Subclinical carotid artery atherosclerosis and cognitive function in older adults.

BACKGROUND: The combined effects of increased life expectancy and the considerable number of persons reaching old age will magnify the dementia epidemic in the USA. Demonstration that subclinical atherosclerosis precedes and is associated with cognitive impairment suggests a modifiable risk factor for age-associated cognitive impairment and dementia. The purpose of this study is to determine whether subclinical atherosclerosis as measured by carotid artery intima-media thickness (CIMT) is associated with changes in cognitive function over time in older adults. METHODS: This study combined longitudinal data from three clinical trials conducted between 2000 and 2013: the B-Vitamin Atherosclerosis Intervention Trial (BVAIT), the Women's Isoflavone Soy Health (WISH) trial, and the Early versus Late Intervention Trial with Estradiol (ELITE). Participants were recruited from the general population in the Greater Los Angeles area and were free of cardiovascular disease and diabetes; no cognitive or psychiatric exclusion criteria were specified. The same standardized protocol for ultrasound image acquisition and measurement of CIMT was used in all trials. CIMT measurements performed at baseline and 2.5 years were used in these analyses. Cognitive function was assessed at baseline and 2.5 years using a battery of 14 standardized cognitive tests. All clinical trials were conducted at the University of Southern California Atherosclerosis Research Unit, Los Angeles, and had at least 2.5 years of cognitive follow-up. RESULTS: A total of 308 men and 1187 women, mean age of 61 years, were included in the combined longitudinal dataset for the primary analysis. No associations were found between CIMT and cognitive function at baseline or at 2.5 years. There was a weak inverse association between CIMT measured at baseline and change in global cognition assessed over 2.5 years (ß (SE) = - 0.056 (0.028) units per 0.1 mm CIMT, 95% CI - 0.110, - 0.001, p = 0.046). No associations between CIMT at baseline and changes in executive function, verbal memory, or visual memory were found. CONCLUSIONS: In this sample of healthy older adults, our findings suggest an association between subclinical atherosclerosis and change in global cognitive function over 2.5 years. Stronger associations were observed longitudinally over 2.5 years than cross-sectionally. When analysis was stratified by age group (<65 and ≥65 years old), the inverse association remained statistically significant for participants in the older age group. Subclinical atherosclerosis of the carotid artery may be a modifiable correlate of cognitive decline in middle and older age. TRIAL REGISTRATION: BVAIT, NCT00114400 . WISH, NCT00118846 . ELITE, NCT00114517 .

Nattokinase atherothrombotic prevention study: A randomized controlled trial.

BACKGROUND: Described to be antithrombotic and antihypertensive, nattokinase is consumed for putative cardiovascular benefit. However, no large-scale, long-term cardiovascular study has been conducted with nattokinase supplementation. OBJECTIVE: To determine the effect of nattokinase on subclinical atherosclerosis progression and atherothrombotic biomarkers. METHODS: In this double-blinded trial, 265 individuals of median age 65.3 years, without clinical evidence of cardiovascular disease (CVD) were randomized to oral nattokinase 2,000 fibrinolytic units or matching placebo. Primary outcome was rate of change in subclinical atherosclerosis measured by serial carotid ultrasound every 6 months as carotid artery intima-media thickness (CIMT) and carotid arterial stiffness (CAS). Additional outcomes determined at least every 6 months were clinical parameters including blood pressure and laboratory measures including metabolic factors, blood rheology parameters, blood coagulation and fibrinolysis factors, inflammatory markers and monocyte/macrophage cellular activation markers. RESULTS: After median 3 years of randomized treatment, annualized rate of change in CIMT and CAS did not significantly differ between nattokinase supplementation and placebo. Additionally, there was no significant effect of nattokinase supplementation on blood pressure or any laboratory determination. CONCLUSIONS: Results of this trial show that nattokinase supplementation has a null effect on subclinical atherosclerosis progression in healthy individuals at low risk for CVD.

Apolipoprotein E4 genotype in combination with poor metabolic profile is associated with reduced cognitive performance in healthy postmenopausal women: implications for late onset Alzheimer's disease.

OBJECTIVE: We hypothesized the association of metabolic profile on cognition in postmenopausal women will be greater among ApoE4 carriers compared with noncarriers. METHODS: Metabolic biomarkers and measures of global cognition, executive functions, and verbal memory, collected among postmenopausal females, were used in this analysis. Clustering analyses of metabolic biomarkers revealed three phenotypes: healthy, predominantly hypertensive, and poor metabolic with (borderline normal laboratory values). General linear models tested whether an association of metabolic cluster with cognition differed by ApoE4 genotype. RESULTS: In the total sample of 497 women, verbal memory was lower in the poor metabolic cluster (P = 0.04). Among ApoE4+ women, performance in all cognitive domains was lowest in the poor metabolic cluster. Differences in executive functions among metabolic clusters were detected only in ApoE4+ women (P value for interaction = 0.003). CONCLUSIONS: In a general population of postmenopausal women, association between poor metabolic profile with reduction in cognitive performance is more apparent in women who carry an ApoE4 allele. These data indicate a window of opportunity for interventions to reverse the trajectory of the preclinical phase of Alzheimer's disease.

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 17ß-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.

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 Alzheimer's 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 Alzheimer's disease.

Associations between urine excretion of isoflavonoids and cognition in postmenopausal women in the Women's Isoflavone Soy Health clinical trial.

OBJECTIVES: To determine effect of change in urine excretion of isoflavonoids on cognitive change. DESIGN: Post hoc analysis of isoflavonoid exposure (mean 2.7 years) during the randomized, placebo-controlled, double-blind Women's Isoflavone Soy Health trial. SETTING: General community. PARTICIPANTS: Healthy postmenopausal women (N = 350). INTERVENTION: Twenty-five grams of isoflavone-rich soy protein (91 mg of aglycone weight isoflavones: 52 mg genistein, 36 mg daidzein, 3 mg glycitein) or milk protein-matched placebo provided daily. MEASUREMENTS: Overnight urine excretion, fasting plasma levels of isoflavonoids, and cognitive function measured at baseline and endpoint. RESULTS: Three hundred women (age: mean 61, range 45-92) completed both cognitive assessments and did not use hormone replacement therapy during the trial. Mean on-trial change from baseline in urine excretion of isoflavonoids was not significantly associated with change in a composite score of global cognition (P = .39). Secondary analyses indicated that change in urine excretion of isoflavonoids was inversely associated with change in a factor score representing general intelligence (P = .02) but not with factor scores representing verbal or visual episodic memory. Mean differences in this general intelligence factor score between women in the lowest and highest quartiles of isoflavonoid change were equivalent to an approximate 4.4-year age-associated decline. Analyses based on plasma isoflavonoid levels yielded similar but attenuated results. CONCLUSION: In healthy postmenopausal women, long-term changes in isoflavonoids are not associated with global cognition, supporting clinical trial results, although greater isoflavonoid exposure from dietary supplements is associated with decrements in general intelligence but not memory; this finding requires confirmation in future studies.

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 (ß=-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.

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

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.

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.

OBJECTIVE: 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. METHODS: We examined cross-sectional associations between subclinical atherosclerosis and cognitive function in a community-based sample of otherwise healthy adults with plasma homocysteine >or=8.5 micromol/L enrolled in the BVAIT study (n = 504, mean age 61 years). Carotid artery intima-media thickness (CIMT), coronary artery calcium (CAC) and abdominal aortic calcium (AAC) were used to measure subclinical atherosclerosis. Cognitive function was assessed with a battery of neuropsychological tests. A principal components analysis was used to extract five uncorrelated cognitive factors from scores on individual tests, and a measure of global cognition was derived. Multivariable linear regression was used to examine the association between subclinical atherosclerosis and cognitive function, adjusting for other correlates of cognition. RESULTS: Increasing thickness of CIMT was associated with significantly lower scores on the verbal learning factor (beta = -0.07 per 0.1 mm increase CIMT [SE(beta) = 0.03], p = 0.01). CAC and AAC were not individually associated with any of the cognitive factors. CONCLUSIONS: This study provides evidence that increasing CIMT is weakly associated with lower verbal learning abilities but not global cognition in a population of otherwise healthy middle-to-older aged adults with elevated plasma homocysteine levels but without clinically evident CVD. The association between CIMT and poor verbal learning may pertain particularly to men.

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

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 (beta = -.14 [SE(beta) = 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 (beta = -.17 [SE(beta) = 0.08], p = .04), semantic memory (beta = -.26 [SE(beta) = 0.08], p = .001) and global cognition (beta = -.15 [SE(beta) = 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.

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.