Jan A. St. John

Components of air pollution and cognitive function in middle-aged and older adults in Los Angeles

While experiments in animals demonstrate neurotoxic effects of particulate matter (PM) and ozone (O3), epidemiologic evidence is sparse regarding the relationship between different constituencies of air pollution mixtures and cognitive function in adults. We examined cross-sectional associations between various ambient air pollutants [O3, PM2.5 and nitrogen dioxide (NO2)] and six measures of cognitive function and global cognition among healthy, cognitively intact individuals (n=1496, mean age 60.5 years) residing in the Los Angeles Basin. Air pollution exposures were assigned to each residential address in 2000-06 using a geographic information system that included monitoring data. A neuropsychological battery was used to assess cognitive function; a principal components analysis defined six domain-specific functions and a measure of global cognitive function was created. Regression models estimated effects of air pollutants on cognitive function, adjusting for age, gender, race, education, income, study and mood. Increasing exposure to PM2.5 was associated with lower verbal learning (β=-0.32 per 10 μg/m(3) PM2.5, 95% CI=-0.63, 0.00; p=0.05). Ambient exposure to NO2 >20 ppb tended to be associated with lower logical memory. Compared to the lowest level of exposure to ambient O3, exposure above 49 ppb was associated with lower executive function. Including carotid artery intima-media thickness, a measure of subclinical atherosclerosis, in models as a possible mediator did not attenuate effect estimates. This study provides support for cross-sectional associations between increasing levels of ambient O3, PM2.5 and NO2 and measures of domain-specific cognitive abilities.

Metabolic syndrome and cognitive function in healthy middle-aged and older adults without diabetes.

ABSTRACT Objective: Few studies have addressed whether the metabolic syndrome (MetS) and its individual components are associated with cognitive function in middle-aged and older populations, as well as whether specific areas of cognition are more affected than others. We examined the cross-sectional association between MetS and six areas of cognitive function in healthy cognitively intact adults without diabetes (n = 853, mean age 61 years) randomized in two intervention trials. Methods: The National Cholesterol Education Program (NCEP) criteria were used to identify subjects with MetS. Cognitive function was assessed with a neuropsychological battery. A principal components analysis was used to extract five uncorrelated factors interpreted to represent five areas of cognition, and a measure of global cognition was calculated. Results: MetS was weakly but non-significantly associated with lower verbal learning (β = −.14 [SE(β) = 0.09], p = .15). As the number of MetS criteria increased, scores on global cognition (p trend = .01), verbal learning (p trend = .06) and semantic memory (p trend = .04) decreased. Hypertension was the only MetS risk factor that was independently correlated with lower verbal learning (β = −.17 [SE(β)  = 0.08], p = .04), semantic memory (β = −.26 [SE(β) = 0.08], p = .001) and global cognition (β = −.15 [SE(β) = 0.07], p = .04). Conclusion: This study adds to the evidence of an association between MetS and lower cognitive function among healthy middle-aged and older adults without CVD and diabetes, as well as confirms the correlation between hypertension and lower cognition.

Cognitive effects of estradiol after menopause A randomized trial of the timing hypothesis

Objective: To test the hypothesis that effects of estrogen-containing hormone therapy on cognitive abilities differ between postmenopausal women near to, and further from, menopause. Methods: In this randomized, double-blind, placebo-controlled trial, healthy women within 6 years of menopause or 10+ years after menopause were randomly assigned to oral 17β-estradiol 1 mg/d or placebo. Women with a uterus received cyclic micronized progesterone vaginal gel or placebo. The primary outcome assessed at 2.5 and 5 years, compared between treatment groups, was change in a standardized composite of neuropsychological test scores assessing verbal episodic memory. Secondary outcomes assessed executive functions and global cognition. Results: A total of 567 women were included in modified intention-to-treat analyses after a mean treatment duration of 57 months. For verbal memory, the mean estradiol minus placebo standardized difference in composite scores (−0.06, 95% confidence interval −0.22 to 0.09) was not significant (2-tailed p = 0.33). Differences were similar in early and late postmenopause groups (2-tailed interaction p = 0.88). Interactions between postmenopause groups and differences between treatment groups were not significant for executive functions or global cognition. Conclusions: Estradiol initiated within 6 years of menopause does not affect verbal memory, executive functions, or global cognition differently than therapy begun 10+ years after menopause. Estradiol neither benefits nor harms these cognitive abilities regardless of time since menopause. Classification of evidence: This study provides Class I evidence that estradiol initiated within 6 years of menopause does not affect cognition at 2.5 years differently than estradiol initiated 10+ years after menopause.

Cognition, mood, and physiological concentrations of sex hormones in the early and late postmenopause

Significance Hormone variations after menopause may influence brain processes concerned with cognition and mood. Effects may differ for exposures near menopause compared with much later. We addressed this prediction using serum concentrations of endogenous estradiol, estrone, progesterone, and testosterone in 643 healthy women not using hormone therapy (early group, <6 y after menopause; late group, 10+ y). In combined analyses, hormone levels were unrelated to verbal memory, executive functions, global cognition, or mood. For serum estradiol (our primary focus), the relation did not differ between postmenopause groups. In early group women, progesterone levels were associated with better memory and global cognition; this finding merits additional study. Results help clarify cognitive effects of physiological concentrations of sex steroids after menopause. Variations in the hormonal milieu after menopause may influence neural processes concerned with cognition, cognitive aging, and mood, but findings are inconsistent. In particular, cognitive effects of estradiol may vary with time since menopause, but this prediction has not been assessed directly using serum hormone concentrations. We studied 643 healthy postmenopausal women not using hormone therapy who were recruited into early (<6 y after menopause) and late (10+ y after menopause) groups. Women were administered a comprehensive neuropsychological battery and assessed with the Center for Epidemiologic Studies Depression Scale. They provided serum for free estradiol, estrone, progesterone, free testosterone, and sex hormone binding globulin measurements. Cognitive outcomes were standardized composite measures of verbal episodic memory, executive functions, and global cognition. Covariate-adjusted linear regression analyses were conducted for each hormone separately and after adjustment for other hormone levels. Endogenous sex steroid levels were unassociated with cognitive composites, but sex hormone binding globulin was positively associated with verbal memory. Results for early and late groups did not differ significantly, although progesterone concentrations were significantly positively associated with verbal memory and global cognition in early group women. Hormone concentrations were not significantly related to mood. Results fail to support the hypothesis that temporal proximity to menopause modifies the relation between endogenous serum levels of estradiol and verbal memory, executive functions, or global cognition. Physiological variations in endogenous postmenopausal levels of sex steroid hormones are not substantially related to these aspects of cognition or mood; positive associations for progesterone and sex hormone binding globulin merit additional study.

Inflammatory Markers and Progression of Subclinical Atherosclerosis in Healthy Postmenopausal Women (from the Estrogen in the Prevention of Atherosclerosis Trial)

The objective of this study was to determine whether high-sensitivity C-reactive protein (hs-CRP) and serum soluble intercellular adhesion molecule-1 (sICAM-1) correlate with progression of subclinical atherosclerosis. Secondarily, the long-term effect of oral estradiol on hs-CRP and sICAM-1 were determined. Data were analyzed from 180 healthy postmenopausal women aged 45 to 80 years randomly assigned to either unopposed micronized 17beta-estradiol 1 mg/day or placebo in the Estrogen in the Prevention of Atherosclerosis Trial (EPAT). Carotid artery intima-media thickness (CIMT), hs-CRP, and sICAM-1 were measured at baseline and every 6 months thereafter for 2 years. Unopposed 17beta-estradiol significantly increased hs-CRP (p = 0.01) and decreased sICAM-1 compared with placebo (p = 0.04). Changes in hs-CRP and sICAM-1 did not correlate with changes in carotid artery intima-media thickness. In conclusion, although unopposed 17beta-estradiol significantly altered hs-CRP and sICAM-1, neither marker was associated with progression of subclinical atherosclerosis.

Mildly Elevated TSH and Cognition in Middle-Aged and Older Adults

BACKGROUND It is accepted that markedly elevated thyroid-stimulating hormone (TSH) levels are associated with impaired cognitive function. However, the findings regarding the association between mildly elevated TSH levels and cognition are equivocal. The objective of this study was to assess the relation between TSH levels in the normal to mildly elevated range (0.3-10.0 mIU/L) and several domains of cognitive function. METHODS A healthy, community-based sample of 489 men and women (40-88 years old, mean = 60.5 years) enrolled in the B-Vitamin Atherosclerosis Intervention Trial were studied. A neuropsychological test battery was used to assess a broad array of cognitive functions. Four uncorrelated neuropsychological factors were extracted by principal component analysis. Using multivariable linear regression, performance on each factor was examined in relation to TSH levels, controlling for age, gender, race-ethnicity, education, homocysteine levels, low-density lipoprotein cholesterol levels, and smoking status. RESULTS TSH levels were not associated with any of the four factor scores in the total sample or in younger (age < 60) or older (age >or= 60) subjects, although there was a trend for older subjects with higher levels of TSH to do more poorly on paragraph recall (p = 0.06). Gender-stratified analyses showed that TSH was positively associated with scores on word list learning for females only (p = 0.003). CONCLUSIONS In this community-based sample of middle-aged to older individuals, increasing TSH levels were not associated with significantly reduced cognitive performance in any domain. Further exploration of the effects of gender on the association between TSH and cognition is warranted.

Subclinical atherosclerosis is weakly associated with lower cognitive function in healthy hyperhomocysteinemic adults without clinical cardiovascular disease.

Atherosclerosis is the most common pathologic process underlying cardiovascular disease (CVD). It is not well known whether subclinical atherosclerosis is an independent risk factor for lower cognitive function among individuals without clinically evident CVD.

Associations Between Urine Excretion of Isoflavonoids and Cognition in Postmenopausal Women in the Women's Isoflavone Soy Health Clinical Trial

To determine effect of change in urine excretion of isoflavonoids on cognitive change.

Identifying postmenopausal women at risk for cognitive decline within a healthy cohort using a panel of clinical metabolic indicators: potential for detecting an at-Alzheimer's risk metabolic phenotype

Detecting at-risk individuals within a healthy population is critical for preventing or delaying Alzheimers disease. Systems biology integration of brain and body metabolism enables peripheral metabolic biomarkers to serve as reporters of brain bioenergetic status. Using clinical metabolic data derived from healthy postmenopausal women in the Early versus Late Intervention Trial with Estradiol (ELITE), we conducted principal components and k-means clustering analyses of 9 biomarkers to define metabolic phenotypes. Metabolic clusters were correlated with cognitive performance and analyzed for change over 5 years. Metabolic biomarkers at baseline generated 3 clusters, representing women with healthy, high blood pressure, and poor metabolic phenotypes. Compared with healthy women, poor metabolic women had significantly lower executive, global and memory cognitive performance. Hormone therapy provided metabolic benefit to women in high blood pressure and poor metabolic phenotypes. This panel of well-established clinical peripheral biomarkers represents an initial step toward developing an affordable, rapidly deployable, and clinically relevant strategy to detect an at-risk phenotype of late-onset Alzheimers disease.

Effect of Reproductive History and Exogenous Hormone Use on Cognitive Function in Mid- and Late Life.

To investigate the association between reproductive history indicators of hormonal exposure, including reproductive period, pregnancy, and use of hormonal contraceptives, and mid‐ and late‐life cognition in postmenopausal women.