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The KEEPS-Cognitive and Affective Study: baseline associations between vascular risk factors and cognition.

ABSTRACT: Midlife vascular risk factors influence later cognitive decline and Alzheimer's disease (AD). The decrease in serum estradiol levels during menopause has been associated with cognitive impairment and increased vascular risk, such as high blood pressure (BP), which independently contributes to cognitive dysfunction and AD. We describe the extent to which vascular risk factors relate to cognition in healthy, middle-aged, recently postmenopausal women enrolled in the Kronos Early Estrogen Prevention Cognitive and Affective Study (KEEPS-Cog) at baseline. KEEPS-Cog is a double-blind, randomized, placebo-controlled, parallel group, clinical trial, investigating the efficacy of low-dose, transdermal 17?-estradiol and oral conjugated equine estrogen on cognition. All results are cross-sectional and represent baseline data only. Analyses confirm that the KEEPS-Cog cohort (n = 571) was middle aged (mean 52.7 years, range 42-59 years), healthy, and free of cognitive dysfunction. Higher systolic BP was weakly related to poorer performance in auditory working memory and attention (p = 0.004; adjusted for multiple comparisons p = 0.10). This relationship was not associated with endogenous hormone levels, and systolic BP was not related to any other cognitive domain. BP levels may be more sensitive than other vascular risk factors in detecting subtle differences in cognitive task performance in healthy, recently menopausal women. Lower BP early in menopause may affect cognitive domains known to be associated with AD.

SUBMITTER: Wharton W

PROVIDER: S-EPMC4367860 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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The KEEPS-Cognitive and Affective Study: baseline associations between vascular risk factors and cognition.

Wharton Whitney W Gleason Carey E CE Dowling N Maritza NM Carlsson Cynthia M CM Brinton Eliot A EA Santoro M Nanette MN Neal-Perry Genevieve G Taylor Hugh H Naftolin Frederick F Lobo Rogerio A RA Merriam George G Manson Joann E JE Cedars Marcelle I MI Miller Virginia M VM Black Dennis M DM Budoff Matthew M Hodis Howard N HN Harman S Mitchell SM Asthana Sanjay S

Journal of Alzheimer's disease : JAD 20140101 2

Midlife vascular risk factors influence later cognitive decline and Alzheimer's disease (AD). The decrease in serum estradiol levels during menopause has been associated with cognitive impairment and increased vascular risk, such as high blood pressure (BP), which independently contributes to cognitive dysfunction and AD. We describe the extent to which vascular risk factors relate to cognition in healthy, middle-aged, recently postmenopausal women enrolled in the Kronos Early Estrogen Preventio ...[more]

PMID: 24430001

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Project description:BackgroundMenopausal hormone therapy (MHT) reportedly increases the risk of cognitive decline in women over age 65 y. It is unknown whether similar risks exist for recently postmenopausal women, and whether MHT affects mood in younger women. The ancillary Cognitive and Affective Study (KEEPS-Cog) of the Kronos Early Estrogen Prevention Study (KEEPS) examined the effects of up to 4 y of MHT on cognition and mood in recently postmenopausal women.Methods and findingsKEEPS, a randomized, double-blinded, placebo-controlled clinical trial, was conducted at nine US academic centers. Of the 727 women enrolled in KEEPS, 693 (95.3%) participated in the ancillary KEEPS-Cog, with 220 women randomized to receive 4 y of 0.45 mg/d oral conjugated equine estrogens (o-CEE) plus 200 mg/d micronized progesterone (m-P) for the first 12 d of each month, 211 women randomized to receive 50 μg/d transdermal estradiol (t-E2) plus 200 mg/d m-P for the first 12 d of each month, and 262 women randomized to receive placebo pills and patches. Primary outcomes included the Modified Mini-Mental State examination; four cognitive factors: verbal learning/memory, auditory attention/working memory, visual attention/executive function, and speeded language/mental flexibility; and a mood measure, the Profile of Mood States (POMS). MHT effects were analyzed using linear mixed-effects (LME) models, which make full use of all available data from each participant, including those with missing data. Data from those with and without full data were compared to assess for potential biases resulting from missing observations. For statistically significant results, we calculated effect sizes (ESs) to evaluate the magnitude of changes. On average, participants were 52.6 y old, and 1.4 y past their last menstrual period. By month 48, 169 (24.4%) and 158 (22.8%) of the 693 women who consented for ancillary KEEPS-Cog were lost to follow-up for cognitive assessment (3MS and cognitive factors) and mood evaluations (POMS), respectively. However, because LME models make full use all available data, including data from women with missing data, 95.5% of participants were included in the final analysis (n = 662 in cognitive analyses, and n = 661 in mood analyses). To be included in analyses, women must have provided baseline data, and data from at least one post-baseline visit. The mean length of follow-up was 2.85 y (standard deviation [SD] = 0.49) for cognitive outcomes and 2.76 (SD = 0.57) for mood outcomes. No treatment-related benefits were found on cognitive outcomes. For mood, model estimates indicated that women treated with o-CEE showed improvements in depression and anxiety symptoms over the 48 mo of treatment, compared to women on placebo. The model estimate for the depression subscale was -5.36 × 10(-2) (95% CI, -8.27 × 10(-2) to -2.44 × 10(-2); ES = 0.49, p < 0.001) and for the anxiety subscale was -3.01 × 10(-2) (95% CI, -5.09 × 10(-2) to -9.34 × 10(-3); ES = 0.26, p < 0.001). Mood outcomes for women randomized to t-E2 were similar to those for women on placebo. Importantly, the KEEPS-Cog results cannot be extrapolated to treatment longer than 4 y.ConclusionsThe KEEPS-Cog findings suggest that for recently postmenopausal women, MHT did not alter cognition as hypothesized. However, beneficial mood effects with small to medium ESs were noted with 4 y of o-CEE, but not with 4 y of t-E2. The generalizability of these findings is limited to recently postmenopausal women with low cardiovascular risk profiles.Trial registrationClinicalTrials.gov NCT00154180 and NCT00623311.

Project description:BackgroundTo determine the association between amyloid-beta (Aβ) plaque deposition and changes in global cognition, executive functions, information processing speed, and falls risk over a 12-month period in older adults with a primary clinical diagnosis of subcortical ischemic vascular cognitive impairment (SIVCI).MethodsThis is a secondary analysis of data acquired from a subset of participants (N = 22) who were enrolled in a randomized controlled trial of aerobic exercise (NCT01027858). The subset of individuals completed an 11C Pittsburgh compound B (PIB) scan. Cognitive function and falls risk were assessed at baseline, 6-months, and 12-months. Global cognition, executive functions, and information processing speed were measured using: 1) ADAS-Cog; 2) Trail Making Test; 3) Digit Span Test; 4) Stroop Test, and 5) Digit Symbol Substitution Test. Falls risk was measured using the Physiological Profile Assessment. Hierarchical multiple linear regression analyses determined the unique contribution of Aβ on changes in cognitive function and falls risk at 12-months after controlling for experimental group (i.e. aerobic exercise training or usual care control) and baseline performance. To correct for multiple comparisons, we applied the Benjamini-Hochberg procedure to obtain a false discovery rate corrected threshold using alpha = 0.05.ResultsHigher PIB retention was significantly associated with greater decrements in set shifting (Trail Making Test, adjusted R2 = 35.3%, p = 0.002), attention and conflict resolution (Stroop Test, adjusted R2 = 33.4%, p = 0.01), and information processing speed (Digit Symbol Substitution Test, adjusted R2 = 24.4%, p = 0.001) over a 12-month period. Additionally, higher PIB retention was significantly associated with increased falls risk (Physiological Profile Assessment, adjusted R2 = 49.1%, p = 0.04). PIB retention was not significantly associated with change in ADAS-Cog and Verbal Digit Span Test (p > 0.05).ConclusionsSymptoms associated with SIVCI may be amplified by secondary Aβ pathology.Trial registrationClinicalTrials.gov, NCT01027858 , December 7, 2009.

Project description:Vascular brain injury results in loss of structural and functional connectivity and leads to cognitive impairment. Its various manifestations, including microinfarcts, microhaemorrhages and white matter hyperintensities, result in microstructural tissue integrity loss and secondary neurodegeneration. Among these, tissue microstructural alteration is a relatively early event compared with atrophy along the aging and neurodegeneration continuum. Understanding its association with cognition may provide the opportunity to further elucidate the relationship between vascular health and clinical outcomes. Magnetic resonance elastography offers a non-invasive approach to evaluate tissue mechanical properties, providing a window into the microstructural integrity of the brain. This retrospective study evaluated brain stiffness as a potential biomarker for vascular brain injury and its role in mediating the impact of vascular dysfunction on cognitive impairment. Seventy-five participants from the Mayo Clinic Study of Aging underwent brain imaging using a 3T MR imager with a spin-echo echo-planar imaging sequence for magnetic resonance elastography and T1- and T2-weighted pulse sequences. This study evaluated the effects of vascular biomarkers (white matter hyperintensities and cardiometabolic condition score) on brain stiffness using voxelwise analysis. Partial correlation analysis explored associations between brain stiffness, white matter hyperintensities, cardiometabolic condition and global cognition. Mediation analysis determined the role of stiffness in mediating the relationship between vascular biomarkers and cognitive performance. Statistical significance was set at P-values < 0.05. Diagnostic accuracy of magnetic resonance elastography stiffness for white matter hyperintensities and cardiometabolic condition was evaluated using receiver operator characteristic curves. Voxelwise linear regression analysis indicated white matter hyperintensities negatively correlate with brain stiffness, specifically in periventricular regions with high white matter hyperintensity levels. A negative association between cardiovascular risk factors and stiffness was also observed across the brain. No significant patterns of stiffness changes were associated with amyloid load. Global stiffness (µ) negatively correlated with both white matter hyperintensities and cardiometabolic condition when all other covariables including amyloid load were controlled. The positive correlation between white matter hyperintensities and cardiometabolic condition weakened and became statistically insignificant when controlling for other covariables. Brain stiffness and global cognition were positively correlated, maintaining statistical significance after adjusting for all covariables. These findings suggest mechanical alterations are associated with cognitive dysfunction and vascular brain injury. Brain stiffness significantly mediated the indirect effects of white matter hyperintensities and cardiometabolic condition on global cognition. Local cerebrovascular diseases (assessed by white matter hyperintensities) and systemic vascular risk factors (assessed by cardiometabolic condition) impact brain stiffness with spatially and statistically distinct effects. Global brain stiffness is a significant mediator between vascular disease measures and cognitive function, highlighting the value of magnetic resonance elastography-based mechanical assessments in understanding this relationship.

Dataset Information

The KEEPS-Cognitive and Affective Study: baseline associations between vascular risk factors and cognition.

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The KEEPS-Cognitive and Affective Study: baseline associations between vascular risk factors and cognition.

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