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Introduction and hypothesis
Acidic fruits are commonly cited in the lay press as potential bladder irritants that may promote urinary incontinence (UI), but no epidemiologic studies have examined this issue. We hypothesized that higher intake of acidic fruits might be related to greater risk of UI incidence and progression in women.
In one set of analyses, we included women without UI at study baseline in the Nurses’ Health Studies (NHS), with 34,144 women aged 54–79 in NHS I and 31,024 women aged 37–54 in NHS II. These cohorts were established among women living in the United States. Incident UI was ascertained over four years of follow up, and acidic fruit consumption was measured by food frequency questionnaire prior to UI onset. In a second set of analyses, we examined UI progression over two years of follow up among 11,764 women in NHS I and 11,299 women in NHS II with existing UI. Multivariable-adjusted relative risks were calculated for the associations of acidic fruit intake and UI incidence and progression.
We found no relation between acidic fruit intake and risk of developing UI, including urgency, mixed, and stress UI. In addition, there was no association between consumption of acidic fruits and UI progression, regardless of UI type.
No associations were detected between acidic fruit intake and UI in this large, prospective study of women. These data have implications for the development of evidence-based dietary guidelines around acidic fruits and UI, particularly because acidic fruits likely have many health benefits.
PMCID: PMC3558558  PMID: 22878474
aging; cohort studies; diet; epidemiology; urinary incontinence
2.  Exposure to ultraviolet-B and risk of developing rheumatoid arthritis among women in the Nurses’ Health Study 
Annals of the rheumatic diseases  2013;72(4):506-511.
To examine the association between ultraviolet-B (UV-B) light exposure and rheumatoid arthritis (RA) risk among women in two large prospective cohort studies, the Nurses’ Health Study (NHS) and the Nurses’ Health Study II (NHSII).
A total of 106 368 women from NHS, aged 30–55 years in 1976, and 115 561 women from NHSII, aged 25–42 in 1989, were included in the analysis. We identified women with incident RA from the start of each cohort until 2008 (NHS) and 2009 (NHSII). Cumulative average UV-B flux, a composite measure of ambient UV exposure based on latitude, altitude and cloud cover, was estimated according to state of residence and categorised as low, medium or high. Estimates of UV-B at birth and age 15 years were also examined. We used multivariable-adjusted Cox proportional hazards models to estimate HR and 95% CI.
1314 incident RA cases were identified in total. Among NHS participants, higher cumulative average UV-B exposure was associated with decreased RA risk; those in the highest versus lowest category had a 21% decreased RA risk (HR (95% CI); 0.79 (0.66 to 0.94)). UV-B was not associated with RA risk among younger women in NHSII (1.12 (0.87 to 1.44)). Results were similar for UV-B at birth and at age 15.
These results suggest that ambient UV-B exposure is associated with a lower RA risk in NHS, but not NHSII. Differences in sun-protective behaviours (eg, greater use of sun block in younger generations) may explain the disparate results.
PMCID: PMC3678095  PMID: 23380431
3.  Cumulative exposure to lead and cognition in persons with Parkinson’s disease 
Dementia is an important consequence of Parkinson’s disease (PD), with few known modifiable risk factors. Cumulative exposure to lead, at levels experienced in the community, may exacerbate PD-related neural dysfunction, resulting in impaired cognition.
Among 101 persons with PD (“cases”) and, separately, 50 persons without PD (“controls”), we evaluated cumulative lead exposure, gauged via tibia and patella bone lead concentrations, in relation to cognitive function, assessed using a telephone battery developed and validated in a separate sample of PD patients. We also assessed the interaction between lead and case-control status.
After multivariable adjustment, higher tibia bone lead concentration among PD cases was associated with worse performance on all of the individual telephone tests. In particular, tibia lead levels corresponded to significantly worse performance on a telephone analogue of the Mini-Mental State Examination and tests of working memory and attention. Moreover, higher tibia bone lead concentration was associated with significantly worse global composite score encompassing all the cognitive tests (P=0.04). The magnitude of association per standard deviation increment in tibia bone lead level was equivalent to the difference in global scores among controls in our study who were about seven years apart in age. The tibia lead-cognition association was notably stronger within cases than within controls (Pdifference=0.06). Patella bone lead concentration was not consistently associated with performance on the tests.
These data provide evidence suggesting that cumulative exposure to lead may result in worsened cognition among persons with PD.
PMCID: PMC3581753  PMID: 23143985
lead exposure; cognitive function; Parkinson’s disease
4.  The Association of Antioxidants and Cognition in the Nurses’ Health Study 
American Journal of Epidemiology  2012;177(1):33-41.
The authors examined long-term antioxidant intake in relation to cognitive decline among older women. Beginning in 1980, Nurses’ Health Study (NHS) participants completed dietary assessments every 4 years; in 1995–2001, 16,010 participants aged ≥70 years completed initial cognitive assessments, which were repeated 3 times at 2-year intervals. Long-term antioxidant intake was averaged from 1980 through the time of initial cognitive interviews. Multivariable-adjusted linear regression was used to estimate mean differences in rates of cognitive decline across categories of vitamin E, vitamin C, and carotenoid intake; statistical tests were 2-sided. No associations were evident for vitamin E or total carotenoid intake and cognitive decline (e.g., after multivariable adjustment, P-trend = 0.44 and P-trend = 0.51, respectively, for a global composite score averaging all 6 cognitive tests), although higher lycopene intake and lower vitamin C intake were related to slower cognitive decline. In alternative analyses of overall cognitive status at older ages (averaging all 4 cognitive assessments), results for vitamins E and C were generally null, but higher carotenoid intake was related to better cognition. Overall, long-term vitamin E and C intakes were not consistently related to cognition, although greater consumption of carotenoids may have cognitive benefits in older adults.
PMCID: PMC3590037  PMID: 23221724
antioxidants; cognition; cohort studies; diet
5.  A Randomized Trial of Long-term Multivitamin Supplementation and Cognitive Function in Men: The Physicians’ Health Study II 
Archives of internal medicine  2007;167(20):10.1001/archinte.167.20.2184.
Despite widespread use of multivitamin supplements, their effect on cognitive health – a critical issue with aging – remains inconclusive. To date, there have been no long-term clinical trials to study multivitamin use and cognitive decline in older persons.
To evaluate whether long-term multivitamin supplementation affects cognitive health in later-life.
Randomized, double-blind, placebo-controlled trial of a multivitamin from 1997 to June 1, 2011. The cognitive function sub-study began in 1998; we completed up to four repeated cognitive assessments by telephone interview over 12 years.
The Physicians’ Health Study II.
5,947 male physicians aged ≥ 65 years.
Daily multivitamin, or placebo.
A global composite score averaging 5 tests of global cognition, verbal memory, and category fluency. The secondary endpoint was a verbal memory score combining 4 tests of verbal memory, a strong predictor of Alzheimer disease.
There was no difference in the mean cognitive change over time between the multivitamin and placebo groups, or in the mean level of cognition at any of the four assessments. Specifically, for the global composite score, the mean difference in cognitive change over follow-up was −0.01 (95% confidence interval [CI] −0.04, 0.02) standard units, comparing treatment versus placebo. Similarly, there was no difference in cognitive performance between the treated and placebo groups on the secondary outcome, verbal memory (e.g., mean difference in cognitive change over follow-up=−0.005, 95% CI −0.04, 0.03).
Doses of vitamins may be too low, or population may be too well-nourished to benefit from multivitamin.
In male physicians aged ≥ 65 years, long-term use of a daily multivitamin did not provide cognitive benefits.
Trial Registration identifier: NCT00270647
PMCID: PMC3858850  PMID: 17998490
multivitamin; cognitive function; randomized clinical trial; men
The Journal of urology  2012;188(5):1816-1821.
Little research has investigated the epidemiology of urinary incontinence (UI) in individuals with type 2 diabetes (T2D). We examined prevalence, incidence, and risk factors for UI among women with T2D in the Nurses’ Health Study (NHS) and NHS II.
Materials and Methods
We obtained UI information at study baseline (2000 in NHS and 2001 in NHS II) and two follow ups (2002 and 2004 in NHS, and 2003 and 2005 in NHS II). Among women with T2D, we calculated UI prevalence for 9,994 women with baseline UI information, and UI incidence rates for 4,331 women with no UI at baseline and UI information during follow up. Multivariable-adjusted odds ratios (ORs) and relative risks (RRs) were estimated for associations between possible risk factors and UI.
Prevalence of at least monthly UI was 48% and at least weekly UI was 29% among women with T2D; corresponding incidence rates were 9.1 and 3.4 per 100 person-years, respectively. White race, higher BMI, higher parity, lower physical activity, current post-menopausal hormone use, and diuretic use were risk factors for prevalent and incident UI in this study, and hysterectomy, vascular disease, and longer duration of diabetes were associated with increased odds of prevalent UI only. Increasing age and microvascular complications were associated with greater risk of developing frequent UI.
UI was very common in this study of women with T2D. We identified multiple risk factors for UI in these women, several of which suggest ways for women with T2D to reduce UI.
PMCID: PMC3646531  PMID: 22999689
urinary incontinence; type 2 diabetes; epidemiology; women
7.  Anti-citrullinated peptide autoantibodies, human leukocyte antigen shared epitope and risk of future rheumatoid arthritis: a nested case–control study 
Arthritis Research & Therapy  2013;15(5):R159.
The aim of this study was to characterize anti-citrullinated peptide antibody (ACPA) serostatus in pre-clinical rheumatoid arthritis (RA) with and without Human Leukocyte Antigen-Shared Epitope (HLA-SE) alleles.
We identified 192 women in the Nurses’ Health Study cohorts with blood samples obtained 4 months to 17 years prior to medical record-confirmed RA diagnosis. Three controls were selected matched on age, cohort, menopausal status and post-menopausal hormone use. Reactivities to 18 ACPAs were measured using a custom BioPlex platform. We used conditional logistic regression to calculate the relative risk (RR) of RA for any ACPA-positive and peptide-specific ACPA-positive and examined RRs by time between blood draw and RA onset. Measures of multiplicative and additive interaction between any ACPA-positive and HLA-SE were calculated.
All ACPAs by peptide groups were significantly associated with RA risk, RRs ranged from 4.7 to 11.7. The association between ACPA and RA varied over time with the strongest association in those with blood draw less than 5 years before onset (RR 17.0 [95% CI 5.8 to 53.7]) and no association 10 or more years prior to onset (RR 1.4 [95% CI 0.5 to 4.3]). Individuals with both HLA-SE and any ACPA-positive had the highest risk of RA. HLA-SE-positive RA cases showed reactivity to more ACPA types than HLA-SE negative (χ2 test for trend, P = 0.01).
There is increasing ACPA reactivity up to 10 years before RA onset with the strongest association within 5 years of RA onset. The magnitude of the response to ACPAs, in combination with the presence of HLA-SE, is most important for identifying those individuals with the highest risk of RA.
PMCID: PMC3953952  PMID: 24286474
8.  Plasma Amyloid β as a Predictor of Dementia and Cognitive Decline: A Systematic Review and Meta-analysis 
Archives of neurology  2012;69(7):824-831.
Preclinical prediction of Alzheimer’s disease is important, critical to effective intervention. Plasma levels of amyloid β-peptides have been a principal focus of the growing literature on blood-based biomarkers, but studies to date have varied in design, assay methods and sample size, making it difficult to readily interpret the overall data.
To conduct a systematic review and meta-analysis of relevant prospective studies in order to determine if plasma amyloid β levels may predict development of dementia, Alzheimer’s disease, and cognitive decline.
Data Sources
Prospective studies published between 1995 and 2011 indexed in the PubMed, EMBASE, and PsycInfo databases were searched.
Study Selection
Selected studies included those measuring at least one relevant plasma amyloid β species (Aβ40, Aβ42, Aβ42:Aβ40 ratio) and reporting an effect estimate for dementia, Alzheimer’s disease, or cognitive change.
Data Extraction
Using a standardized extraction form, appropriate study parameters on subject information, exposure, and outcome were extracted. Random effects models were utilized to generate summary risk ratios and 95% confidence intervals, comparing the bottom versus top quantile for each plasma measure.
Thirteen studies with a total of 10,303 subjects met inclusion criteria for meta-analysis. Lower Aβ42:Aβ40 ratios were significantly associated with development of Alzheimer’s disease (summary RR=1.60, 95% CI=1.04,2.46; p=0.03) and dementia (RR=1.67 95% CI=1.02,2.75; p=0.04). Significant heterogeneity was found for both summary estimates, which could not be explained by participants’ age, sex distribution, the study’s follow-up time, or year of publication. Plasma levels of Aβ40 and Aβ42 alone were not significantly associated with either outcome.
Overall, the literature indicates that plasma Aβ42:Aβ40 ratios predict development of Alzheimer’s disease and dementia. However, significant heterogeneity in the meta-analysis underlines the need for substantial further investigation of plasma amyloid β levels as a preclinical biomarker.
PMCID: PMC3772635  PMID: 22451159
9.  Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease 
Epidemiology (Cambridge, Mass.)  2008;19(6):766-779.
The Women’s Health Initiative randomized trial found greater coronary heart disease (CHD) risk in women assigned to estrogen/progestin therapy than in those assigned to placebo. Observational studies had previously suggested reduced CHD risk in hormone users.
Using data from the observational Nurses’ Health Study, we emulated the design and intention-to-treat (ITT) analysis of the randomized trial. The observational study was conceptualized as a sequence of “trials” in which eligible women were classified as initiators or noninitiators of estrogen/progestin therapy.
The ITT hazard ratios (95% confidence intervals) of CHD for initiators versus noninitiators were 1.42 (0.92 – 2.20) for the first 2 years, and 0.96 (0.78 – 1.18) for the entire follow-up. The ITT hazard ratios were 0.84 (0.61 – 1.14) in women within 10 years of menopause, and 1.12 (0.84 – 1.48) in the others (P value for interaction = 0.08). These ITT estimates are similar to those from the Women’s Health Initiative. Because the ITT approach causes severe treatment misclassification, we also estimated adherence-adjusted effects by inverse probability weighting. The hazard ratios were 1.61 (0.97 – 2.66) for the first 2 years, and 0.98 (0.66 – 1.49) for the entire follow-up. The hazard ratios were 0.54 (0.19 – 1.51) in women within 10 years after menopause, and 1.20 (0.78 – 1.84) in others (P value for interaction = 0.01). Finally, we also present comparisons between these estimates and previously reported NHS estimates.
Our findings suggest that the discrepancies between the Women’s Health Initiative and Nurses’ Health Study ITT estimates could be largely explained by differences in the distribution of time since menopause and length of follow-up.
PMCID: PMC3731075  PMID: 18854702
10.  Dietary fat types and 4-year cognitive change in community-dwelling older women 
Annals of Neurology  2012;72(1):124-134.
To relate dietary fat types to cognitive change in healthy community-based elders.
Among 6,183 older participants in the Women’s Health Study, we related intake of major fatty acids (FAs) (saturated [SFA], mono-unsaturated [MUFA], total poly-unsaturated [PUFA], trans-unsaturated) to late-life cognitive trajectory. Serial cognitive testing, conducted over 4 years, began 5 years post-dietary assessment. Primary outcomes were global cognition (averaging tests of general cognition, verbal memory and semantic fluency) and verbal memory (averaging tests of recall). We used analyses of response profiles and logistic regression to estimate multivariable-adjusted differences in cognitive trajectory and risk of worst cognitive change (worst 10%) by fat intake.
Higher SFA intake was associated with worse global cognitive (p-linear-trend=0.008) and verbal memory (p-linear-trend=0.01) trajectories. There was a higher risk of worst cognitive change, comparing highest vs. lowest SFA quintiles: the multivariable-adjusted odds ratio (OR) (95% confidence interval, CI) was 1.64 (1.04,2.58) for global cognition and 1.65 (1.04,2.61) for verbal memory. By contrast, higher MUFA intake was related to better global cognitive (p-linear-trend<0.001) and verbal memory (p-linear-trend=0.009) trajectories, and lower OR (95% CI) of worst cognitive change in global cognition (0.52 [0.31,0.88]) and verbal memory (0.56 [0.34,0.94]). Total fat, PUFA, and trans fat intakes were not associated with cognitive trajectory.
Higher SFA intake was associated with worse global cognitive and verbal memory trajectories, while higher MUFA intake was related to better trajectories. Thus, different consumption levels of the major specific fat types, rather than total fat intake itself, appeared to influence cognitive aging.
PMCID: PMC3405188  PMID: 22605573
11.  Risk factors for fecal incontinence in older women 
To estimate the prevalence of fecal incontinence (FI) in older women, and examine associations between potential risk factors and prevalent FI.
We conducted a cross-sectional study of prevalent FI in 64,559 women, aged 62–87 years, in the Nurses' Health Study. Since 1976, participants provided information on health and lifestyle on mailed biennial questionnaires. Data on FI were collected in 2008. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for FI were calculated using logistic regression models.
The reported prevalence of liquid or solid stool incontinence at least monthly increased from 9% in women age 62 to 64 years to 17% in women age 85 to 87. Prevalent FI was 50% less common in black women compared with white women (6% vs. 12%, respectively). Other variables associated with increased odds of FI at least monthly were pregnancy, higher body mass index, lower physical activity, functional limitations, current cigarette smoking, type 2 diabetes, high blood pressure, and neurologic disease. Urinary incontinence (UI) was a strong correlate of FI, with 63% of women with FI reporting UI at least monthly compared with 45% of women in the whole study population.
FI is a common condition among older women, and often co-occurs with UI. Potentially modifiable risk factors include body mass index, physical activity, and cigarette smoking.
PMCID: PMC3537864  PMID: 23090350
12.  Dietary intake of berries and flavonoids in relation to cognitive decline 
Annals of neurology  2012;72(1):135-143.
Berries are high in flavonoids, especially anthocyanidins, and improve cognition in experimental studies. We prospectively evaluated whether greater long-term intakes of berries and flavonoids are associated with slower rates of cognitive decline in older women.
Beginning in 1980, a semi-quantitative food frequency questionnaire was administered every four years to Nurses’ Health Study participants. In 1995–2001, we began measuring cognitive function in 16,010 participants, aged ≥70 years; follow-up assessments were conducted twice, at two-year intervals. To ascertain long-term diet, we averaged dietary variables from 1980 through the initial cognitive interview. Using multivariable-adjusted, mixed linear regression, we estimated mean differences in slopes of cognitive decline by long-term berry and flavonoid intakes.
Greater intakes of blueberries and strawberries were associated with slower rates of cognitive decline (e.g., for a global score averaging all six cognitive tests, for blueberries: p-trend=0.014 and mean difference=0.04 [95% CI=0.01, 0.07] comparing extreme categories of intake; for strawberries: p-trend= 0.022 and mean difference=0.03 [95% CI=0.00, 0.06] comparing extreme categories of intake), after adjusting for multiple potential confounders. These effect estimates were equivalent to those we find for approximately 1.5 to 2.5 years of age in our cohort, indicating that berry intake appears to delay cognitive aging by up to 2.5 years. Additionally, in further supporting evidence, greater intakes of anthocyanidins and total flavonoids were associated with slower rates of cognitive decline (p-trends= 0.015 and 0.053, respectively, for the global score).
Higher intake of flavonoids, particularly from berries, appears to reduce rates of cognitive decline in older adults.
PMCID: PMC3582325  PMID: 22535616
13.  Mediterranean diet and cognitive decline in women with cardiovascular disease or risk factors 
Cardiovascular disease and vascular risk factors increase rates of cognitive impairment, but very little is known regarding prevention in this high-risk group. The heart-healthy Mediterranean-type dietary pattern may beneficially influence both vascular and cognitive outcomes.
We examined the association between Mediterranean-style diet and cognitive decline in women with prevalent vascular disease or ≥3 coronary risk factors.
Design / Participants / Setting
Prospective cohort study among 2504 women participants of the Women’s Antioxidant Cardiovascular Study (WACS), a cohort of female health professionals Adherence to the Mediterranean diet was determined at WACS baseline (1995–1996) using a zero-to-nine-point scale with higher scores indicating higher adherence. In 1998–2000, participants aged ≥ 65 years underwent a telephone cognitive battery including five tests of global cognition, verbal memory, and category fluency. Tests were administered three additional times over 5.4 years.
Statistical analyses performed
We used multivariable-adjusted generalized linear models for repeated measures to compare the annual rates of cognitive score changes across tertiles of Mediterranean diet score, as assessed at WACS baseline.
In both basic- and multivariable-adjusted models, Mediterranean diet was not related to cognitive decline. No effect modification was detected by age, education, depression, cardiovascular disease severity at WACS baseline, or level of cognition at initial assessment.
In women at higher risk of cognitive decline due to vascular disease or risk factors, adherence to the Mediterranean diet was not associated with subsequent 5-year cognitive change.
PMCID: PMC3378990  PMID: 22709809
cognitive decline; vascular disease; hypertension; Mediterranean diet; longitudinal study
14.  Caffeine Intake and Risk of Urinary Incontinence Progression Among Women 
Obstetrics and Gynecology  2012;119(5):950-957.
To estimate the association between long-term caffeine intake and risk of urinary incontinence (UI) progression over 2 years among women with moderate UI.
We conducted a prospective cohort study in 21,564 women with moderate UI enrolled in the Nurses’ Health Study and Nurses’ Health Study II. Incontinence progression was identified from questionnaires during 2 years of follow-up. Baseline caffeine intake (ie, average intake during the past year) and change in caffeine intake during the 4 years prior to baseline were measured using food frequency questionnaires. Odds ratios (ORs) for incontinence progression according to caffeine intake were calculated for each cohort separately, and then for both cohorts combined.
The percentage of women with UI progression was similar across categories of baseline level of caffeine intake and change in caffeine intake prior to baseline. For example, percentages were 21% versus 22% comparing 450 mg or more to less than 150 mg of caffeine per day (adjusted OR 0.87, 95% confidence interval [CI] 0.70-1.08). Comparing women with increased caffeine intake to those with stable caffeine intake, percentages with progression were 22% versus 20% (OR 1.08, 95% CI 0.95-1.22). Results were similar in separate analyses of urgency and stress UI.
Long-term caffeine intake over one year was not associated with risk of UI progression over 2 years among women with moderate incontinence, although we could not examine acute effects of caffeine. Improved understanding of the effect of caffeine on the bladder is needed to better advise women with incontinence about caffeine intake.
PMCID: PMC3336097  PMID: 22525905
15.  Exposure to Particulate Air Pollution and Cognitive Decline in Older Women 
Archives of internal medicine  2012;172(3):219-227.
Chronic exposure to particulate air pollution may accelerate cognitive decline in older adults, although data on this association are limited. Our objective was to examine long-term exposure to particulate matter (PM) air pollution, both coarse ([PM 2.5–10 μm in diameter [PM2.5-10]) and fine (PM <2.5 μm in diameter [PM2.5]), in relation to cognitive decline.
The study population comprised the Nurses’ Health Study Cognitive Cohort, which included 19 409 US women aged 70 to 81 years. We used geographic information system–based spatiotemporal smoothing models to estimate recent (1 month) and long-term (7–14 years) exposures to PM2.5-10, and PM2.5 preceding base-line cognitive testing (1995–2001) of participants residing in the contiguous United States. We used generalized estimating equation regression to estimate differences in the rate of cognitive decline across levels of PM2.5-10 and PM2.5 exposures. The main outcome measure was cognition, via validated telephone assessments, administered 3 times at approximately 2-year intervals, including tests of general cognition, verbal memory, category fluency, working memory, and attention.
Higher levels of long-term exposure to both PM2.5-10 and PM2.5 were associated with significantly faster cognitive decline. Two-year decline on a global score was 0.020 (95% CI, −0.032 to −0.008) standard units worse per 10 μg/m3 increment in PM2.5-10 exposure and 0.018 (95% CI, −0.035 to −0.002) units worse per 10 μg/m3 increment in PM2.5 exposure. These differences in cognitive trajectory were similar to those between women in our cohort who were approximately 2 years apart in age, indicating that the effect of a 10-μg/m3 increment in long-term PM exposure is cognitively equivalent to aging by approximately 2 years.
Long-term exposure to PM2.5-10 and PM2.5 at levels typically experienced by many individuals in the United States is associated with significantly worse cognitive decline in older women.
PMCID: PMC3622279  PMID: 22332151
16.  The relation between insulin, insulin-related factors, and plasma amyloid beta peptide levels at mid-life in a population-based study 
Little is known regarding factors associated with soluble amyloid beta peptide (Aβ) concentrations in humans at late midlife, when Aβ is likely most critical to Alzheimer disease pathogenesis. We examined the association between insulin, insulin-related factors, and plasma Aβ at late midlife. Plasma Aβ42, Aβ40, fasting insulin, and c-peptide were measured in 468 women without diabetes, aged 59–69 years (median 63 years). Prior to blood draw, participants reported body mass index, waist circumference, physical activity, alcohol intake, hypertension, and diabetes family history. Linear regression was used to calculate age-adjusted mean differences in Aβ42 to Aβ40 ratio, and Aβ42 levels, by insulin and insulin-related factors. The ratio of Aβ42 to Aβ40 was statistically significantly lower in women with diabetes family history, and Aβ42 was significantly lower with less physical activity, greater waist circumference, hypertension, and diabetes family history (p<0.05 for all). Aβ42 to Aβ40 ratio, and Aβ42 levels, appeared lower with higher c-peptide levels (p-trend=0.07 and 0.06, respectively), although these were not statistically significant. In summary, insulin-related factors appear associated with lower plasma Aβ42 to Aβ40 ratio, and Aβ42, at late mid-life, consistent with increased brain sequestration of Aβ42 (relative to Aβ40), suggesting insulin merits focus in strategies to prevent dementia.
PMCID: PMC3140548  PMID: 21502851
amyloid beta peptide; insulin; epidemiology
17.  Postmenopausal Hormone Therapy, Timing of Initiation, APOE and Cognitive Decline 
Neurobiology of aging  2010;33(7):1129-1137.
Associations between postmenopausal hormone therapy (HT) and cognitive decline may depend on apolipoprotein E (APOE) status or timing of initiation.
We included 16,514 Nurses’ Health Study participants aged 70–81 years who were followed since 1976 and completed up to three telephone cognitive assessments (2 years apart), between 1995 and 2006. The tests assessed general cognition (Telephone Interview of Cognitive Status (TICS)), verbal memory, and category fluency. We used longitudinal analyses to estimate differences in cognitive decline across hormone groups. APOE genotype was available in 3697 participants.
Compared with never users, past or current HT users showed modest but statistically significant worse rates of decline in the TICS: the multivariable-adjusted difference in annual rate of decline in the TICS among current estrogen only users versus never users was −0.04 (95% CI = −0.07, −0.004); for current estrogen+progestin users, the mean difference was −0.05 (95% CI = −0.10, −0.002). These differences were equivalent to those observed in women who are 1–2 years apart in age. We observed no protective associations with early timing of hormone initiation. We found suggestive interactions with APOE e4 status (e.g., on TICS, p-interaction = 0.10), where the fastest rate of decline was observed among APOE e4 carriers who were current HT users.
Regardless of timing of initiation, HT may be associated with worse rates of decline in general cognition, especially among those with an APOE e4 allele.
PMCID: PMC3483632  PMID: 21122949
High homocysteine levels may be neurotoxic and contribute to cognitive decline in older persons.
Examine the effect of supplementation with folic acid, vitamin B12 and vitamin B6 on cognitive change among women with cardiovascular disease (CVD) or CVD risk factors.
The Women's Antioxidant and Folic Acid Cardiovascular Study is a randomized, placebo-controlled trial to test a combination of B vitamins (folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg, daily) for secondary prevention of CVD. Randomization took place among 5,442 female health professionals, 40+ years, with CVD or at least three coronary risk factors in 1998 (after folic acid fortification began in the US). Shortly after randomization (mean=1.2 years), a cognitive function substudy was initiated among 2009 participants aged 65+ years. Telephone cognitive function testing was administered up to four times over 5.4 years with 5 tests of general cognition, verbal memory and category fluency. Repeated measures analyses were conducted. The primary outcome was a global composite score averaging all tests.
Mean cognitive change from baseline did not differ between the B vitamin and placebo groups (difference in change in global score= 0.03, 95% CI −0.03, 0.08; p=0.30). However, supplementation appeared to confer benefits in preserving cognition among women with low baseline dietary intake of B vitamins.
Combined B vitamin supplementation did not delay cognitive decline among women with CVD or CVD risk factors. Possible cognitive benefits of supplementation among women with low dietary intake of B vitamins warrant further study.
PMCID: PMC3470481  PMID: 19064521
19.  Physical activity and cognition in women with vascular conditions 
Archives of internal medicine  2011;171(14):1244-1250.
Individuals with vascular disease or risk factors have substantially higher rates of cognitive decline, yet little is known on means of maintaining cognition in this group.
We examined the relation between physical activity and cognitive decline in participants of the Women’s Antioxidant Cardiovascular Study (WACS), a cohort of women with prevalent vascular disease or ≥3 coronary risk factors. Recreational physical activity was assessed at baseline (1995–1996) and every two years thereafter. In 1998–2000, participants aged ≥65 years underwent a telephone cognitive battery including five tests of global cognition, verbal memory, and category fluency (n=2809). Tests were administered three additional times over 5.4 years. We used multivariable-adjusted generalized linear models for repeated measures to compare the annual rates of cognitive score changes across levels of total physical activity and on walking, as assessed at WACS baseline.
We found a significant trend (p-trend<0.001) of slower rates of cognitive decline with increasing energy expenditure. Compared to the bottom quintile of total physical activity, significant differences in rates of cognitive decline were observed from the fourth quintile (p=0.04 for fourth quintile, p<0.001 for fifth quintile) or the equivalent of daily 30-minute walks at a brisk pace. This difference was equivalent to the difference in cognitive decline observed for women who were younger by 5–7 years. Walking was also strongly related to slower rates of cognitive decline (p-trend=0.003).
Regular physical activity, including walking, was associated with better preservation of cognitive function in older women with vascular disease or risk factors.
PMCID: PMC3153432  PMID: 21771894
20.  Fluid intake and risk of stress, urgency, and mixed urinary incontinence 
We investigated the relation between total fluid intake and incident urinary incontinence in the Nurses’ Health Study cohorts.
Study Design
We measured daily fluid intake using food frequency questionnaires among 65,167 women, aged 37–79 years, without urinary incontinence at study baseline (2000–2001). Women reported incontinence incidence on questionnaires during 4 years of follow-up. Multivariable-adjusted hazard ratios and 95% confidence intervals were calculated using Cox proportional hazards models.
We found no association between total fluid intake and risk of incident incontinence (hazard ratio 1.04, 95% confidence interval 0.98–1.10 comparing top versus bottom quintile of fluid intake). In analyses of incontinence type, total fluid intake was not associated with risks of incident stress, urgency, or mixed incontinence.
No significant risk of incident urinary incontinence was found with higher fluid intake in women. These findings suggest that women should not restrict their fluid intake to prevent incontinence development.
PMCID: PMC3135667  PMID: 21481835
epidemiology; fluid intake; urinary incontinence
21.  Caffeine intake and risk of stress, urgency, and mixed urinary incontinence 
The Journal of urology  2011;185(5):1775-1780.
Although caffeine consumption is common, and is generally believed to affect bladder function, little is known regarding caffeine intake and incident urinary incontinence.
Materials and Methods
We conducted a prospective cohort study of 65,176 women without incontinence, aged 37–79 years, in the Nurses’ Health Studies. Incident incontinence was identified from questionnaires, during 4 years of follow-up. Caffeine intake was measured using food frequency questionnaires administered prior to incontinence development. Multivariable-adjusted relative risks for the relation between caffeine intake and incontinence risk were calculated, as well as attributable risks.
Caffeine was not associated with incontinence monthly or more, but there was a modest, significantly increased risk of incontinence at least weekly among women with the highest versus the lowest intake (RR 1.19, 95% CI 1.06–1.34, comparing >450 vs. <150 mg/day) and a significant trend of increasing risk with increasing intake (p-value for trend=0.01). This risk appeared focused in incident urgency incontinence (RR 1.34, 95% CI 1.00–1.80 comparing >450 vs. <150 mg/day, p-value for trend=0.05), but not stress or mixed incontinence (p-values for trend=0.75 and 0.19, respectively). The attributable risk for urgency incontinence associated with high caffeine intake was 25%.
Our findings suggest that high caffeine intake, but not lower levels, is associated with a modest increase in incidence of frequent urgency incontinence; one-quarter of these cases among women with the highest level of caffeine consumption might be eliminated if high caffeine intake was eliminated. Confirmation of these findings in other studies is needed before recommendations can be made.
PMCID: PMC3077934  PMID: 21420114
urinary incontinence; caffeine; epidemiology
22.  Remission and progression of urinary incontinence among Asian, black, and white women in the United States 
The American journal of nursing  2011;111(4):26-35.
Growing evidence suggests that urinary incontinence prevalence and incidence in women vary by race. However, little is known regarding potential racial differences in remission and progression of incontinence, which would have meaningful implications for clinicians who treat incontinence.
To compare changes in incontinence frequency over two years among Asian, black, and white women with incontinence.
Participants in the Nurses’ Health Study cohorts provided information on their race and incontinence frequency on mailed questionnaires. Prospective analyses over two years of follow-up included 57,900 women aged 37–79 years with at least monthly incontinence at baseline.
Changes in incontinence frequency appeared to vary by race, even after adjusting for a large variety of risk factors for incontinence. Specifically, compared with white women, black women were more likely to report no incontinence at follow-up (14% remission in black women vs. 9% in white women). Asian women were more likely to report any decrease in incontinence frequency (40% improvement in Asian women vs. 31% in white women). Incontinence improvement was also more common in black versus white women in analyses restricted to older women, although reports of improvement were similar among black and white women aged 54 years and younger. Black women were less likely to report a higher frequency of incontinence at follow-up (30% progression in black women vs. 34% in white women), and this difference was borderline statistically significant.
Higher odds of incontinence remission in black women, and improvement in Asian American women, compared with white women, may account for some of the previously observed differences in incontinence prevalence across racial groups, and were independent of health and lifestyle factors. Although incontinence is a common condition in women of all races, clinicians should be aware that the natural history of incontinence may differ across racial groups.
PMCID: PMC3201776  PMID: 21451292
urinary incontinence; race; epidemiology
23.  Relative Telomere Length and Cognitive Decline in the Nurses’ Health Study 
Neuroscience Letters  2011;492(1):15-18.
Telomeres are short DNA repeats on the ends of mammalian chromosomes, which can undergo incomplete replication leading to gradual shortening with each cell cycle. Age and oxidative stress are contributors to telomere shortening; thus, telomere length may be a composite measure of biologic aging, and a potential predictor of health status in older adults. We evaluated whether relative telomere length (the proportion of telomere repeat copy number to single gene copy number, using a real-time PCR method) predicts cognitive decline measured ten years later among ~2,000 older participants in the Nurses’ Health Study (NHS). Mixed linear regression was used to evaluate mean differences in cognitive decline according to telomere length. After adjustment for potential confounders, we found that decreasing telomere length was associated with more cognitive decline, although associations were modest (e.g. for a global score, averaging all six tests in our cognitive battery, mean difference=0.03 standard units per SD increase in telomere length; p=0.04). The magnitude of these estimates was similar to the differences we find in this cohort for women one year apart in age (e.g. the differences that we observe between women who are 73 versus 74 years of age); thus, our results suggest that telomere length is not a particularly powerful marker of impending cognitive decline.
PMCID: PMC3306217  PMID: 21295115
Telomeres; cognitive function; aging; epidemiology
24.  Specific Subjective Memory Complaints in Older Persons May Indicate Poor Cognitive Function 
To examine the association between the type and number of subjective memory complaints (SMCs) and performance on objective cognitive tests.
Nurses’ Health Study.
Sixteen thousand nine hundred sixty-four women (mean age 74) who provided information on SMCs.
Telephone cognitive assessments and seven questions regarding SMCs were administered. Cognitive impairment was defined as a score of less than 31 on the Telephone Interview for Cognitive Status (TICS) and below the 10th percentile on other cognitive measures. To assess associations with SMCs, multivariable logistic regression was used to calculate odds ratios for cognitive impairment and multivariable linear regression to calculate mean differences in cognitive test scores, adjusting for age and depressive symptoms.
Some SMCs, such as trouble following a group conversation or finding one’s way around familiar streets, were more highly associated than others with odds of cognitive impairment. The complaint of forgetting things from one second to the next, generally considered part of normal aging, was not associated with cognitive impairment. In addition, there were strong, linear trends of increasingly worse scores on cognitive tests with increasing numbers of memory complaints. For each additional SMC endorsed, the odds of cognitive impairment increased approximately 20% when each SMC was weighted equally.
SMCs are associated with objective cognitive status and may be considered by primary care physicians in determining whether follow-up is warranted.
PMCID: PMC3315361  PMID: 21919893
memory complaints; cognitive function; aging
25.  Adiposity and weight change in mid-life in relation to healthy survival after age 70 in women: prospective cohort study 
Objective To examine the hypothesis that mid-life adiposity is associated with a reduced probability of maintaining an optimal health status among those who survive to older ages.
Design Prospective cohort study.
Setting The Nurses’ Health Study, United States.
Participants 17 065 women who survived until at least the age of 70, provided information on occurrence of chronic disease, cognitive function, physical function, and mental health at older ages, and were free from major chronic diseases at mid-life (mean age was 50 at baseline in 1976).
Main outcome measures Healthy survival to age 70 and over was defined as having no history of 11 major chronic diseases and having no substantial cognitive, physical, or mental limitations.
Results Of the women who survived until at least age 70, 1686 (9.9%) met our criteria for healthy survival. Increased body mass index (BMI) at baseline was significantly associated with linearly reduced odds of healthy survival compared with usual survival, after adjustment for various lifestyle and dietary variables (P<0.001 for trend). Compared with lean women (BMI 18.5-22.9), obese women (BMI ≥30) had 79% lower odds of healthy survival (odds ratio 0.21, 95% confidence interval 0.15 to 0.29). In addition, the more weight gained from age 18 until mid-life, the less likely was healthy survival after the age of 70. The lowest odds of healthy survival were among women who were overweight (BMI ≥25) at age 18 and gained ≥10 kg weight (0.18, 0.09 to 0.36), relative to women who were lean (BMI 18.5-22.9) and maintained a stable weight.
Conclusions These data provide evidence that adiposity in mid-life is strongly related to a reduced probability of healthy survival among women who live to older ages, and emphasise the importance of maintaining a healthy weight from early adulthood.
PMCID: PMC3230231  PMID: 19789407

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