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1.  Alzheimer’s disease: review of hormone therapy trials and implications for treatment and prevention after menopause 
Hormonal changes associated with the menopausal transition and postmenopause have the potential to influence processes linked to Alzheimer’s disease symptoms and pathogenesis, but effects of menopause on Alzheimer risk can be addressed only indirectly. Nine randomized clinical trials of estrogen-containing hormone therapy in Alzheimer’s disease patients were identified by a systematic literature search. Findings suggest that hormone therapy does not improve cognitive symptoms of women with Alzheimer’s disease. No clinical trials of hormone therapy address Alzheimer prevention, but one clinical trial provides moderate evidence that continuous, combined estrogen plus progestogen initiated at age 65 years or older increases the risk of dementia. The timing, or critical window, hypothesis suggests that hormone therapy initiated at a younger age in closer temporal proximity to menopause may reduce the risk of Alzheimer’s disease. This hypothesis is supported by observational research but is not addressed by clinical trial data. Unrecognized confounding is of concern in interpreting observational results, and research that helps resolve this issue will have important public health implications. Well-designed cohort studies, convergent evidence from appropriate laboratory models, and long-term clinical trials using surrogate biomarkers of brain function and neural pathology could provide relevant answers. Other estrogenic compounds are of theoretical interest with respect to Alzheimer treatment and risk. Effects of selective estrogen receptor modulators such as raloxifene may differ from those of estrogens; potential effects of phytoestrogens are not well studied.
PMCID: PMC3830600  PMID: 23727128
Alzheimer’s disease; estrogen; hormone therapy; menopause; selective estrogen receptor modulator
2.  Three Midlife Strategies to Prevent Cognitive Impairment Due to Alzheimer’s Disease 
The slow, progressive accumulation of pathology characteristic of Alzheimer’s disease is the principal determinant of cognitive decline leading to dementia. Risk-reduction strategies during midlife focus on raising the clinical threshold for the appearance of cognitive symptoms and on reducing the extent of Alzheimer pathology. Best available evidence suggests an approach based on three, conceptually distinct strategies. (1) Raise the threshold for cognitive symptoms by improving brain health. To achieve this goal, the tactic is to reduce cerebrovascular risks mediated by hypertension, diabetes, cigarette smoking, and hyperlipidemia. (2) Raise the threshold for cognitive symptoms by enhancing cognitive reserve. Here, tactics focus on mental stimulation associated with occupation, leisure activities and social engagement. (3) Reduce the burden of Alzheimer pathology. The most promising tactic toward this end is regular aerobic exercise. Tactics in support of strategies to reduce cognitive impairment due to Alzheimer pathology are not yet substantiated by robust, consistent clinical trial evidence. There is pressing need for well designed pragmatic trials to provide stronger evidence on preventive strategies for late-life cognitive decline and dementia.
PMCID: PMC4236238  PMID: 24893836
3.  Estrogens, Episodic Memory, and Alzheimer’s Disease: A Critical Update 
Seminars in reproductive medicine  2009;27(3):283-293.
Estrogen-containing hormone therapy initiated during the late postmenopause does not improve episodic memory (an important early symptom of Alzheimer’s disease), and it increases dementia risk. Cognitive consequences of exogenous estrogen exposures during midlife are less certain. Observational evidence implies that use of hormone therapy at a younger age close to the time of menopause may reduce risk of Alzheimer’s disease later in life. However, there are concerns that observational findings may be systematically biased. Partial insight on this critical issue may be gleaned from results of ongoing clinical trials involving midlife postmenpausal women (Early versus Late Intervention Trial with Estrogen; Kronos Early Estrogen Prevention Study). The effects of exogenous midlife estrogen exposures and Alzheimer risk can also be approached through better animal models, through carefully designed cohort studies, and through use of surrogate outcomes in randomized controlled trials in midlife women. Selective estrogen receptor modulators have the potential to affect cognitive outcomes and also merit additional study.
PMCID: PMC3683552  PMID: 19401959
Alzheimer’s disease; estrogen; memory; SERM
4.  Hormone therapy and the risk of stroke: perspectives ten years after the Women’s Health Initiative trials 
Principle findings on stroke from the Women’s Health Initiative (WHI) clinical trials of hormone therapy indicate that estrogen, alone or with a progestogen, increases a woman’s risk of stroke. These results were not unexpected, and research during the past decade has tended to support these findings. Consistent evidence from clinical trials and observational research indicates that standard dose hormone therapy increases stroke risk for postmenopausal women by about a third; increased risk may be limited to ischemic stroke. Risk is not modified by age of hormone initiation or use, or by temporal proximity to menopause, and risk is similar for estrogen plus progestogen and for unopposed estrogen. Limited evidence implies that lower doses of transdermal estradiol (≤50μg/d) may not alter stroke risk. For women less than 60 years of age, the absolute risk of stroke from standard dose hormone therapy is rare, about 2 additional strokes per 10,000 person-years of use; the absolute risk is considerably greater for older women. Other hormonally active compounds — including raloxifene, tamoxifen, and tibolone — can also affect stroke risk.
PMCID: PMC3675220  PMID: 22612608
estrogen; progestogen; hormone therapy; raloxifene; tamoxifen; tibolone; review; stroke; women’s health initiative
5.  Dementia Prevention: optimizing the use of observational data for personal, clinical, and public health decision-making 
Worldwide, over 35 million people suffer from Alzheimer’s disease and related dementias. This number is expected to triple over the next 40 years. How can we improve the evidence supporting strategies to reduce the rate of dementia in future generations? The risk of dementia is likely influenced by modifiable factors such as exercise, cognitive activity, and the clinical management of diabetes and hypertension. However, the quality of evidence is limited and it remains unclear whether specific interventions to reduce these modifiable risk factors can, in turn, reduce the risk of dementia. Although randomized controlled trials are the gold-standard for causality, the majority of evidence for long-term dementia prevention derives from, and will likely continue to derive from, observational studies. Although observational research has some unavoidable limitations, its utility for dementia prevention might be improved by, for example, better distinction between confirmatory and exploratory research, higher reporting standards, investment in effectiveness research enabled by increased data-pooling, and standardized exposure and outcome measures. Informed decision-making by the general public on low-risk health choices that could have broad potential benefits could be enabled by internet-based tools and decision-aids to communicate the evidence, its quality, and the estimated magnitude of effect.
PMCID: PMC4487813  PMID: 26146610
Alzheimer’s; primary prevention; non-randomized studies; low-risk; communication
6.  Aging, Estrogens, and Episodic Memory in Women 
To review the relation in midlife and beyond between estrogen exposures and episodic memory in women.
Episodic memory performance declines with usual aging, and impairments in episodic memory often portend the development of Alzheimer's disease. In the laboratory, estradiol influences hippocampal function and animal learning. However, it is controversial whether estrogens affect memory after a woman's reproductive years.
Focused literature review, including a summary of a systematic search of clinical trials of estrogens in which outcomes included an objective measure of episodic memory.
The natural menopause transition is not associated with objective changes in episodic memory. Strong clinical trial evidence indicates that initiating estrogen-containing hormone therapy after about age 60 years does not benefit episodic memory. Clinical trial findings in middle-age women before age 60 are limited by smaller sample sizes and shorter treatment durations, but these also do not indicate substantial memory effects. Limited short-term evidence, however, suggests that estrogens may improve verbal memory after surgical menopause. Although hormone therapy initiation in old age increases dementia risk, observational studies raise the question of an early critical window during which midlife estrogen therapy reduces late-life Alzheimer's disease. However, almost no data address whether midlife estrogen therapy affects episodic memory in old age.
Episodic memory is not substantially impacted by the natural menopause transition or improved by use of estrogen-containing hormone therapy after age 60. Further research is needed to determine whether outcomes differ after surgical menopause or whether episodic memory later in life is modified by midlife estrogenic exposures.
PMCID: PMC2791907  PMID: 19996872
Alzheimer's disease; estrogens; memory
7.  Cognitive Changes After Menopause: Influence of Estrogen 
The natural menopause is not associated with substantial cognitive change. Limited clinical trial evidence suggests that estrogen-containing hormone therapy has little effect on cognition during midlife, but prompt initiation after surgical menopause may improve aspects of memory. Among older postmenopausal women, strong clinical trial evidence demonstrates that hormone initiation does not improve cognition. More limited clinical trial evidence indicates no improvement in Alzheimer symptoms, and the Women’s Health Initiative Memory Study found an increase in dementia risk among older women. Observational findings of reduced Alzheimer risk may reflect early hormone use in younger women, or findings may be biased. Cognitive effects of selective estrogen receptor modulators are not yet well studied.
PMCID: PMC2637911  PMID: 18677155
Alzheimer disease; cognition; estrogen; memory; menopause; selective estrogen receptor modulators
8.  Sex Modifies the APOE-Related Risk of Developing Alzheimer's Disease 
Annals of neurology  2014;75(4):563-573.
The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). Case-control studies suggest the APOE4 link to AD is stronger in women. We examined the APOE4-by-sex interaction in conversion risk (from healthy aging to mild cognitive impairment (MCI)/AD or from MCI to AD) and cerebrospinal fluid (CSF) biomarker levels.
Cox proportional hazards analysis was used to compute hazards ratios (HR) for an APOE-by-sex interaction on conversion in controls (N=5,496) and MCI patients (N=2,588). The interaction was also tested in CSF biomarker levels of 980 subjects from the AD Neuroimaging Initiative.
Among controls, male and female carriers were more likely to convert to MCI/AD, but the effect was stronger in women (HR=1.81 women; HR=1.27 men; interaction P=0.0106). The interaction remained significant in a pre-defined sub-analysis restricted to APOE3/3 and APOE3/4 genotypes. Among MCI patients, male and female carriers were more likely to convert to AD (HR=2.16 women; HR=1.64 men). The effect was nominally stronger in women, but the interaction was not significant (P=0.136). In the sub-analysis restricted to APOE3/3 and APOE 3/4 genotypes, the interaction was significant (P= 0.022; HR=2.17 women; HR=1.51 men). The APOE4-by-sex interaction on biomarker levels was significant for MCI patients in total-tau and the tau-to-Abeta-ratio (P=0.0088 and P=0.020, respectively; more AD-like in women).
APOE4 confers greater AD risk in women. Biomarker results suggest that increased APOE-related risk in women may be associated with tau pathology. These findings have important clinical implications and suggest novel research approaches into AD pathogenesis.
PMCID: PMC4117990  PMID: 24623176
9.  Associations of Urine Excretion of Isoflavonoids with Cognition in Postmenopausal Women in the Women’s Isoflavone Soy Health Clinical Trial 
Results from randomized trials of soy supplements on cognition in postmenopausal women are equivocal. We sought to determine associations of change in urine excretion of isoflavonoids on cognitive change.
Post hoc analysis of isoflavonoid exposures (mean 2.7 years) during the randomized, placebo-controlled, double-blind Women’s Isoflavone Soy Health trial.
General community.
350 healthy postmenopausal women.
25 g 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.
Overnight urine excretion and fasting plasma levels of isoflavonoids, and cognitive function, measured at baseline and endpoint.
300 women (mean age = 61 years, range 45-92 years) 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=0.39). Secondary analyses indicated that change in urine excretion of isoflavonoids was inversely associated with change in a factor score representing general intelligence (p=0.02), but not with factor scores representing verbal or visual episodic memory. Mean differences in this general intelligence factor score among women in the first compared to highest quartile of isoflavonoid change are equivalent to an approximate 4.4 year age-associated decline. Analyses based on plasma isoflavonoid levels yielded similar but attenuated results.
Among healthy postmenopausal women, long-term changes in isoflavonoids are not associated with global cognition, supporting clinical trial results. Increasing isoflavonoid exposure from dietary supplements is, however, associated with decrements in general intelligence but not memory; this finding requires confirmation in future studies.
PMCID: PMC4226524  PMID: 24617349
Cognition; isoflavones; menopause; soy; women’s health
10.  Components of Air Pollution and Cognitive Function in Middle-aged and Older Adults in Los Angeles 
Neurotoxicology  2013;40:1-7.
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=1,496, 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 ug/m3 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.
PMCID: PMC3946571  PMID: 24148924
air pollution; cognitive dysfunction; dementia; particulate matter; ozone; verbal learning
11.  Supply and demand analysis of the current and future US neurology workforce 
Neurology  2013;81(5):470-478.
This study estimates current and projects future neurologist supply and demand under alternative scenarios nationally and by state from 2012 through 2025.
A microsimulation supply model simulates likely career choices of individual neurologists, taking into account the number of new neurologists trained each year and changing demographics of the neurology workforce. A microsimulation demand model simulates utilization of neurology services for each individual in a representative sample of the population in each state and for the United States as a whole. Demand projections reflect increased prevalence of neurologic conditions associated with population growth and aging, and expanded coverage under health care reform.
The estimated active supply of 16,366 neurologists in 2012 is projected to increase to 18,060 by 2025. Long wait times for patients to see a neurologist, difficulty hiring new neurologists, and large numbers of neurologists who do not accept new Medicaid patients are consistent with a current national shortfall of neurologists. Demand for neurologists is projected to increase from ∼18,180 in 2012 (11% shortfall) to 21,440 by 2025 (19% shortfall). This includes an increased demand of 520 full-time equivalent neurologists starting in 2014 from expanded medical insurance coverage associated with the Patient Protection and Affordable Care Act.
In the absence of efforts to increase the number of neurology professionals and retain the existing workforce, current national and geographic shortfalls of neurologists are likely to worsen, exacerbating long wait times and reducing access to care for Medicaid beneficiaries. Current geographic differences in adequacy of supply likely will persist into the future.
PMCID: PMC3776531  PMID: 23596071
12.  Effects of Physical Activity on Vasomotor Symptoms: Examination Using Objective and Subjective Measures 
Menopause (New York, N.Y.)  2012;19(10):1095-1103.
Physical activity (PA) is essential for successful aging and for the prevention and management of common chronic diseases. The empirical support for the beneficial effects of PA on vasomotor symptoms has however been mixed. The purpose of this study was to assess the effects of acute aerobic exercise and daily PA on menopausal vasomotor symptoms.
Community-dwelling midlife women (N = 121; age range 40–60 years) not on hormone therapy were recruited for a 15-day daily diary study. Women completed psychological, cardiorespiratory fitness, body composition, and hormonal status screening, followed by a 15-day prospective assessment in a “real-life” setting using a personal digital assistant device. Participants also completed a 30 minute moderate-intensity aerobic exercise bout on a treadmill between days 5–8. Daily PA was assessed objectively through accelerometry and all symptomatic women (n = 92) completed two 24-hour Biolog sternal skin conductance recordings of hot flashes (HFs), one at baseline and one immediately following treadmill exercise.
Both total objective (p = .054) and total subjective (p < .05) HFs decreased following the acute exercise bout. At the between-person level, daily PA was not associated with self-reported HFs. However, at the within-person level, performing more moderate physical activity than usual was associated with more self-reported HFs in women with lower fitness levels.
Moderate aerobic exercise decreases objective and subjective HFs 24 hours following exercise, however, in women with lower fitness levels, more daily moderate PA leads to more self-reported symptoms.
PMCID: PMC3460032  PMID: 22735162
Menopause; Vasomotor Symptoms; Hot Flashes; Physical Activity; Exercise
13.  Gonadal Hormones and Cognitive Aging: A Midlife Perspective 
Gonadal steroids affect a variety of brain processes. Cognitive consequences of hormonal changes associated with menopause are of scientific interest and of public heath relevance. Natural menopause is a normal physiological process that can be directly studied only through observational research. Similarly, surgical menopause in humans is rarely directly amenable to experimental research. Causality with respect to cognitive outcomes is therefore difficult to infer. Cross-sectional and longitudinal findings from the Melbourne Women’s Midlife Health Project, the Study of Women’s health Across the Nation, and other midlife cohorts suggest that cognitive consequences of the natural menopausal transition are probably small, at least during midlife and at least for episodic memory, a key cognitive domain for which data are the most robust. Midlife episodic memory performance is similar shortly after natural menopause compared to shortly before, and serum estradiol concentration in midlife is unassociated episodic memory performance. Effects of natural menopause on other cognitive domains, cognitive consequences of surgical menopause, and late-life cognitive consequences of midlife hormonal exposures are less well understood and merit continued study.
PMCID: PMC3675221  PMID: 21175393
Cognition; Dementia; Estrogen; Memory; Menopause; Testosterone
14.  Hormone therapy, dementia, and cognition: the Women's Health Initiative ten years on 
Principle findings on dementia from the Women's Health Initiative Memory Study (WHIMS) showed that conjugated equine estrogens plus medroxyprogesterone acetate (CEE/MPA) increase dementia risk in women aged 65 years and above, but not risk of mild cognitive impairment. The dementia finding was unexpected, given consistent observational evidence that associates estrogen-containing hormone therapy use with reduced risk of Alzheimer's disease. It remains controversial whether hormone use by younger postmenopausal women near the time of menopause reduces dementia risk or whether WHIMS findings should be generalized to younger women. Given the challenges of conducting a primary prevention trial to address that question, it is helpful to consider the impact of hormone therapy on cognitive test performance, particularly verbal memory, for its own sake and as a proxy for dementia risk. The WHI Study of Cognitive Aging (WHISCA) showed that CEE/MPA worsened verbal memory, whereas CEE alone had no influence on cognition. These findings have been replicated in several randomized clinical trials. The apparent negative effect of CEE/MPA on verbal memory does not appear to be age-dependent. Additional investigations are needed to understand the impact of other hormonally active compounds on dementia and cognitive outcomes.
PMCID: PMC3667708  PMID: 22612612
Alzheimer's disease; cognition; dementia; estrogen; hormone therapy; menopause; memory; progestogen; review; selective estrogen receptor modulator; women's health initiative
15.  Exploring the interaction between SNP genotype and postmenopausal hormone therapy effects on stroke risk 
Genome Medicine  2012;4(7):57.
Genome-wide association studies have identified several genomic regions that are associated with stroke risk, but these provide an explanation for only a small fraction of familial stroke aggregation. Genotype by environment interactions may contribute further to such an explanation. The Women's Health Initiative (WHI) clinical trial found increased stroke risk with postmenopausal hormone therapy (HT) and provides an efficient setting for evaluating genotype-HT interaction on stroke risk.
We examined HT by genotype interactions for 392 SNPs selected from candidate gene studies, and 2,371 SNPs associated with changes in blood protein concentrations after hormone therapy, in analyses that included 2,045 postmenopausal women who developed stroke during WHI clinical trial and observational study follow-up and one-to-one matched controls. A two-stage procedure was implemented where SNPs passing the first stage screening based on marginal association with stroke risk were tested in the second stage for interaction with HT using case-only analysis.
The two-stage procedure identified two SNPs, rs2154299 and rs12194855, in the coagulation factor XIII subunit A (F13A1) region and two SNPs, rs630431 and rs560892, in the proprotein convertase subtilisin kexin 9 (PCSK9) region, with an estimated false discovery rate <0.05 based on interaction tests. Further analyses showed significant stroke risk interaction between these F13A1 SNPs and estrogen plus progestin (E+P) treatment for ischemic stroke and for ischemic and hemorrhagic stroke combined, and suggested interactions between PCSK9 SNPs with either E+P or estrogen-alone treatment.
Genotype by environment interaction information may help to define genomic regions relevant to stroke risk. Two-stage analysis among postmenopausal women generates novel hypotheses concerning the F13A1 and PCSK9 genomic regions and the effects of hormonal exposures on postmenopausal stroke risk for subsequent independent validation.
PMCID: PMC3580413  PMID: 22794791
16.  Perimenopausal Use of Hormone Therapy is Associated with Enhanced Memory and Hippocampal Function Later in Life 
Brain research  2010;1379:232-243.
Evidence suggests that initiation of some forms of hormone therapy (HT) early in the perimenopausal or postmenopausal stage might confer benefit to verbal memory and the neural systems underlying memory, whereas late-life initiation confers no benefit or harm. This “critical window hypothesis” remains a topic of debate. Using functional magnetic resonance imaging (fMRI), we examined the long-term impact of perimenopausal HT use on brain function during performance of verbal and figural memory tasks. Participants were 34 postmenopausal women (mean age 60 years) from the Melbourne Women’s Midlife Health Project and included 17 early (perimenopausal) and continuous users of HT and 17 never users matched on age, education, and verbal knowledge. Continuous HT use from the perimenopausal stage versus no use was validated with prospective daily diary records and study visit data. The primary outcome was patterns of brain activation in an a priori region of interest in the medial temporal lobe during verbal encoding and recognition of words. Results indicated that perimenopausal HT users performed better than nonusers on the imaging verbal memory task (p < .05). During verbal recognition, perimenopausal HT users showed increased activation in the left hippocampus and decreased activation in the parahippocampal gyrus bilaterally compared with never users. Each of these patterns of activation was associated with better memory performance on the imaging memory task. These results suggest that perimenopausal use of HT might confer long-term benefits to verbal memory and the brain systems underlying verbal memory. More generally, the results support the critical window hypothesis.
PMCID: PMC3046212  PMID: 21078303
hormone therapy; estrogen; memory; fMRI; hippocampus; menopause
17.  Summary of the NIA-sponsored Conference on Depressive Symptoms and Cognitive Complaints in the Menopausal Transition 
Menopause (New York, N.Y.)  2010;17(4):815-822.
This NIA-sponsored workshop was aimed at understanding the impact of the menopausal transition on mood symptoms and cognitive disorders during the menopausal transition and identifying research priorities for further investigation. Longitudinal studies provide insights into the frequency of these problems in representative samples of midlife women. The majority of women do not experience serious depressive symptoms during the transition, but a subgroup of women is at increased risk. Slight changes in memory function and processing speed are evident during the transition, and physiological factors associated with hot flashes may contribute to memory problems. Clinical trial evidence indicates that estradiol therapy can be effective in treating perimenopausal depression. There is some limited evidence of a cognitive benefit with estrogen alone therapy in younger postmenopausal women, and stronger evidence that certain forms of combination hormone therapy produce modest deficits in verbal memory in younger and older women. Identifying a cognitively neutral or beneficial combination therapy for the treatment of menopausal symptoms in naturally menopausal women is an important goal for future research. Pharmacological challenge studies bridge the basic science and clinical literatures to provide insights into the extent to which changes in endogenous and exogenous hormones and other neurotransmitter systems contribute to cognitive and mood problems. Routine evaluation of depressive symptoms in perimenopausal women is warranted by the literature. Quick and valid screening tools for assessing depression in the clinic are available on-line and free of charge.
PMCID: PMC2901893  PMID: 20616668
Menopause; Cognition; Mood; Perimenopause; Depression
18.  Subtypes of Mild Cognitive Impairment in Older Postmenopausal Women: The Women’s Health Initiative Memory Study 
Mild cognitive impairment (MCI) is a transitional state between normal cognitive functioning and dementia. A proposed MCI typology1 classifies individuals by the type and extent of cognitive impairment, yet few studies have characterized or compared these subtypes. 447 women 65 years of age and older from the Women’s Health Initiative Memory Study2 were classified into the four MCI subgroups and a ‘no impairment’ group and compared on clinical, sociodemographic, and health variables.
82.1% of participants had a cognitive deficit in at least one domain with most (74.3%) having deficits in multiple cognitive domains. Only 4.3% had an isolated memory deficit, while 21.3% had an isolated non-memory deficit. Of the 112 women who met all MCI criteria examined, the most common subtype was amnestic multi-domain MCI (42.8%) followed by non-amnestic multiple domain MCI (26.7%), non-amnestic single domain (24.1%) and amnestic single domain MCI (6.3%). Subtypes were similar with respect to education, health status, smoking, depression and pre- and on-study use of hormone therapy.
Despite the attention it receives in the literature amnestic MCI is the least common type highlighting the importance of identifying and characterizing other non-amnestic and multi-domain subtypes. Further research is needed on the epidemiology of MCI subtypes, clinical and biological differences between them and rates for conversion to dementia.
PMCID: PMC2929315  PMID: 20473134
MCI; women; WHIMS; postmenopausal; cognition; dementia; hormone therapy
19.  The Relationship Between Cognitive Function and Physical Performance in Older Women: Results From the Women’s Health Initiative Memory Study 
Cognitive function and physical performance are associated, but the common sequence of cognitive and physical decline remains unclear.
In the Women’s Health Initiative Memory Study (WHIMS) clinical trial, we examined associations at baseline and over a 6-year follow-up period between the Modified Mini-Mental State (3MS) Examination and three physical performance measures (PPMs): gait speed (meters/second), chair stands (number of stands in 15 seconds), and grip strength (kilograms). Using mixed models, we examined the baseline 3MS as predictor of change in PPM, change in the 3MS as predictor of change in PPM, and baseline PPM as predictors of 3MS change.
Among 1,793 women (mean age = 70.3 years, 89% white, and mean 3MS score = 95.1), PPM were weakly correlated with 3MS—gait speed: r = .06, p = .02; chair stands: r = .09, p < .001; and grip strength: r = .10, p < .001. Baseline 3MS score was associated with subsequent PPM decline after adjustment for demographics, comorbid conditions, medications, and lifestyle factors. For every SD (4.2 points) higher 3MS score, 0.04 SD (0.04 m/s) less gait speed and 0.05 SD (0.29 kg) less grip strength decline is expected over 6 years (p ≤ .01 both). Changes in 3MS and PPM were associated, particularly with chair stands and grip strength (p < .003 both). Baseline PPMs were not associated with subsequent 3MS change.
Baseline global cognitive function and change in global cognitive function were associated with physical performance change, but baseline physical performance was not associated with cognitive change in this cohort. These analyses support the hypothesis that cognitive decline on average precedes or co-occurs with physical performance decline.
PMCID: PMC2822281  PMID: 19789197
Cognitive function; Physical performance; Cognition; Physical function
20.  Frontiers proposal. National Institute on Aging “bench to bedside: estrogen as a case study” 
Age  2009;31(3):199-210.
On 28–29 September 2004, the National Institute on Aging (NIA) convened scientists for a workshop on the aging female brain focused on translating into clinical practice discoveries concerning estrogens and progestogens. Workshop objectives were to examine effects of estrogen and progestogen on brain and cognitive function in relation to aging, to examine consistencies and apparent discrepancies between Women’s Health Initiative Memory Study findings and other research on cognitive function, to determine whether additional hormone interventions could be developed in this area, and to offer advice on design of clinical trials for other interventions that might ameliorate cognitive aging. Following the workshop, participants joined by other interested scientists organized into regional work groups to continue the dialogue begun in Bethesda and to propose recommendations for NIA. The resulting recommendations, referred to as the “Frontiers Proposal for Estrogen and Cognitive Aging”, acknowledge the persistence of critical gaps in our understanding of how decline in ovarian steroid secretion during reproductive aging and use of ovarian steroid hormone therapy affect normal brain function and risk for late-life neurodegenerative disorders such as Alzheimer’s disease. There is a pressing need for preclinical, human, and integrated studies on the relationship between the menopausal transition and midlife exposures to estrogens, progestogens and related compounds, and risks for age-associated cognitive disorders. Research is also needed on better predictors of adverse cognitive outcomes, valid biomarkers for risks associated with hormone therapy use, enhanced tools for monitoring brain function and disease progression, and novel forms of therapy for improving long-term cognitive outcomes.
PMCID: PMC2734241  PMID: 19277902
Aging; Alzheimer’s disease; Cognition; Dementia; Estrogen; Menopause; Progestogen
21.  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.
We examined cross-sectional associations between subclinical atherosclerosis and cognitive function in a community-based sample of otherwise healthy adults with plasma homocysteine ≥8.5 µmol/L enrolled in the BVAIT study (n=504, mean age 61 years). Carotid artery intima-media thickness (CIMT), coronary (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.
Increasing thickness of CIMT was associated with significantly lower scores on the verbal learning factor (β = −0.07 per 0.1 mm increase CIMT [SE(β)=0.03], p=0.01). CAC and AAC were not individually associated with any of the cognitive factors.
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 but without clinically evident CVD. The association between CIMT and poor verbal learning may pertain particularly to men.
PMCID: PMC2661006  PMID: 18836986
cognitive function; atherosclerosis; cardiovascular disease; memory; verbal learning
22.  Mildly Elevated TSH and Cognition in Middle-Aged and Older Adults 
Thyroid  2009;19(2):111-117.
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.
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.
TSH levels were not associated with any of the four factor scores in the total sample or in younger (age < 60) or older (age ≥ 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).
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.
PMCID: PMC2715222  PMID: 19191743
23.  Metabolic Syndrome and Cognitive Function in Healthy Middle-Aged and Older Adults without Diabetes 
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.
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.
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).
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.
PMCID: PMC2742696  PMID: 18608045
Metabolic syndrome; Cognitive function; Hypertension; Memory; Verbal learning; Global cognition
24.  Mildly Elevated TSH and Cognition in Middle-Aged and Older Adults 
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.
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.
TSH levels were not associated with any of the four factor scores in the total sample or in younger (age<60) or older (age≥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).
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.
PMCID: PMC2715222  PMID: 19191743

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