Cardiometabolic outcomes in Kronos Early Estrogen Prevention Study continuation: 14-year follow-up of a hormone therapy trial.

OBJECTIVE: This study aimed to determine long-term cardiometabolic effects of hormone therapies initiated within 3 years of onset of menopause after a 14-year follow-up study of participants of the Kronos Early Estrogen Prevention Study (KEEPS). METHODS: KEEPS was a multisite clinical trial that recruited recently menopausal women with good cardiovascular health for randomization to oral conjugated equine estrogens (Premarin, 0.45 mg/d) or transdermal 17ß-estradiol (Climara, 50 µg/d) both with micronized progesterone (Prometrium, 200 mg/d) for 12 d/mo, or placebo pills and patch for 4 years. KEEPS continuation recontacted KEEPS participants 14 years after randomization and 10 years after the completion of the 4-year clinical trial to attend in-person clinic visits. RESULTS: Participants of KEEPS continuation (n = 299 of the 727 KEEPS participants; 41%) had an average age of 67 years (range, 58-73 y). Measurements of systolic and diastolic blood pressures, waist-to-hip ratio, fasting levels of glucose, insulin, lipid profiles, and homeostasis model assessment of insulin resistance were not different among the treatment groups at either KEEPS baseline or at KEEPS continuation visits, or for change between these two visits. The frequency of self-reported diabetes ( P = 0.007) and use of diabetes medications was higher in the placebo than the oral conjugated equine estrogens ( P = 0.045) or transdermal 17ß-estradiol ( P = 0.02) groups, but these differences were not supported by the laboratory measurements of glycemia or insulin resistance. CONCLUSIONS: There was no evidence of cardiovascular and/or metabolic benefits or adverse effects associated with 4 years use of oral or transdermal forms of hormone therapy by recently menopausal women with good cardiovascular health after 10 years.

Expression analysis of BACH1 with clinical variables using the US breast cancer patient cohort.

Background: Studies on functional roles of BACH1 reveal that BACH1 promotes cancer metastasis and regulates metabolic networks for metastatic processes. However, little is known about BACH1 protein expression in breast tumors and its relevance to clinical variables as a biomarker for patients with breast tumors. Methods: Using a tissue microarray (TMA) of breast tumor tissues isolated from a patient cohort (N = 130) expression of BACH1 and its target gene MCT1 (encoded by SLC16A1) were monitored by immunohistochemistry (IHC) assays and scored for further analyses. We examined the association between scores of BACH1 (Allredscoretotal) or MCT1 (Hscoretotal3×2×1x) with clinical variables including: breast cancer subtypes, tissue types, tumor size, patient's racial/ethnic background, and age group. Groups were compared using the Mann-Whitney U test (or the non-parametric Kruskal-Wallis test when appropriate) for numerical data. A proportional odds ordinal logistic model was used to examine multiple covariates. Associations between variables were evaluated with the Spearman's correlation coefficient. Results: BACH1 and MCT1 expression were detected in 90.76% (N = 118/130) and 92.30% (N = 120/130) of patients by IHC, respectively, in our study. After dichotomizing tumor size (small: 3-25 in diameter vs. big: 27-85 mm in diameter), BACH1 expression scores were significantly higher (p = 0.015) in the bigger tumor group (mean [SD]; 4.20 [1.796]) compared with the smaller tumor group (3.920 [1.693]). Of interest, we also observed significantly higher BACH1 scores (p = 0.004) in tumors from Black women (3.971 [1.514]; N = 69) compared with those of White women (3.02 [1.942]; N = 49). Consistent with mRNA expression analysis, BACH1 expression is most abundant in the basal-like tumors among all subtypes, specifically in Black women, whereas MCT1 expression scores are considerably higher in the basal-like tumors regardless of race. In addition, there was a positive association between BACH1 and MCT1 IHC scores in tumors from Black women, although a weak association between them in tumors from White women. In general, we did not detect associations between MCT1 IHC scores and race, tumor size, tissue types, or patient's age. Conclusions: We found strong associations of BACH1 expression with tumor size and the basal-like subtype, respectively. Importantly, BACH1 expresses significantly higher in tumors from Black women than White women, as well as in the basal-like subtype of breast tumors from Black women. Our study suggests that BACH1 expression could serve as a potential race-associated biomarker indicating poor prognosis.

Associations between pituitary-ovarian hormones and cognition in recently menopausal women independent of type of hormone therapy.

OBJECTIVES: To examine associations of pituitary-ovarian hormone levels with cognition before and after different formulations of hormone therapy (HT) or placebo independent of treatment group. METHODS: Recently menopausal, healthy women were randomized to 0.45 mg/day oral conjugated equine estrogens (o-CEE, n = 109), 50 µg/day transdermal 17ß (tE2, n = 107) or placebo pills and patches (n = 146); women on active treatment received oral 200 mg/day micronized progesterone for 12 days per month. Levels of estrone, 17ß-estradiol, follicle stimulating hormone, luteinizing hormone, androstenedione, and testosterone were determined prior to and after 48 months of study participation. Neuropsychological testing was administered at baseline, and months 18, 36 and 48. Latent growth curve models controlling for education level, age, APOE allele status, waist circumference, and treatment examined the trajectories of each cognitive domain after accounting for the effect of hormone levels at baseline and months 18, 36 and 48. A linear multivariate mixed model examined the effect of changes in hormone levels on changes in trajectories of complex attention tasks with varying degrees of difficulty. RESULTS: All women were adherent to treatment at month 48. Higher baseline estrone levels were associated with poorer global cognition, auditory attention and working memory, visual attention, and executive function, but not working memory. Higher levels of baseline 17ß-E2 were associated with poorer cognitive performance, with marginal significance at baseline in speeded language and mental flexibility (p = 0.013). Other hormone levels were not associated with cognition. Controlling for all treatments, hormone levels at baseline and at month 48 did not have any significant correlation with cognitive trajectories over time. SUMMARY: In healthy, recently menopausal women, baseline estrone levels were inversely associated with selected cognitive factors independent of two types of HT or placebo during 4 years of follow-up. Baseline levels of the other pituitary-ovarian hormones studied were not associated with baseline cognition, nor were changes in any hormones associated with changes in cognition during the study. The marginal association between estradiol levels and cognitive factors warrants further investigation. GOV NUMBERS: NCT00154180, NCT00623311.

Applications of artificial intelligence in dementia research.

More than 50 million older people worldwide are suffering from dementia, and this number is estimated to increase to 150 million by 2050. Greater caregiver burdens and financial impacts on the healthcare system are expected as we wait for an effective treatment for dementia. Researchers are constantly exploring new therapies and screening approaches for the early detection of dementia. Artificial intelligence (AI) is widely applied in dementia research, including machine learning and deep learning methods for dementia diagnosis and progression detection. Computerized apps are also convenient tools for patients and caregivers to monitor cognitive function changes. Furthermore, social robots can potentially provide daily life support or guidance for the elderly who live alone. This review aims to provide an overview of AI applications in dementia research. We divided the applications into three categories according to different stages of cognitive impairment: (1) cognitive screening and training, (2) diagnosis and prognosis for dementia, and (3) dementia care and interventions. There are numerous studies on AI applications for dementia research. However, one challenge that remains is comparing the effectiveness of different AI methods in real clinical settings.

Marijuana Use and Older Adults' Self-Reported Difficulty Concentrating, Remembering, or Making Decisions.

OBJECTIVE: This study investigated the relationship, in adults 50 years and older, between self-reported past-month marijuana use and difficulty concentrating, remembering, or making decisions (SDCRMD) because of a physical, mental, or emotional condition, using the Behavioral Risk Factor Surveillance System (BRFSS). METHOD: We relied on a sample of 294,000 adults (53.4% female), 50 years and older, from 21 U.S. states and two territories over 4 years (2016-2019). We conducted descriptive analyses to examine the prevalence of past-month marijuana use and SDCRMD and used multivariate logistic regression to examine the association between marijuana use and SDCRMD, controlling for demographic and health-related variables. RESULTS: The overall prevalence of SDCRMD was 11.0%, 95% confidence interval (CI) [10.6%, 11.5%], and the prevalence of self-reported past-month marijuana use was 7.1%, 95% CI [6.7%, 7.5%]. Of those reporting past-month marijuana use, 19.9%, 95% CI [17.8%, 22.1%] reported SDCRMD. Past-month marijuana users were 1.5, 95% CI [1.1, 2.1] times more likely to report SDCRMD than nonusers. Prevalence of past-month marijuana use was higher in states with legalization of both medical and recreational marijuana; however, prevalence of SDCRMD was not. CONCLUSIONS: We found a strong, positive, and statistically significant relationship between past-month marijuana use and SDCRMD. This finding serves as an important first step in identifying the relationship between older adults' self-reported marijuana use and their difficulty concentrating, remembering, and decision-making because of a physical, mental, or emotional condition; however, additional research is needed.

Feasibility of the Savvy Caregiver Program for LGBTQ+ Caregivers of People Living with Alzheimer's Disease and Related Dementias.

Nearly 350,000 lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ+) adults in the U.S. are currently living with Alzheimer's disease and related dementias (ADRD). Informal caregivers face challenges impacting their ability to access and receive adequate and inclusive care for LGBTQ+ persons living with ADRD. The purpose of this study was to determine the feasibility and acceptability of the Savvy Caregiver Program for caregivers of LGBTQ+ individuals living with ADRD. Data for this secondary analysis come from caregivers (n = 17) who completed 6 sessions of the Savvy program. Caregivers were very satisfied with tailored program activities. Analyses of trends suggest non-significant increases in positive aspects of caregiving and decreases in caregiver burden and depressive symptoms. This is the first known study assessing the feasibility of the Savvy Caregiver Program for caregivers of LGBTQ+ individuals living with ADRD. Future research on the Savvy Caregiver Program for caregivers of LGBTQ+ people living with ADRD is needed.

Emotional characteristics of socially isolated older adults with MCI using tablet administered NIH toolbox: I-CONECT study.

Introduction: Examining the emotional functioning of individuals with mild cognitive impairment (MCI) could help describe their cognitive status and inform the development of interventions. This study compared the emotional characteristics of socially isolated older adults with and without MCI. Methods: We used baseline data from the Internet-based Conversational Engagement Clinical Trial. Emotional characteristics were assessed with the National Institutes of Health Toolbox Emotion Battery (NIHTB-EB). MCI status was determined with a consensus clinical diagnosis. Results: This study included 163 participants (mean age = 81.2 years, non-Hispanic Black = 20.7%, MCI = 52.8%). MCI was associated with higher negative affect and lower psychological well-being. Non-Hispanic Black participants scored lower in sadness, higher in positive affect, and higher in meaning and purpose than non-Hispanic White participants. Conclusion: Older adults with MCI experience more negative emotions and worse psychological well-being than those with normal cognition. The NIHTB-EB appears to be a sensitive tool to detect emotional characteristics associated with cognitive decline.

The role of dyadic cognitive report and subjective cognitive decline in early ADRD clinical research and trials: Current knowledge, gaps, and recommendations.

Efficient identification of cognitive decline and Alzheimer's disease (AD) risk in early stages of the AD disease continuum is a critical unmet need. Subjective cognitive decline is increasingly recognized as an early symptomatic stage of AD. Dyadic cognitive report, including subjective cognitive complaints (SCC) from a participant and an informant/study partner who knows the participant well, represents an accurate, reliable, and efficient source of data for assessing risk. However, the separate and combined contributions of self- and study partner report, and the dynamic relationship between the two, remains unclear. The Subjective Cognitive Decline Professional Interest Area within the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment convened a working group focused on dyadic patterns of subjective report. Group members identified aspects of dyadic-report information important to the AD research field, gaps in knowledge, and recommendations. By reviewing existing data on this topic, we found evidence that dyadic measures are associated with objective measures of cognition and provide unique information in preclinical and prodromal AD about disease stage and progression and AD biomarker status. External factors including dyad (participant-study partner pair) relationship and sociocultural factors contribute to these associations. We recommend greater dyad report use in research settings to identify AD risk. Priority areas for future research include (1) elucidation of the contributions of demographic and sociocultural factors, dyad type, and dyad relationship to dyad report; (2) exploration of agreement and discordance between self- and study partner report across the AD syndromic and disease continuum; (3) identification of domains (e.g., memory, executive function, neuropsychiatric) that predict AD risk outcomes and differentiate cognitive impairment due to AD from other impairment; (4) development of best practices for study partner engagement; (5) exploration of study partner report as AD clinical trial endpoints; (6) continued development, validation, and optimization, of study partner report instruments tailored to the goals of the research and population.

Cognitive Impairment after Lacunar Stroke and the Risk of Recurrent Stroke and Death.

INTRODUCTION: Patients with poststroke cognitive impairment appear to be at higher risk of recurrent stroke and death. However, whether cognitive impairment after lacunar stroke is associated with recurrent stroke and death remains unclear. We assessed whether global or domain-specific cognitive impairment after lacunar stroke is associated with recurrent stroke and death. METHODS: We considered patients from the Secondary Prevention of Small Subcortical Strokes (SPS3) trial with a baseline cognitive exam administered in English by certified SPS3 personnel, 14-180 days after qualifying lacunar stroke. We considered a baseline score of ≤86 on the Cognitive Assessment Screening Instrument to indicate global cognitive impairment, <10 on the Clock Drawing on Command test to indicate executive function impairment, and domain-specific summary scores in the lowest quartile to indicate memory and nonmemory impairment. We used Cox proportional hazards models to estimate the association between poststroke cognitive impairment and subsequent risk of recurrent stroke and death. RESULTS: The study included 1,528 participants with a median enrollment time of 62 days after qualifying stroke. During a mean follow-up of 3.9 years, 11.4% of participants had recurrent stroke and 8.2% died. In the fully adjusted models, memory impairment was independently associated with an increased risk of recurrent stroke (hazard ratio, 1.48; 95% confidence interval [95% CI]: 1.04-2.09) and death (hazard ratio, 1.87; 95% CI: 1.25-2.79). Global impairment (hazard ratio, 1.66; 95% CI: 1.06-2.59) and nonmemory impairment (hazard ratio, 1.74; 95% CI: 1.14-2.67) were associated with an increased risk of death. DISCUSSION/CONCLUSION: After lacunar stroke, memory impairment was an independent predictor of recurrent stroke and death, while global and nonmemory impairment were associated with death. Cognitive screening in lacunar stroke may help identify populations at higher risk of recurrent stroke and death.

Comparison of Education and Episodic Memory as Modifiers of Brain Atrophy Effects on Cognitive Decline: Implications for Measuring Cognitive Reserve.

OBJECTIVE: This study compared the level of education and tests from multiple cognitive domains as proxies for cognitive reserve. METHOD: The participants were educationally, ethnically, and cognitively diverse older adults enrolled in a longitudinal aging study. We examined independent and interactive effects of education, baseline cognitive scores, and MRI measures of cortical gray matter change on longitudinal cognitive change. RESULTS: Baseline episodic memory was related to cognitive decline independent of brain and demographic variables and moderated (weakened) the impact of gray matter change. Education moderated (strengthened) the gray matter change effect. Non-memory cognitive measures did not incrementally explain cognitive decline or moderate gray matter change effects. CONCLUSIONS: Episodic memory showed strong construct validity as a measure of cognitive reserve. Education effects on cognitive decline were dependent upon the rate of atrophy, indicating education effectively measures cognitive reserve only when atrophy rate is low. Results indicate that episodic memory has clinical utility as a predictor of future cognitive decline and better represents the neural basis of cognitive reserve than other cognitive abilities or static proxies like education.

Sleep quality and cortical amyloid-ß deposition in postmenopausal women of the Kronos early estrogen prevention study.

Hormone therapy improves sleep in menopausal women and recent data suggest that transdermal 17ß-estradiol may reduce the accumulation of cortical amyloid-ß. However, how menopausal hormone therapies modify the associations of amyloid-ß accumulation with sleep quality is not known. In this study, associations of sleep quality with cortical amyloid-ß deposition and cognitive function were assessed in a subset of women who had participated in the Kronos early estrogen prevention study. It was a randomized, placebo-controlled trial in which recently menopausal women (age, 42-58; 5-36 months past menopause) were randomized to (1) oral conjugated equine estrogen (n = 19); (2) transdermal 17ß-estradiol (tE2, n = 21); (3) placebo pills and patch (n = 32) for 4 years. Global sleep quality score was calculated using Pittsburgh sleep quality index, cortical amyloid-ß deposition was measured with Pittsburgh compound-B positron emission tomography standard uptake value ratio and cognitive function was assessed in four cognitive domains 3 years after completion of trial treatments. Lower global sleep quality score (i.e., better sleep quality) correlated with lower cortical Pittsburgh compound-B standard uptake value ratio only in the tE2 group (r = 0.45, P = 0.047). Better global sleep quality also correlated with higher visual attention and executive function scores in the tE2 group (r = -0.54, P = 0.02) and in the oral conjugated equine estrogen group (r = -0.65, P = 0.005). Menopausal hormone therapies may influence the effects of sleep on cognitive function, specifically, visual attention and executive function. There also appears to be a complex relationship between sleep, menopausal hormone therapies, cortical amyloid-ß accumulation and cognitive function, and tE2 formulation may modify the relationship between sleep and amyloid-ß accumulation.

Estimation of dementia prevalence at the local level in the United States.

INTRODUCTION: Ensuring adequate and equitable distribution of resources to support persons living with dementia relies on understanding the burden and distribution of dementia in a population. Our goal was to develop an approach to estimate dementia prevalence at the local level in the United States using publicly available data. METHODS: Our approach combines publicly available data on dementia prevalence and demographic data from the US Census to estimate dementia prevalence. We illustrate this approach by estimating dementia prevalence in persons aged 65 and older in Philadelphia, PA; Chicago, IL; and Atlanta, GA. RESULTS: Overall, we estimate the prevalence of dementia among those 65 and older to be 11.9% in Philadelphia, 11.8% Chicago, and 12.3% in Atlanta. Estimates across Philadelphia localities vary from 9.3% to 15.9%. DISCUSSION: Our approach provides a cost-effective method to generate estimates of dementia prevalence at the local level. HIGHLIGHTS: Brain health needs assessments require understanding of local dementia prevalence.Our approach can be used to estimate dementia prevalence in individual communities.This information can inform decisions about distribution of resources.

Trends in Relative Incidence and Prevalence of Dementia Across Non-Hispanic Black and White Individuals in the United States, 2000-2016.

Importance: In the US, dementia risk is higher in non-Hispanic Black individuals than in non-Hispanic White individuals. To evaluate progress toward reducing such disparities, tracking secular trends in racial disparities in dementia prevalence is essential. Objective: To examine whether relative racial disparities in dementia prevalence or incidence have changed in the US from 2000 to 2016. Design, Settings, and Participants: The Health and Retirement Study (HRS) is a nationally representative study of adults 50 years or older. New participants are recruited every 6 years, and study visits occur biennially. Approximately 17 000 to 22 000 respondents have been surveyed at each wave since 2000, achieving response rates of 81% to 89%. Data for this cohort study were obtained from non-Hispanic White and non-Hispanic Black participants aged 70 years and older from the 2000 to 2016 waves. For analyses of secular trends in racial disparities in dementia prevalence, each HRS wave was considered separately (range of participants meeting eligibility criteria in each wave, 6322-7579). For analyses of secular trends in racial disparities in dementia incidence, 7 subcohorts were created (range of participants meeting eligibility criteria in each subcohort, 5322-5961) following up people without dementia for 4 years from subcohort baseline visits in 2000, 2002, 2004, 2006, 2008, 2010, and 2012. Data were analyzed from October 2019 to August 2020. Exposures: Race based on self-response to closed-ended survey questions. Main Outcomes and Measures: Dementia status was determined using 3 algorithms with similar sensitivity and specificity across non-Hispanic White and Black participants. Disparities were characterized using ratio measures. Results: In this study, the mean age and percentage of male participants eligible for inclusion in analyses of racial disparities in dementia prevalence increased over time among non-Hispanic White participants (from 78.2 years and 40% in 2000 to 78.7 years and 44% in 2016) but remained steady in non-Hispanic Black participants during the same period (from 78.0 years and 37% in 2000 to 77.9 years and 38% in 2016). Prevalence ratios comparing Black and White participants ranged from approximately 1.5 to 1.9 across algorithms and years, whereas hazard ratios ranged from approximately 1.4 to 1.8. Although results suggest stable or declining dementia risk overall, there was no evidence suggesting change in relative racial disparities in dementia prevalence or incidence during follow-up. Conclusions and Relevance: This study did not find evidence to suggest that the ratio of dementia risk across Black and White individuals changed in the US between 2000 and 2016. Additional efforts to identify and mitigate the source of these disparities is warranted.

Cholinergic stimulation improves electrophysiological rate adaptation during pressure overload-induced heart failure in rats.

BACKGROUND: Left ventricular (LV) electrical maladaptation to increased heart rate in failing myocardium contributes to morbidity and mortality. Recently, cardiac cholinergic neuron activation reduced loss of contractile function resulting from chronic trans-aortic constriction (TAC) in rats. We hypothesized that chronic activation of cardiac cholinergic neurons would also reduce TAC-induced derangement of cardiac electrical activity. METHODS: We investigated electrophysiological rate adaptation in TAC rat hearts with and without daily chemogenetic activation of hypothalamic oxytocin neurons for downstream cardiac cholinergic neuron stimulation. Sprague Dawley rat hearts were excised, perfused, and optically mapped under dynamic pacing after 16 weeks of TAC with or without 12 weeks of daily chemogenetic treatment. Action potential duration (APD60) and conduction velocity (CV) maps were analyzed for regional rate adaptation to dynamic pacing. RESULTS: At lower pacing rates, untreated TAC induced elevated LV epicardial APD60. Fitted APD60 steady state (APDss) was reduced in treated TAC hearts. At higher pacing rates, treatment heterogeneously reduced APD60 compared to untreated TAC hearts. Variance of conduction loss was reduced in treated hearts compared to untreated hearts during fast pacing. However, CV was markedly reduced in both treated and untreated TAC hearts throughout dynamic pacing. At 150msec pacing cycle length, APD60 v. diastolic interval (DI) dispersion was reduced in treated hearts compared to untreated hearts. CONCLUSIONS: Chronic activation of cardiac cholinergic neurons improved electrophysiological adaptation to increases in pacing rate during development of TAC-induced heart failure. This provides insight into the electrophysiological benefits of cholinergic stimulation as a treatment for heart failure patients.

Do nurse practitioner-led medical homes differ from physician-led medical homes?

BACKGROUND/PURPOSE: The patient-centered medical home (PCMH) is an enhanced model of primary care. This study examined to what extent nurse practitioner (NP)-led PCMHs differed from traditional physician-led PCMHs. METHODS: We tested for differences between 391 NP-led PCMHs and 11,479 physician-led PCMHs, as well as across two distinct clusters identified by the Two-Step cluster analysis procedure using a sample of 136 practices. FINDINGS: NP-led PCMHs were more likely to serve vulnerable populations in rural and underserved areas than physician-led PCMHs. NP-led PCMHs tended to be more responsive to population health needs in the areas during the recognition process, while physician-led PCMHs emphasized practice improvements through enhanced access to care and management of patient information data. DISCUSSION: The findings suggest possible differences in capabilities, priorities and needs of the population served across practices. This is an important guide as policymakers track the adoption of PCMHs.

A Method for Examining the Equating of Psychometric Scales and Tests: An Application Using Dementia Screening Test Batteries.

Equating of psychometric scales and tests is frequently required and conducted in educational, behavioral, and clinical research. Construct comparability or equivalence between measuring instruments is a necessary condition for making decisions about linking and equating resulting scores. This article is concerned with a widely applicable method for examining if two scales or tests cannot be equated. A latent variable modeling method is discussed that can be used to evaluate whether the tests or parts thereof measure latent constructs that are distinct from each other. The approach can be routinely used before an equating procedure is undertaken, in order to assess whether equating could be meaningfully carried out to begin with. The procedure is readily applicable in empirical research using popular software. The method is illustrated with data from dementia screening test batteries administered as part of two studies designed to evaluate a wide range of biomarkers throughout the process of normal aging to dementia or Alzheimer's disease.

Impact of menopausal hormone formulations on pituitary-ovarian regulatory feedback.

Changes in pituitary-ovarian hormones across the menopausal transition have multiple physiological consequences. However, little is known about how the major types of postmenopausal hormone therapy (HT) affect pituitary-ovarian hormonal relationships. This study evaluated these relationships in recently menopausal women (52.45 ± 2.49 yr of age) in the Kronos Early Estrogen Prevention Study (KEEPS) who were compliant to randomized, double-blinded treatment with oral conjugated equine estrogen (o-CEE; n = 109), transdermal 17ß-estradiol (t-E2; n = 107), or placebo (n = 146). Androstenedione, testosterone, 17ß-estradiol, estrone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured in serum before (baseline) and 48 mo after randomization to treatment. Descriptive summaries of hormone levels were performed, and multiple regression analyses were used to examine the effects of o-CEE, t-E2, and placebo on these hormone levels at 48 mo, adjusting for baseline levels. A network analysis examined the covariance of changes in hormone levels over the 48 mo within treatment groups. As expected, at 48 mo of treatment, hormone levels differed between women in the two active treatment groups compared with placebo, and network analysis indicated stronger relationships among hormone levels in the t-E2 and o-CEE groups compared with placebo. Associations among testosterone, 17ß-estradiol, FSH, and LH differed between the o-CEE group compared with t-E2 and placebo groups. Thus, two common HT regimens differentially alter pituitary-ovarian hormone levels, altering feedback cycles and interhormonal associations in recently menopausal women. These interactions provide the basis for future studies investigating the impact of hormonal modulation of aging, including cognitive decline in women.

Dynamic change of cognitive reserve: associations with changes in brain, cognition, and diagnosis.

Cognitive reserve is inherently a dynamic construct; however, traditional methods of estimating reserve have focused on static proxy variables. A recently proposed psychometric approach entails modeling reserve as residual cognition not explained by demographic and brain variables. In this study, we extended this approach to longitudinal measurement and examined how change in reserve relates to clinical outcomes in late life and influences the effect of brain atrophy on cognitive decline. Results indicated that cognitive reserve changes were associated with progression of clinical diagnosis. More rapid depletion of cognitive reserve was associated with faster decline in nonmemory cognitive functions, even after accounting for longitudinal brain atrophy. The effect of longitudinal brain atrophy on cognitive decline differed based on the extent to which an individual's reserve changed. Whereas depletion of reserve appeared to unmask the effects of brain atrophy on cognitive decline, maintenance of reserve buffered against the negative effects of brain atrophy. Study results highlight that changes in reserve may have important implications for individual differences in cognitive aging trajectories.

The Kronos Early Estrogen Prevention Study (KEEPS): what have we learned?

OBJECTIVE: The Kronos Early Estrogen Prevention Study (KEEPS) was designed to address gaps in understanding the effects of timely menopausal hormone treatments (HT) on cardiovascular health and other effects of menopause after the premature termination of the Women's Health Initiative. METHOD: The KEEPS was a randomized, double-blinded, placebo-controlled trial to test the hypothesis that initiation of HT (oral conjugated equine estrogens [o-CEE] or transdermal 17ß-estradiol [t-E2]) in healthy, recently postmenopausal women (n = 727) would slow the progression of atherosclerosis as measured by changes in carotid artery intima-media thickness (CIMT). RESULTS: After 4 years, neither HT affected the rate of increase in CIMT. There was a trend for reduced accumulation of coronary artery calcium with o-CEE. There were no severe adverse effects, including venous thrombosis. Several ancillary studies demonstrated a positive effect on mood with o-CEE, and reduced hot flashes, improved sleep, and maintenance of bone mineral density with both treatments. Sexual function improved with t-E2. There were no significant effects of either treatment on cognition, breast pain, or skin wrinkling. Variants of genes associated with estrogen metabolism influenced the age of menopause and variability in effects of the HT on CIMT. Platelet activation associated with the development of white matter hyperintensities in the brain. CONCLUSIONS: KEEPS and its ancillary studies have supported the value and safety of the use of HT in recently postmenopausal women and provide a perspective for future research to optimize HT and health of postmenopausal women. The KEEPS continuation study continues to pursue these issues.

Examining Population Differences in Within-Person Variability in Longitudinal Designs Using Latent Variable Modeling: An Application to the Study of Cognitive Functioning of Older Adults.

Longitudinal studies have steadily grown in popularity across the educational and behavioral sciences, particularly with the increased availability of technological devices that allow the easy collection of repeated measures on multiple dimensions of substantive relevance. This article discusses a procedure that can be used to evaluate population differences in within-person (intraindividual) variability in such longitudinal investigations. The method is based on an application of the latent variable modeling methodology within a two-level modeling framework. The approach is used to obtain point and interval estimates of the differences in within-person variance and in the strength of correlative effects of repeated measures between normal and very mildly demented persons in a longitudinal study of a diagnostic cognitive test assessing verbal episodic memory.