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2.  Intraindividual Variability in Domain-Specific Cognition and Risk of Mild Cognitive Impairment and Dementia 
Intraindividual variability among cognitive domains may predict dementia independently of interindividual differences in cognition. A multidomain cognitive battery was administered to 2305 older adult women (mean age 74 years) enrolled in an ancillary study of the Women's Health Initiative. Women were evaluated annually for probable dementia and mild cognitive impairment (MCI) for an average of 5.3 years using a standardized protocol. Proportional hazards regression showed that lower baseline domain-specific cognitive scores significantly predicted MCI (N = 74), probable dementia (N = 45), and MCI or probable dementia combined (N = 101) and that verbal and figural memory predicted each outcome independently of all other cognitive domains. The baseline intraindividual standard deviation across test scores (IAV Cognitive Domains) significantly predicted probable dementia and this effect was attenuated by interindividual differences in verbal episodic memory. Slope increases in IAV Cognitive Domains across measurement occasions (IAV Time) explained additional risk for MCI and MCI or probable dementia, beyond that accounted for by interindividual differences in multiple cognitive measures, but risk for probable dementia was attenuated by mean decreases in verbal episodic memory slope. These findings demonstrate that within-person variability across cognitive domains both at baseline and longitudinally independently accounts for risk of cognitive impairment and dementia in support of the predictive utility of within-person variability.
doi:10.1155/2013/495793
PMCID: PMC3881440  PMID: 24454359
3.  The Effect of Calcium plus Vitamin D on Risk for Invasive Cancer: Results of the Women’s Health Initiative (WHI) Calcium Plus Vitamin D Randomized Clinical Trial 
Nutrition and Cancer  2011;63(6):827-841.
In the Women’s Health Initiative (WHI) trial of calcium plus vitamin D (CaD), we examined the treatment effect on incidence and mortality for all invasive cancers. Postmenopausal women (N = 36,282) were randomized to 1,000 mg of elemental calcium with 400 IU vitamin D3 or placebo. Cox models estimated risk of cancer incidence and mortality. After 7.0 yr, 1,306 invasive cancers were diagnosed in the supplement and 1,333 in the placebo group [hazard ratio (HR) = 0.98; CI = 0.90, 1.05, unweighted P = 0.54]. Mortality did not differ between supplement (315, annualized% = .26) and placebo [(347, 0.28%; P = 0.17; HR = 0.90 (0.77, 1.05)]. Significant treatment interactions on incident cancer were found for family history of cancer, personal total intake of vitamin D, smoking, and WHI dietary trial randomized group. Calcium/vitamin D supplementation did not reduce invasive cancer incidence or mortality. Supplementation lowered cancer risk in the WHI healthy diet trial arm and in women without a first-degree relative with cancer. The interactions are only suggestive given multiple testing considerations. The low vitamin D dose provided, limited adherence, and lack of serum 25(OH)D values should be considered when interpreting these findings.
doi:10.1080/01635581.2011.594208
PMCID: PMC3403703  PMID: 21774589
4.  Toward a Positive Aging Phenotype for Older Women: Observations From the Women’s Health Initiative 
Background.
To develop a positive aging phenotype, we undertook analyses to describe multiple dimensions of positive aging and their relationships to one another in women 65 years of age and older and evaluate the performance of individual indicators and composite factors of this phenotype as predictors of time to death, years of healthy living, and years of independent living.
Methods.
Data from Women’s Health Initiative clinical trial and observational study participants ages 65 years and older at baseline, including follow-up observations up to 8 years later, were analyzed using descriptive statistics and principal components analysis to identify the factor structure of a positive aging phenotype. The factors were used to predict time to death, years of healthy living (without hospitalization or diagnosis of a serious health condition), and years of independent living (without nursing home admission or use of special services).
Results.
We identified a multidimensional phenotype of positive aging that included two factors: Physical–Social Functioning and Emotional Functioning. Both factors were predictive of each of the outcomes, but Physical–Social Functioning was the strongest predictor. Each standard deviation of increase in Physical–Social Functioning was accompanied by a 23.7% reduction in mortality risk, a 19.4% reduction in risk of major health conditions or hospitalizations, and a 26.3% reduction in risk of dependent living.
Conclusions.
Physical–Social Functioning and Emotional Functioning constitute important components of a positive aging phenotype. Physical–Social Functioning was the strongest predictor of outcomes related to positive aging, including years of healthy living, years of independent living, and time to mortality.
doi:10.1093/gerona/gls117
PMCID: PMC3667695  PMID: 22518819
Positive aging; Phenotypes; Women's health; Healthy life span
5.  Menopausal Symptom Experience Before and After Stopping Estrogen Therapy in the Women’s Health Initiative Randomized Placebo-Controlled Trial 
Menopause (New York, N.Y.)  2010;17(5):946-954.
Objective
To assess vasomotor and other menopausal symptoms before, one year later, again at trial closure and after stopping estrogens or placebo. The role of baseline symptoms and age was examined as was the frequency and determinants of hormone use and symptom management strategies after discontinuing conjugated equine estrogens or placebo.
Methods
Intention-to-treat analyses of 10,739 postmenopausal women before and one year after randomization to conjugated equine estrogens (CEE) or placebo at 40 clinical centers, and a cohort analysis of participants (n=3496) who continued taking assigned study pills up to trial closure and completed symptom surveys shortly before (mean 7.4 + 1.1 years from baseline) and after stopping pills (mean 306 + 55 days after trial closure). Generalized linear regression modeled vasomotor symptoms, vaginal dryness, breast tenderness, pain/stiffness and mood swings, as a function of treatment assignment and baseline symptoms, before and after stopping study pills.
Results
Approximately one-third of participants reported at least one moderate-to-severe symptom at baseline. Fewer symptoms were reported with increasing age, except joint pain/stiffness, which was similar among age groups. At one year, hot flashes, night sweats and vaginal dryness were reduced by CEE, whereas, breast tenderness was increased. Breast tenderness was also significantly higher in the CEE group at trial closure. Post-stopping, vasomotor symptoms were reported by significantly more women who had reported symptoms at baseline, compared to those who had not, and by significantly more participants assigned to CEE (9.8%) versus placebo (3.2%); however, among women with no moderate or severe symptoms at baseline, over 5 times as many reported hot flashes after stopping CEE (7.2%) versus placebo (1.5%).
Conclusions
CEE significantly reduced vasomotor symptoms and vaginal dryness in women with baseline symptoms, but increased breast tenderness. The likelihood of experiencing symptoms was significantly higher after stopping CEE than placebo regardless of baseline symptom status. These potential effects should be considered before initiating CEE to relieve menopausal symptoms.
doi:10.1097/gme.0b013e3181d76953
PMCID: PMC3770143  PMID: 20505547
estrogen therapy; randomized trial; symptoms; post-menopause
6.  Vitamin D Supplementation and Depression in the Women’s Health Initiative Calcium and Vitamin D Trial 
While observational studies have suggested that vitamin D deficiency increases risk of depression, few clinical trials have tested whether vitamin D supplementation affects the occurrence of depression symptoms. The authors evaluated the impact of daily supplementation with 400 IU of vitamin D3 combined with 1,000 mg of elemental calcium on measures of depression in a randomized, double-blinded US trial comprising 36,282 postmenopausal women. The Burnam scale and current use of antidepressant medication were used to assess depressive symptoms at randomization (1995–2000). Two years later, women again reported on their antidepressant use, and 2,263 completed a second Burnam scale. After 2 years, women randomized to receive vitamin D and calcium had an odds ratio for experiencing depressive symptoms (Burnam score ≥0.06) of 1.16 (95% confidence interval: 0.86, 1.56) compared with women in the placebo group. Supplementation was not associated with antidepressant use (odds ratio = 1.01, 95% confidence interval: 0.92, 1.12) or continuous depressive symptom score. Results stratified by baseline vitamin D and calcium intake, solar irradiance, and other factors were similar. The findings do not support a relation between supplementation with 400 IU/day of vitamin D3 along with calcium and depression in older women. Additional trials testing higher doses of vitamin D are needed to determine whether this nutrient may help prevent or treat depression.
doi:10.1093/aje/kwr482
PMCID: PMC3385159  PMID: 22573431
antidepressive agents; calcium; clinical trial; depression; dietary supplements; postmenopause; vitamin D; women
7.  Long Term Effects of Conjugated Equine Estrogens Therapies on Domain-Specific Cognitive Function: Results from the Women's Health Initiative Study of Cognitive Aging (WHISCA) Extension 
Objectives
Conjugated equine estrogen (CEE) therapies when initiated among older women have been shown to produce small decrements in global cognitive function. We are interested whether these persist after cessation and extend to specific cognitive domains.
Design
Randomized controlled clinical trial
Setting
Fourteen clinical centers of the Women's Health Initiative
Participants
2,304 women aged 65-80 years and free of probable dementia at enrollment
Intervention
0.625 mg/day of CEE, with or without medroxyprogesterone acetate (MPA, 10 mg/day), and matching placebos
Measurements
Annual administrations of a battery of cognitive tests during and following the trial
Methods
General linear models were used to compare on-trial and post-trial mean standardized test scores between treatment groups, with adjustment for baseline risk factors for cognitive impairment.
Results
Assignment to CEE-based therapies was associated with small mean relative decrements in global and several domain-specific cognitive functions on-trial, which largely persisted through up to 4 years post-trial. The strongest statistical evidence was for global cognitive function: 0.07 standard deviation decrements both on-trial (p=0.007) and post-trial (p=0.01). Among domain specific scores, the mean relative decrements were slightly smaller, were less significant, and tended to be larger for CEE-alone therapy.
Conclusions
CEE-based therapies, when initiated after age 65 years, produce a small broad-based decrement in cognitive function that persists after their use is stopped. The differences in cognitive function however are small and would not be detectable or have clinical significance for an individual woman. Differences in effects among cognitive domains suggest that more than one mechanism may be involved.
doi:10.1111/j.1532-5415.2010.02953.x
PMCID: PMC2917208  PMID: 20649689
Postmenopausal hormone therapy; Cognitive function; Women's health
8.  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.
doi:10.1097/WAD.0b013e3181d715d5
PMCID: PMC2929315  PMID: 20473134
MCI; women; WHIMS; postmenopausal; cognition; dementia; hormone therapy
9.  Application of machine learning methods to describe the effects of conjugated equine estrogens therapy on region-specific brain volumes 
Magnetic resonance imaging  2011;29(4):546-553.
Use of conjugated equine estrogens (CEE) has been linked to smaller regional brain volumes in women aged ≥65 years, however it is unknown whether this results in a broad-based characteristic pattern of effects. Structural MRI was used to assess regional volumes of normal tissue and ischemic lesions among 513 women who had been enrolled in a randomized clinical trial of CEE therapy for an average of 6.6 years, beginning at ages 65-80 years. A multivariate pattern analysis, based on a machine learning technique that combined Random Forest and logistic regression with L1 penalty, was applied to identify patterns among regional volumes associated with therapy and whether patterns discriminate between treatment groups. The multivariate pattern analysis detected smaller regional volumes of normal tissue within the limbic and temporal lobes among women that had been assigned to CEE therapy. Mean decrements ranged as high as 7% in the left entorhinal cortex and 5% in the left perirhinal cortex, which exceeded the effect sizes reported previously in frontal lobe and hippocampus. Overall accuracy of classification based on these patterns, however, was projected to be only 54.5%. Prescription of CEE therapy for an average of 6.6 years is associated with lower regional brain volumes, but it does not induce a characteristic spatial pattern of changes in brain volumes of sufficient magnitude to discriminate users and non-users.
doi:10.1016/j.mri.2010.12.001
PMCID: PMC3079024  PMID: 21292420
Hormone therapy; MRI; Random Forest; WHIMS
10.  Depressive Symptoms, Bone Loss, and Fractures in Postmenopausal Women 
Background
Osteoporosis and depression may be associated through common physiologic systems or risk factors.
Objective
To assess the associations between depressive symptoms (Burnam’s scale) or antidepressant use and bone outcomes.
Design
Prospective cohort study.
Participants
A total of 93,676 postmenopausal women (50 to 79 years old) enrolled in the Women’s Health Initiative Observational Study.
Measurements
Self-reported fractures (n = 14,982) (hip [adjudicated], spine, wrist, and “other”). Analyses included 82,410 women with complete information followed on average for 7.4 years. Bone mineral density (BMD) of the hip (n = 4539), spine (n = 4417), and whole body (n = 4502) was measured at baseline and 3 years in women enrolled at 3 densitometry study sites.
Results
Overall, there were no statistically significant associations between depressive symptoms or antidepressant therapy and 3-year change in BMD. In a subset of women not using antidepressants, there was a significant difference in whole-body BMD change between women with and without depressive symptoms (P = .05). Depressive symptoms (hazard ratio [HR] 1.08; 95% CI = 1.02 to 1.14) and antidepressant therapy (HR = 1.22; CI = 1.15 to 1.30) independently increased risk of any fracture, the majority of which occurred at “other” anatomic sites. Antidepressant therapy increased the risk of spine fracture (HR = 1.36; CI = 1.14 to 1.63). No associations were observed between depressive symptoms or antidepressant therapy and hip or wrist fracture.
Conclusion
In this study of postmenopausal women, average age 64, we observed minimal association between depressive symptoms and 3-year changes in either BMD or fracture risk. Antidepressant use was not associated with changes in BMD, but was associated with increased risk of fractures at the spine and “other ” anatomic sites.
doi:10.1007/s11606-008-0525-0
PMCID: PMC2324136  PMID: 18286345
depressive symptoms; antidepressants; bone density; fractures; prospective
11.  Sleep Duration and Risk of Ischemic Stroke in Postmenopausal Women 
Background
Many studies have shown a U-shape association between sleep duration and mortality, but epidemiological evidence linking cardiovascular diseases (CVD) with habitual sleep patterns is limited and mixed.
Methods
We conducted a prospective study on 93175 older women (aged 50–79 years) in the Women’s Health Initiative Observational Study cohort to examine the risk of ischemic stroke in relation to self-reported sleep duration. Cox models were used to investigate the putative associations, adjusting for multiple sociodemographic and lifestyle factors, depression, snoring, sleepiness symptoms, and other CVD-related clinical characteristics.
Results
At baseline, 8.3% of subjects had their reported sleep duration ≤5h/night and 4.6% with long sleep (≥9h/night). After an average of 7.5 years of follow-up, 1166 cases of ischemic stroke had occurred. Multivariable-adjusted relative risks (RR; 95% confidence intervals) for ischemic stroke (using a sleep time of 7h/night as the reference) were 1.14 (0.97, 1.33), 1.24 (1.04, 1.47) and 1.70 (1.32, 2.21) for women reporting 6 or less, 8, and 9 or more hours of sleep. A modestly stronger association with sleep duration ≤ 6h/night (RR=1.22; 1.03, 1.44) was noted among women without prevalent CVD at baseline. Our analyses also reveal that the adverse effect of long sleep is likely independent of the increased risk for ischemic stroke associated with frequent snoring and sleepiness (RR=1.31; 1.00, 1.72).
Conclusions
Habitual sleep patterns are important neurobehavioral determinants of risk for ischemic stroke in postmenopausal women. The underlying neurobiology and mechanistic mediators for the putative adverse effect of long sleep (≥9h/night) need further elucidation.
doi:10.1161/STROKEAHA.108.521773
PMCID: PMC2587518  PMID: 18635832
cerebral infarction; cohort studies; sleep disorders; risk factors

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