aged 60 or older, had a complete blood count measured from venous blood as well as cognitive function tests including episodic memory, executive function and verbal fluency. Linear regression was used to test the associations between blood measures (including anemia and hemoglobin concentration (g/dL)) with 11 cognitive domains. All models were adjusted for age and gender with the full model containing adjustments for rural location, years of education, smoking, region, BMI and population weights.Results from LASI-DAD were validated using the USA-based Health and Retirement Study (HRS) cohort (n=5720) to replicate associations between blood cell measures and global cognition. Results: In LASI-DAD, we showed an association between anemia and poor memory (p=0.0054). We found a positive association between hemoglobin concentration and ten cognitive domains tested (ß=0.041-0.071, p<0.05). The strongest association with hemoglobin was identified for memory-based tests (immediate episodic, delayed episodic and broad domain memory, ß=0.061-0.071, p<0.005). Positive associations were also shown between the general cognitive score and the other red blood count tests including mean corpuscular hemoglobin concentration (MCHC, ß=0.06, p=0.0001) and red cell distribution width (RDW, ß =-0.11, p<0.0001). In the HRS cohort, positive associations were replicated between general cognitive score and other blood count tests (Red Blood Cell, MCHC and RDW, p<0.05). Conclusion: We have established in a large South Asian population that low hemoglobin and anaemia are associated with low cognitive function, therefore indicating that anaemia could be an important modifiable risk factor. We have validated this result in an external cohort demonstrating both the variability of this risk factor cross-nationally and its generalizable association with cognitive outcomes.

Links Between Mortality and Socioeconomic Characteristics, Disease Burden, and Biological and Physical Functioning in the Aging Chinese Population.

OBJECTIVES: Determinants of mortality may depend on the time and place where they are examined. China provides an important context in which to study the determinants of mortality at older ages because of its unique social, economic, and epidemiological circumstances. This study uses a nationally representative sample of persons in China to determine how socioeconomic characteristics, early-life conditions, biological and physical functioning, and disease burden predict 4-year mortality after age 60. METHODS: We used data from the China Health and Retirement Longitudinal Study. We employed a series of Cox proportional hazard models based on exact survival time to predict 4-year all-cause mortality between the 2011 baseline interview and the 2015 interview. RESULTS: We found that rural residence, poor physical functioning ability, uncontrolled hypertension, diabetes, cancer, a high level of systemic inflammation, and poor kidney functioning are strong predictors of mortality among older Chinese. DISCUSSION: The results show that the objectively measured indicators of physical functioning and biomarkers are independent and strong predictors of mortality risk after accounting for several additional self-reported health measures, confirming the value of incorporating biological and performance measurements in population health surveys to help understand health changes and aging processes that lead to mortality. This study also highlights the importance of social and historical context in the study of old-age mortality.

Ascertaining cause of mortality among middle-aged and older persons using computer-coded and expert review verbal autopsies in the China Health and Retirement Longitudinal Study.

BACKGROUND: Verbal autopsy is designed to ascertain causes of death that are not registered or certified. Verbal autopsy has been validated in multiple settings but has not been as widely evaluated for older populations as for younger age groups. OBJECTIVE: This study aims to provide empirical evidence of the value of verbal autopsy interviews in the context of population-based surveys of older adults by comparing the cause-of-death assignments derived from two methods of interpreting verbal autopsy data. METHODS: Data used in this study come from the China Health and Retirement Longitudinal Study, a nationally representative longitudinal survey of older Chinese. We compared 407 causes of death determined using InterVA, which is a computer-coded method, and causes of death as assigned by experts; then evaluated factors that affect the results of the two approaches. RESULTS: Among the 407 deaths, neoplasms, cardiac disease, and stroke are the leading causes of death according to both approaches. The consistency of the two approaches is about 45% at the individual level. The primary reason for the mismatch is that no cause of death could be assigned for more than 25% of the sample based on expert review. A higher likelihood of mismatch is associated with advanced age and a long period between death and verbal autopsy interview. CONCLUSION: Both approaches identify the same leading causes of death at the aggregate level, but consistency is relatively low at the individual level. InterVA works well when causes of death are characterized by distinctive signs and symptoms. Grouping the various causes of death with shared etiology or common risk factors may help improve the quality of the ascertainment of causes of death. Open-ended narratives are helpful because they provide information about the circumstances surrounding the death that are not available in the structured verbal autopsy interviews.

Characterization of pertussis toxoid by two-dimensional liquid chromatography-tandem mass spectrometry.

Pertussis toxoid, an acellular pertussis vaccine prepared by hydrogen peroxide treatment in the presence of Fe(3+), has not been well characterized. Because the toxoid has been a part of the DTaP vaccine for infants, it is of interest and significance to have a clear understanding of its structure. The five subunits of pertussis toxin (PT) have a combined molecular weight of approximately 95,000Da. The peroxide treatment in toxoid formation introduces additional complexity into the protein sequence. To maximize sequence coverage, a two-dimensional liquid chromatography-tandem mass spectrometry (2D LC-MS/MS) approach was used to analyze the tryptic digest of toxoid as a whole. An analytical-scale high-performance liquid chromatography (HPLC) instrument using a pentafluorophenyl (PFP) column was used as the first-dimensional LC for fraction collection. The fractions were then analyzed by nanoLC-MS/MS using a C18 column to acquire collision-activated dissociation (CAD) spectra of the tryptic peptides. It is shown that a PFP column has a different peptide retention specificity from a C18 column. A combination of a PFP column and a C18 column is a viable approach for dispersing peptides in a complex mixture. From the structures of 65 peptides that represented approximately 50% of its sequence, PT was found to have sustained heavy oxidative damages during toxoid preparation. Nearly all methionine, cysteine, and (likely) tryptophan residues were oxidized. Evidence of histidine and tyrosine oxidation was also observed. In addition, a large percentage of asparagine was found hydrolyzed to aspartic acid. These findings corrrelate well with the reduction of PT toxicity by peroxide treatment.

Alcohol, tobacco, and nonmedical drug use in older U.S. Adults: data from the 2001/02 national epidemiologic survey of alcohol and related conditions.

OBJECTIVES: To examine the prevalence and sociodemographic and health-related correlates of substance use, including alcohol, tobacco, and nonmedical drug use, in adults aged 65 and older. DESIGN: Cross-sectional, retrospective survey of a population-based sample, the 2001/02 National Epidemiologic Survey on Alcohol and Related Conditions. SETTING: United States. PARTICIPANTS: Eight thousand two hundred five U.S. adults aged 65 and older. MEASUREMENTS: Prevalence of lifetime and previous-12-month alcohol, tobacco, and nonmedical drug use and associations between substance use and sociodemographic and health-related factors. RESULTS: Almost 80% of older adults had used any of the three substances over their lifetimes, and more than 50% reported such use over the previous 12 months. Alcohol was the most commonly used substance over the lifetime (74%) and in the previous 12 months (45%), followed by tobacco (52% lifetime; 14% previous 12 months); far fewer reported nonmedical use of drugs (5% lifetime; 1% previous 12 months). In general, being younger, male, and divorced or separated were factors consistently associated with use of any of the three substances. CONCLUSION: Most older adults had used substances over their lifetimes and in the previous 12 months. Alcohol is the substance of choice for this age group, followed by tobacco; few report nonmedical drug use.

Inflammation and rate of cognitive change in high-functioning older adults.

BACKGROUND: Inflammatory proteins including interleukin-6 (IL-6) and C-reactive protein (CRP) have been associated with incident cognitive impairment, but little research has addressed their effects on the rate of cognitive change, and findings are mixed. The purpose of this study was to examine the relationship between serum levels of IL-6 and CRP and the rate of cognitive change across a range of cognitive domains in a sample of healthy older persons. METHODS: Growth curve analysis was performed on data from the MacArthur Study of Successful Aging, a longitudinal cohort study of high-functioning older adults aged 70-79 years at baseline in 1988 and reinterviewed in 1991 and 1995 (N = 851). Individual growth curve parameters were derived from baseline and follow-up performance in abstraction, language, spatial ability, verbal recall, spatial recognition, and global cognitive function based on age, IL-6, CRP, and covariates. RESULTS: Cross-sectionally, there is a generally linear negative relationship between inflammation and cognition, such that higher levels of inflammation are associated with lower levels of baseline cognitive function. After controlling for potential confounders, there was no effect of inflammation on baseline cognitive function or the rate of longitudinal cognitive change. However, persons in the top tertile on IL-6 were at an increased risk of incident declines on the Short Portable Mental Status Questionnaire (SPMSQ). CONCLUSIONS: Although high levels of inflammation are associated with incident cognitive impairment, these results do not generalize to the full range of cognitive changes, where the role of inflammation appears to be marginal.

Relation of oxytocin to psychological stress responses and hypothalamic-pituitary-adrenocortical axis activity in older women.

OBJECTIVE: Animal research suggests that oxytocin (OT) plays a role in stress responses and that in females, this role is modulated by estrogen. Yet little is known about the relation of OT to human stress responses. This study was conducted to examine the relations between estrogen activity and OT, identify stressors distinctively associated with elevations in OT, and investigate whether OT is related to cardiovascular and hypothalamic-pituitary-adrenocortical (HPA) activity in a laboratory challenge paradigm. METHODS: Seventy-three postmenopausal women who were on hormone therapy (HT) or not completed questionnaires assessing psychological distress and social relationships and then participated in a laboratory stress challenge (Trier Social Stress Task), during which OT, cortisol, and blood pressure were assessed. RESULTS: HT was significantly associated with higher plasma OT. Controlling for HT, elevated plasma OT was significantly associated with gaps in social relationships, with less positive relationships with a primary partner, and with elevated cortisol levels. OT was not associated with stress reactivity or recovery. CONCLUSION: In women, plasma OT signals relationship stress and is associated with elevated cortisol; it does not appear to significantly affect cortisol or blood pressure responses to acute stress.

Progestins affect mechanism of estrogen-induced C-reactive protein stimulation.

PURPOSE: To determine whether the mechanisms of C-reactive protein production differ depending on the presence or absence of a progestin in the regimen. SUBJECTS AND METHODS: We examined data from the Postmenopausal Estrogen Progestin Intervention (PEPI) study, a 5-group (3 different combined estrogen-progestin regimens, conjugated equine estrogen-only, and placebo) randomized clinical trial. This substudy included 221 postmenopausal women assigned to active treatment groups who took at least 80% of pills and had stored plasma specimens available to assess 12-month changes in estrone, sex hormone binding globulin, interleukin (IL)-6, and C-reactive protein levels. RESULTS: All treatments resulted in increases in estrone, sex hormone binding globulin, and C-reactive protein at 12 months compared with baseline values. In all progestin-containing groups, 12-month change in IL-6 was positively correlated with 12-month change in C-reactive protein (r between 0.34 and 0.65, each P <.010). By contrast, in the conjugated equine estrogen-only group, 12-month change in IL-6 was negatively correlated with 12-month change in C-reactive protein (r value -0.31, P = .055). In adjusted models predicting 12-month C-reactive protein change, an interaction between change in IL-6 and treatment group was highly significant (P=.0008-P <.0001) for each of the progestin-containing groups compared with the conjugated equine estrogen-only group. In the conjugated equine estrogen-only group, the change in C-reactive protein per unit increase in IL-6 was -0.88, whereas in the progestin-containing groups it ranged from 1.46 to 2.85 (P <.0001 for each comparison with conjugated equine estrogen-only). CONCLUSION: Progestins in combination with conjugated equine estrogen potentiate the IL-6 (inflammatory)-mediated stimulation of C-reactive protein. These findings support the hypothesis that progestins plus estrogen, not estrogen alone, generate C-reactive protein through an inflammatory mechanism.

The effects of hormone therapy on the markers of inflammation and endothelial function and plasma matrix metalloproteinase-9 level in postmenopausal women: the postmenopausal estrogen progestin intervention (PEPI) trial.

OBJECTIVE: The objective of this study was to determine whether oral conjugated equine estrogen (CEE) alone or with one of the three progestin regimens causes changes in biomarkers predictive of adverse cardiovascular events: C-reactive protein (CRP), interleukin-6 (IL-6), intercellular adhesion molecule (ICAM) and matrix metalloproteinase-9 (MMP-9). METHODS AND RESULTS: The analysis included 271 postmenopausal women from the postmenopausal estrogen progestin intervention (PEPI) trial. Plasma levels of biomarkers were measured on frozen samples obtained at baseline, 1- and 3-year follow-up visits. Multivariable linear mixed effects models were used to estimate changes in CRP, IL-6, ICAM and MMP-9 levels from baseline to follow-up visits by treatment groups. Women assigned to CEE only or CEE plus a progestin had 121 and 150% 1-year increase in CRP levels, respectively. In contrast, these treatments caused no significant change in IL-6 levels. Women assigned to CEE with or without a progestin had a 6-8% decline in ICAM and a 26-33% decline in MMP-9. CONCLUSIONS: The linkage between CEE alone or with a progestin and increased cardiovascular events may be associated with a rise in CRP level, but not through the mechanisms of IL-6-mediated inflammation, endothelial dysfunction or increased MMP activity.

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.

BACKGROUND: It remains unclear to what extent the associations between low serum beta-carotene concentration and increased risk for cardiovascular disease and cancers are attributable to inflammation. The objective of this study was to evaluate simultaneously the effects of serum beta-carotene concentration and inflammation on the subsequent all-cause mortality risk in high-functioning older persons. METHODS: The authors conducted a prospective cohort study using information from 672 participants from the MacArthur Studies of Successful Aging. Baseline information was obtained for serum concentrations of beta-carotene, C-reactive protein, interleukin-6, cholesterols, and albumin; body mass index; waist:hip ratio; prevalent medical conditions; health behaviors; and medications. Sex-specific univariate and multivariate logistic regression analyses were used to study the effects of low beta-carotene, high inflammation burden, or both on 7-year all-cause mortality rates while adjusting for other confounders. RESULTS: The serum beta-carotene concentration was inversely associated with C-reactive protein and interleukin-6 levels. After adjustment for inflammation markers and other covariates, the relative risks for low beta-carotene for the 7-year all-cause mortality risk were 2.30 (95% confidence interval [CI], 1.23 to 4.31) in men and 0.85 (95% CI, 0.42 to 1.75) in women. Compared with men with high beta-carotene levels and low inflammation, the multiply adjusted relative risk for low beta-carotene and high inflammation burden was 3.78 (95% CI, 1.69 to 8.47) in men. CONCLUSIONS: Low levels of serum beta-carotene are independently associated with an increased all-cause mortality risk in older men, even after adjustment for the effects of inflammation and other risk factors. In men, but not women, a synergistic effect occurs between low beta-carotene concentration and high inflammation burden in predicting higher mortality rates.