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1.  Low dose aspirin and cognitive function in middle aged to elderly adults: randomised controlled trial  
Objective To determine the effects of low dose aspirin on cognitive function in middle aged to elderly men and women at moderately increased cardiovascular risk.
Design Randomised double blind placebo controlled trial.
Setting Central Scotland.
Participants 3350 men and women aged over 50 participating in the aspirin for asymptomatic atherosclerosis trial.
Intervention Low dose aspirin (100 mg daily) or placebo for five years.
Main outcome measures Tests of memory, executive function, non-verbal reasoning, mental flexibility, and information processing five years after randomisation, with scores used to create a summary cognitive score (general factor).
Results At baseline, mean vocabulary scores (an indicator of previous cognitive ability) were similar in the aspirin (30.9, SD 4.7) and placebo (31.1, SD 4.7) groups. In the primary intention to treat analysis, there was no significant difference at follow-up between the groups in the proportion achieving over the median general factor cognitive score (32.7% and 34.8% respectively, odds ratio 0.91, 95% confidence interval 0.79 to 1.05, P=0.20) or in mean scores on the individual cognitive tests. There were also no significant differences in change in cognitive ability over the five years in a subset of 504 who underwent detailed cognitive testing at baseline.
Conclusion Low dose aspirin does not affect cognitive function in middle aged to elderly people at increased cardiovascular risk.
Trial registration ISRCTN 66587262.
doi:10.1136/bmj.a1198
PMCID: PMC2527654  PMID: 18762476
2.  Plasma c-peptide levels and rates of cognitive decline in older, community-dwelling women without diabetes 
Psychoneuroendocrinology  2008;33(4):455-461.
SUMMARY
Background
Both type 2 diabetes and hyperinsulinemia have been related to diminished cognition. To address independent effects of increasing mid-life insulin secretion on late-life cognition, we prospectively examined the relation of plasma c-peptide levels to cognitive decline in a large sample of older women without diabetes or stroke.
Methods
Plasma c-peptide levels were measured in 1,187 “young-old” women (mean age=64 years) without diabetes in the Nurses’ Health Study. Cognitive decline was assessed approximately 10 years later. Three repeated cognitive batteries were administered over an average of 4.4 years using telephone-based tests of general cognition, verbal memory, category fluency, and attention. Primary outcomes were general cognition (measured by the Telephone interview for Cognitive Status [TICS], as well as a global score averaging all tests) and a verbal memory score averaging 4 tests of word-list and paragraph recall. Linear mixed effects models were used to compute associations between c-peptide levels and rates of cognitive decline.
Results
Higher c-peptide levels were associated with faster decline in global cognition and verbal memory. Compared to those in the lowest c-peptide quartile, multivariable-adjusted mean differences (95% CI) in rates of decline for women in the highest quartile were −0.03 (−0.06, − 0.00) units/year for the global score, and −0.05 (−0.09, −0.02) units/year for verbal memory. Each one standard-deviation increase in c-peptide was associated with significantly faster decline on the TICS (p-trend=0.05), global score (p-trend=0.04) and verbal memory (p-trend=0.006).
Conclusions
Higher levels of insulin secretion in those without diabetes may be related to decline in general cognition and verbal memory.
doi:10.1016/j.psyneuen.2008.01.002
PMCID: PMC2396343  PMID: 18261857
insulin; c-peptide; diabetes; cognitive decline; aging
3.  Is there any evidence for a protective effect of antithrombotic medication on cognitive function in men at risk of cardiovascular disease? Some preliminary findings. 
To explore whether antithrombotic medication may protect against cognitive decline, tests of verbal memory, attention, abstract reasoning, verbal fluency, and mental flexibility were administered to 405 men at risk of cardiovascular disease. These subjects were a subgroup of those who had been participating in a randomised double blind factorial trial of low dose aspirin (75 mg daily) and low intensity oral anticoagulation with warfarin (international normalised ratio of 1.5) at 35 general practices across the United Kingdom for at least five years, were at least 55 years old at trial entry, and had been randomly allocated to one of four groups: active warfarin and active aspirin, active warfarin and placebo aspirin, placebo warfarin and active aspirin, and double placebo. Verbal fluency and mental flexibility were significantly better in subjects taking antithrombotic medication than in subjects taking placebo. Aspirin may have contributed more than warfarin to any beneficial effect. These results provide tentative evidence that antithrombotic medication may protect cognitive function in men at risk of cardiovascular disease.
PMCID: PMC1064157  PMID: 9069483
4.  Physical activity and cognition in women with vascular conditions 
Archives of internal medicine  2011;171(14):1244-1250.
Background
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.
Methods
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.
Results
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).
Conclusions
Regular physical activity, including walking, was associated with better preservation of cognitive function in older women with vascular disease or risk factors.
doi:10.1001/archinternmed.2011.282
PMCID: PMC3153432  PMID: 21771894
5.  Effect of Low Dose Aspirin on Functional Outcome from Cerebral Vascular Events in Women 
Background and Purpose
While aspirin is effective in prevention of stroke, fewer studies have examined the impact of aspirin on stroke morbidity.
Methods
The Women’s Health Study is a completed randomized, placebo-controlled trial designed to test the effect of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer which enrolled 39,876 women. We used multinomial logistic regression to evaluate the relationship between randomized aspirin assignment and functional outcomes from stroke. Possible functional outcomes were no stroke nor TIA, modified Rankin scale (mRS) score 0–1, mRS 2–3 and mRS 4–6.
Results
After a mean of 9.9 years of follow-up, 460 confirmed strokes (366 ischemic, 90 hemorrhagic and 4 unknown type) and 405 confirmed transient ischemic attacks (TIAs) occurred. With regard to total and ischemic stroke, women who were randomized to aspirin had a non-significant decrease in risk of any outcome compared to women not randomized to aspirin. This decrease in risk only reached statistical significance for those experiencing TIA compared to participants without stroke or TIA (OR=0.77; 95% CI: 0.63, 0.94). For hemorrhagic stroke, a non-significant increase in the risk of achieving a modified Rankin Scale (mRS) score 2–3 or mRS 4–6 compared to no stroke or TIA was observed for the women randomized to aspirin compared to those randomized to placebo.
Conclusions
Results from this large randomized clinical trial provide evidence that 100mg of aspirin every other day may reduces the risk of ischemic cerebral vascular events, but does not have differential effects on functional outcomes from stroke.
doi:10.1161/STROKEAHA.112.672451
PMCID: PMC3552068  PMID: 23306328
cerebrovascular disease; epidemiology; aspirin
6.  Low-Dose Aspirin in the Primary Prevention of Rheumatoid Arthritis: The Women’s Health Study 
Arthritis care & research  2010;62(4):545-550.
Background
Low-dose aspirin may reduce the risk of developing rheumatoid arthritis (RA) through its effect on cyclooxygenase activity and its anti-oxidant pathways. Previous randomized trial data have demonstrated a beneficial effect of low-dose aspirin in reducing other inflammatory diseases, such as asthma and colorectal adenomas, but no trial has evaluated the role of aspirin in RA prevention.
Methods
The Women’s Health Study is a randomized, double-blind, placebo-controlled trial conducted between 1992 and 2004 designed to evaluate the risks and benefits of low-dose aspirin (100 mg every other day) and vitamin E in the primary prevention of cardiovascular disease and cancer among 39,876 female health professionals age 45 years and older throughout the US. In the present study, 39,144 women were evaluated after excluding women with RA at baseline. A definite diagnosis of RA was assessed during follow-up by self-report and confirmed using a connective tissue disease screening questionnaire (CSQ), followed by medical record review for ACR criteria by a rheumatologist.
Results
During an average follow-up of 10 years, 106 women developed definite RA, 48 women in the aspirin group and 58 in the placebo group. There was a non-significant relative risk (RR) for RA of 0.83 (95% confidence interval [CI] 0.56–1.21, p=0.33) associated with aspirin. There were 64 (60%) seropositive RA cases and 42 (40%) women with seronegative RA. Aspirin also had no significant effect on either seropositive (RR, 1.0; 95% CI, 0.61–1.63) or seronegative RA (RR, 0.62; 95% CI, 0.33–1.15).
Conclusion
100 mg of aspirin taken every other day is not associated with a significant reduction in the risk of developing RA among women in a randomized, double-blind, placebo-controlled trial.
doi:10.1002/acr.20042
PMCID: PMC2990344  PMID: 20391510
rheumatoid arthritis; randomized controlled trial; aspirin; antioxidants
7.  A Randomized Trial of Low-Dose Aspirin in the Prevention of Clinical Type 2 Diabetes in Women  
Diabetes Care  2009;32(1):3-8.
OBJECTIVE—Subclinical inflammation is linked with the development of type 2 diabetes, and epidemiologic data suggest that this association may be stronger in women. Although small clinical studies have shown a prominent hypoglycemic effect of short-term high-dose aspirin, no randomized trials have directly evaluated the efficacy of aspirin in diabetes prevention at doses acceptable for use in routine clinical practice. We evaluated whether chronic low-dose aspirin prevents the development of clinical diabetes among initially healthy American women.
RESEARCH DESIGN AND METHODS—Subjects were enrolled in the Women's Health Study, a 10-year randomized double-blind, placebo-controlled trial of aspirin and vitamin E for primary prevention of cardiovascular disease and cancer. Between 1992 and 1995, 38,716 women aged ≥45 years and free of clinical diabetes were randomly assigned to either low-dose aspirin or placebo (median follow-up 10.2 years). Documented clinical type 2 diabetes was prospectively evaluated throughout the trial.
RESULTS—Among women randomly assigned to receive aspirin (n = 19,326) or placebo (n = 19,390), there was no statistically significant difference in the incidence of type 2 diabetes. There were 849 cases of diabetes in the aspirin group and 847 in the placebo group (rate ratio 1.01 [95% CI 0.91–1.11]). Stratification by diabetes risk factors including age, BMI, family history of diabetes, physical activity, A1C, and high-sensitivity C-reactive protein did not support a modulating effect of these variables. Analyses accounting for treatment duration and adherence similarly found no beneficial effects.
CONCLUSIONS—These data suggest that long-term low-dose aspirin does not prevent the development of clinical type 2 diabetes in initially healthy women.
doi:10.2337/dc08-1206
PMCID: PMC2606820  PMID: 18835953
8.  Aspirin and Decreased Adult-Onset Asthma 
Rationale: In an observational cohort study, women who self-selected for frequent aspirin use developed less newly diagnosed asthma than women who did not take aspirin.
Objective: To explore whether low-dose aspirin decreased the risk of newly diagnosed asthma in a randomized, double-blind, placebo-controlled trial.
Methods: The Physicians' Health Study randomized 22,071 apparently healthy male physicians, aged 40–84 yr at baseline and tolerant of aspirin, over an 18-wk run-in period, to 325 mg aspirin or placebo on alternate days. The aspirin component was terminated after 4.9 yr due principally to the emergence of a statistically extreme 44% reduction in risk of first myocardial infarction among those randomly assigned to aspirin.
Measurements: Physicians could self-report an asthma diagnosis on questionnaires at baseline, 6 mo, and annually thereafter. Asthma was not an a priori endpoint of the trial.
Results: Among 22,040 physicians without reported asthma at randomization, there were 113 new asthma diagnoses in the aspirin group and 145 in the placebo group. The hazard ratio was 0.78 (95% confidence interval, 0.61–1.00; p = 0.045). This apparent 22% lower risk of newly diagnosed asthma among those assigned to aspirin was not modified by baseline characteristics including smoking, body mass index, or age.
Conclusions: Aspirin reduced the risk of newly diagnosed adult-onset asthma in a large, randomized clinical trial of apparently healthy, aspirin-tolerant men. This result requires replication in randomized trials designed a priori to test this hypothesis; it does not imply that aspirin improves symptoms in patients with asthma.
doi:10.1164/rccm.200603-411OC
PMCID: PMC1899281  PMID: 17068328
asthma; aspirin; NSAIDs; analgesics; obstructive airways disease
9.  Caffeine and cognitive decline in elderly women at high vascular risk 
Journal of Alzheimer's disease : JAD  2013;35(2):10.3233/JAD-122371.
Background
Persons with vascular disorders are at higher risk of cognitive decline.
Objective
To determine whether caffeine may be associated with cognitive decline reduction in elderly at high vascular risk.
Methods
We included 2475 women aged 65+ years in the Women’s Antioxidant Cardiovascular Study, a randomized trial of antioxidants and B vitamins for cardiovascular disease secondary prevention. We ascertained regular caffeine intake at baseline (1995–1996) using a validated 116 item-food frequency questionnaire. From 1998–2000 to 2005–2006, we administered four telephone cognitive assessments at two-year intervals evaluating global cognition, verbal memory and category fluency. The primary outcome was the change in global cognitive score, which was the average of the z-scores of all tests. We used generalized linear models for repeated measures that were adjusted for various sociodemographic, health and lifestyle factors to evaluate the difference in cognitive decline rates across quintiles of caffeine intake.
Results
We observed significantly slower rates of cognitive decline with increasing caffeine intake (p-trend=0.02). The rate difference between the highest and lowest quintiles of usual caffeine intake (> 371 versus < 30 mg/day) was equivalent to that observed between those who were 7 years apart in age (p=0.006). Consumption of caffeinated coffee was significantly related to slower cognitive decline (p-trend=0.05), but not other caffeinated products (e.g., decaf, tea, cola, chocolate). We conducted interaction analyses and observed stronger associations in women assigned to vitamin B supplementation (p-interaction = 0.02).
Conclusions
Caffeine intake was related to moderately better cognitive maintenance over 5 years in older women with vascular disorders.
doi:10.3233/JAD-122371
PMCID: PMC3807252  PMID: 23422357
Cognition; Aging; Caffeine; Cohort studies; Risk factors; Epidemiology
10.  The Relation of Education and Income to Cognitive Function among Professional Women 
Neuroepidemiology  2005;26(2):93-101.
We investigated the relation of educational attainment and annual household income to cognitive function and cognitive decline in community-dwelling women aged 66 years or older. Subjects were 6,314 health professionals participating in the Women’s Health Study, among whom information on education and income was self-reported. From 1998 to 2000, we administered five cognitive tests, measuring general cognition, episodic memory and verbal fluency, using a validated telephone interview. Second cognitive assessments were conducted approximately two years later; information was complete for 5,573 women at the time of analysis, with 94% follow-up. We used linear and logistic regression to calculate multivariate-adjusted mean differences, and odds of cognitive impairment (defined as worst 10% of test distribution) and of substantial decline in performance (worst 10% of distribution), across various levels of education and income. After adjusting for numerous potential confounding factors, we found strong trends of increasing mean cognitive performance with increasing level of education (p-trend<0.0005 on all cognitive measures). Odds of cognitive impairment also consistently decreased with increasing education (eg, on summary score combining all tests, OR=0.6, 95% CI 0.3–0.9 comparing those with a doctoral degree to those with a 3-year associate’s degree). For income, we found significant trends of increasing mean cognitive performance with increasing income on the summary score and on episodic memory (p-trends<0.0001). For example, the OR was 0.6 (95% CI 0.4–0.8) comparing those with the highest income to the lowest income on the summary score. Results were generally similar for cognitive decline over two years, although somewhat weaker. Thus, in these well-educated, professional women, educational attainment and income both predicted cognitive function and decline.
doi:10.1159/000090254
PMCID: PMC1361359  PMID: 16352912
educational attainment; income; cognitive function; cognitive decline
11.  Fasting Insulin Levels and Cognitive Decline in Older Women without Diabetes 
Neuroepidemiology  2008;30(3):174-179.
Background
Type 2 diabetes has been associated with an increased risk of dementia. To assess possible independent effects of insulin, we investigated the relation of insulin levels to cognitive decline in nondiabetic women.
Methods
Fasting plasma insulin levels were measured in mid-life in 1,416 nondiabetic Nurses’ Health Study participants, who also completed cognitive testing that began 10 years later (current age: 70–75 years). Over 4 years, 3 assessments of general cognition, verbal memory, category fluency and attention were administered. Primary outcomes were the Telephone Interview for Cognitive Status (TICS) performance, the global score (average of all tests) and verbal memory (average of verbal recall tests). Linear mixed-effects models were used to calculate the association between insulin and cognitive decline.
Results
Higher insulin levels were associated with a faster decline on the TICS and verbal memory. For analysis, batch-specific quartiles of insulin levels were constructed. Compared to the lowest quartile, adjusted differences in the annual rates of decline (with 95% CI values in parentheses) for the second, third and fourth quartiles were: TICS, −0.06 (−0.16, 0.03), −0.14 (−0.24, −0.04), and −0.09 (−0.19, 0.01) points (p trend = 0.04); verbal memory, −0.01 (−0.04, 0.02), −0.05 (−0.08, −0.02), and −0.02 (−0.05, 0.01) units (p trend = 0.02). These associations remained after multivariable adjustment.
Conclusions
Our study provides evidence for a potential role of higher fasting insulin levels in cognitive decline, possibly independent of diabetes.
doi:10.1159/000126909
PMCID: PMC2821443  PMID: 18421217
Diabetes; Insulin, cognitive performance; Aging, cognitive decline; Dementia
12.  Validation of a cognitive assessment battery administered by telephone 
Background
While the gold standard method of cognitive assessment is a face-to-face administration, telephone-based assessments offer several advantages if they demonstrate reliability and validity.
Design
Observational study; 110 participants randomly assigned to receive two administrations of the same cognitive test battery 6 months apart in one of four combinations (1st administration/2nd administration): telephone/telephone; telephone/face-to-face; face-to-face/telephone; or face-to-face/face-to-face.
Setting
Academic medical center
Participants
110 non-demented women between the ages of 65 and 90 years.
Measures
The battery included tests of attention, verbal learning and memory, verbal fluency, executive function, working memory and global cognitive functioning plus self-report measures of perceived memory problems, depressive symptoms, sleep disturbance and health-related quality of life. Test-retest reliability, concurrent validity, relative bias associated with telephone administration, and change scores were evaluated.
Results
There were no statistically significant differences in scores on any of the cognitive tests or questionnaires between randomly assigned modes of administration at baseline indicating equivalence across modes. There was no significant bias for tests or questionnaires administered by telephone (ps>0.01). Nor was there a difference in mean change scores between administration modes except for the Category Fluency (p = 0.01) and the California Verbal Learning Test long delay-free recall (p < 0.01). Mean test-retest coefficients for the battery were not significantly different across groups though individual test-retest correlation coefficients were generally higher within mode than across mode.
Conclusions
Telephone administration of cognitive tests and questionnaires to older women is both reliable and valid. Use of telephone batteries can substantially reduce the economic cost and burden of cognitive assessments and increase enrollment, retention and data completeness thereby improving study validity.
doi:10.1111/j.1532-5415.2012.04111.x
PMCID: PMC3448122  PMID: 22985137
cognition; assessment; telephone; validation; tests
13.  Dietary fat intake in relation to cognitive change in high-risk women with cardiovascular disease or vascular factors 
European journal of clinical nutrition  2010;64(10):1134-1140.
Background/Objectives
Dietary fat intake may influence the rate of cognitive change among those at high risk due to vascular disease or risk factors.
Subjects/Methods
Women’s Antioxidant Cardiovascular Study began in 1995-96 as a randomized trial of antioxidants and B vitamin supplementation for secondary prevention in women with cardiovascular disease or ≥ 3 coronary risk factors. From 1998-99, eligible participants aged ≥ 65 years were administered a telephone cognitive battery including five tests of general cognition, memory and category fluency (n=2 551). Tests were administered four times over 5.4 years. The primary outcome was a global composite score averaging z-scores of all tests. Multivariable generalized linear models for repeated measures were used to evaluate the difference in cognitive decline rates across tertiles of total fat and various types of fat.
Results
Total fat intake or different types of fat were not related to cognitive decline. However, older age significantly modified the association: among the oldest participants, higher intakes of mono- and poly-unsaturated fat were inversely related to cognitive decline (p-interaction: 0.06 and 0.04, respectively), and the rate differences between the highest and lowest tertiles were cognitively equivalent to the rate differences observed with being 4-6 years younger.
Conclusions
In women at high risk of cognitive decline due to vascular disease or risk factors, dietary fat intake was not associated with 5-year cognitive change. However, a possible protective relation of unsaturated fats with cognitive decline in the oldest women warrants further study.
doi:10.1038/ejcn.2010.113
PMCID: PMC3095099  PMID: 20648044
cognition; epidemiology; fats; risk factors; women; cardiovascular disease
14.  Prospective study of type 2 diabetes and cognitive decline in women aged 70-81 years 
BMJ : British Medical Journal  2004;328(7439):548.
Objective To examine the association of type 2 diabetes with baseline cognitive function and cognitive decline over two years of follow up, focusing on women living in the community and on the effects of treatments for diabetes.
Design Nurses' health study in the United States. Two cognitive interviews were carried out by telephone during 1995-2003.
Participants 18 999 women aged 70-81 years who had been registered nurses completed the baseline interview; to date, 16 596 participants have completed follow up interviews after two years.
Main outcome measures Cognitive assessments included telephone interview of cognitive status, immediate and delayed recalls of the East Boston memory test, test of verbal fluency, delayed recall of 10 word list, and digit span backwards. Global scores were calculated by averaging the results of all tests with z scores.
Results After multivariate adjustment, women with type 2 diabetes performed worse on all cognitive tests than women without diabetes at baseline. For example, women with diabetes were at 25-35% increased odds of poor baseline score (defined as bottom 10% of the distribution) compared with women without diabetes on the telephone interview of cognitive status and the global composite score (odds ratios 1.34, 95% confidence interval 1.14 to 1.57, and 1.26, 1.06 to 1.51, respectively). Odds of poor cognition were particularly high for women who had had diabetes for a long time (1.52, 1.15 to 1.99, and 1.49, 1.11 to 2.00, respectively, for ≥ 15 years' duration). In contrast, women with diabetes who were on oral hypoglycaemic agents performed similarly to women without diabetes (1.06 and 0.99), while women not using any medication had the greatest odds of poor performance (1.71, 1.28 to 2.281, and 1.45, 1.04 to 2.02) compared with women without diabetes. There was also a modest increase in odds of poor cognition among women using insulin treatment. All findings were similar when cognitive decline was examined over time.
Conclusions Women with type 2 diabetes had increased odds of poor cognitive function and substantial cognitive decline. Use of oral hypoglycaemic therapy, however, may ameliorate risk.
doi:10.1136/bmj.37977.495729.EE
PMCID: PMC381043  PMID: 14980984
15.  Low-Dose Aspirin and Medical Record Confirmed Age-related Macular Degeneration in a Randomized Trial of Women 
Ophthalmology  2009;116(12):2386-2392.
Objective
To test whether alternate day low-dose aspirin affects incidence of age-related macular degeneration (AMD) in a large-scale randomized trial of women.
Design
Randomized, double-masked, placebo-controlled trial
Participants
Thirty-nine thousand eight hundred seventy six healthy female health professionals aged 45 years or older.
Intervention
Participants were randomly assigned to receive either 100 mg of aspirin on alternate days or placebo and were followed for the presence of AMD for an average of 10 years.
Main Outcome Measure
Incident AMD responsible for a reduction in best-corrected visual acuity to 20/30 or worse based on self-report confirmed by medical record review.
Results
After 10 years of treatment and follow-up, there were 111 cases of AMD in the aspirin group and 134 cases in the placebo group (hazard ratio [HR], 0.82; 95 percent confidence interval [CI], 0.64 to 1.06).
Conclusions
In a large-scale randomized trial of female health professionals with 10 years of treatment and follow-up, low-dose aspirin had no large beneficial or harmful effect on risk of AMD.
doi:10.1016/j.ophtha.2009.05.031
PMCID: PMC2787838  PMID: 19815293
16.  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.
Background
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.
Objective
To evaluate whether long-term multivitamin supplementation affects cognitive health in later-life.
Design
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.
Setting
The Physicians’ Health Study II.
Patients
5,947 male physicians aged ≥ 65 years.
Intervention
Daily multivitamin, or placebo.
Measurements
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.
Results
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).
Limitations
Doses of vitamins may be too low, or population may be too well-nourished to benefit from multivitamin.
Conclusions
In male physicians aged ≥ 65 years, long-term use of a daily multivitamin did not provide cognitive benefits.
Trial Registration
http://www.clinicaltrials.gov identifier: NCT00270647
doi:10.1001/archinte.167.20.2184
PMCID: PMC3858850  PMID: 17998490
multivitamin; cognitive function; randomized clinical trial; men
17.  Aspirin, Nonsteroidal Anti-inflammatory Drug Use, and Risk for Crohn Disease Ulcerative Colitis 
Annals of Internal Medicine  2012;156(5):350-359.
Background
Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are anti-inflammatory but have been linked in some studies to Crohn disease (CD) and ulcerative colitis (UC).
Objective
To assess the association between aspirin and NSAID use and incident CD and UC.
Design
Prospective cohort study.
Setting
Nurses' Health Study I.
Patients
76 795 U.S. women who provided biennially updated data about aspirin and NSAID use.
Measurements
Incident CD and UC between 1990 and 2008 (outcome) and NSAID and aspirin use (exposure).
Results
123 incident cases of CD and 117 cases of UC occurred over 18 years and 1 295 317 person-years of follow-up. Compared with nonusers, women who used NSAIDs at least 15 days per month seemed to have increased risk for both CD (absolute difference in age-adjusted incidence, 6 cases per 100 000 person-years [95% CI, 0 to 13]; multivariate hazard ratio, 1.59 [CI, 0.99 to 2.56]) and UC (absolute difference, 7 cases per 100 000 person-years [CI, 1 to 12]; multivariate hazard ratio, 1.87 [CI, 1.16 to 2.99]). Less frequent NSAID use was not clearly associated with risk for CD or UC, and there was no clear association between aspirin use and disease.
Limitations
Cohort participants were exclusively women, most of whom were white. Aspirin and NSAID use were self-reported.
Conclusion
Frequent use of NSAIDs but not aspirin seemed to be associated with increased absolute incidence of CD and UC. The findings have more mechanistic than clinical implications, because the absolute incidence of CD or UC associated with NSAIDs was low and the increase in risk for CD or UC associated with NSAIDs is unlikely to alter the balance of more common and clinically significant risks and benefits associated with these agents.
Primary Funding Source
American Gastroenterological Association, IBD Working Group, Broad Medical Research Program, and National Institutes of Health.
doi:10.1059/0003-4819-156-5-201203060-00007
PMCID: PMC3369539  PMID: 22393130
18.  RANDOMISED ASPIRIN ASSIGNMENT AND RISK OF ADULT-ONSET ASTHMA IN THE WOMEN'S HEALTH STUDY 
Thorax  2008;63(6):514-518.
Rationale
Randomised data in men showed a small but significant reduction in risk of adult-onset asthma among those assigned to aspirin. Results from an observational study in women suggest that frequent use of aspirin decreased the risk of adult-onset asthma. Randomised data in women are lacking.
Objective
To test the effect of 100 mg of aspirin on alternate days or placebo on the risk of adult-onset asthma in the Women's Health Study.
Methods
Post-hoc analyses from a randomised, double-blind, placebo-controlled clinical trial of aspirin and vitamin E in apparently healthy US women with no indication or contraindication to aspirin therapy and free of a history of asthma at study entry.
Measurements
Female health professionals could self-report an asthma diagnosis on yearly questionnaires.
Results
Among 37,270 women without reported history of asthma prior to randomisation and during 10 years of follow-up, there were 872 new reports of asthma diagnosis in the aspirin group and 963 in the placebo group (hazard ratio=0.90; 95% confidence interval=0.82−0.99; P=0.027). This apparent 10% lower relative risk of incident adult-onset asthma among those assigned to aspirin was significantly modified by body mass index, indicating no effect among women with a body mass index of ≥30 kg/m2. There was no significant effect modification by age, smoking status, exercise levels, postmenopausal hormone use, or randomised vitamin E assignment.
Conclusions
In this large, randomised clinical trial of apparently healthy adult women, assignment of 100 mg of aspirin on alternate days reduced the relative risk of newly reported diagnosis of asthma.
doi:10.1136/thx.2007.091447
PMCID: PMC2631398  PMID: 18339679
asthma; aspirin; randomised trial
19.  Dietary fat types and 4-year cognitive change in community-dwelling older women 
Annals of Neurology  2012;72(1):124-134.
Objective
To relate dietary fat types to cognitive change in healthy community-based elders.
Methods
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.
Results
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.
Interpretation
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.
doi:10.1002/ana.23593
PMCID: PMC3405188  PMID: 22605573
20.  Long-term Use of Aspirin and Nonsteroidal Anti-inflammatory Drugs and Risk of Colorectal Cancer 
Context
Randomized trials of short-term aspirin use for prevention of recurrent colorectal adenoma have provided compelling evidence of a causal relationship between aspirin and colorectal neoplasia. However, data on long-term risk of colorectal cancer according to dose, timing, or duration of therapy with aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) remain limited.
Objective
To examine the influence of aspirin and NSAIDs in prevention of colorectal cancer.
Design, Setting, and Participants
Prospective cohort study of 82 911 women enrolled in the Nurses’ Health Study providing data on medication use biennially since 1980 and followed up through June 1, 2000.
Main Outcome Measure
Incident colorectal cancer.
Results
Over a 20-year period, we documented 962 cases of colorectal cancer. Among women who regularly used aspirin (≥2 standard [325-mg] tablets per week), the multivariate relative risk (RR) for colorectal cancer was 0.77 (95% confidence interval [CI], 0.67–0.88) compared with nonregular users. However, significant risk reduction was not observed until more than 10 years of use (P≤.001 for trend). The benefit appeared related to dose: compared with women who reported no use, the multivariate RRs for cancer were 1.10 (95% CI, 0.92–1.31) for women who used 0.5 to 1.5 standard aspirin tablets per week, 0.89 (95% CI, 0.73–1.10) for 2 to 5 aspirin per week, 0.78 (95% CI, 0.62–0.97) for 6 to 14 aspirin per week, and 0.68 (95% CI, 0.49–0.95) for more than 14 aspirin per week (P<.001 for trend). Notably, women who used more than 14 aspirin per week for longer than 10 years in the past had a multivariate RR for cancer of 0.47 (95% CI, 0.31–0.71). A similar dose-response relationship was found for nonaspirin NSAIDs (P=.007 for trend). The incidence of reported major gastrointestinal bleeding events per 1000 person-years also appeared to be dose-related: 0.77 among women who denied any aspirin use; 1.07 for 0.5 to 1.5 standard aspirin tablets per week; 1.07 for 2 to 5 aspirin per week; 1.40 for 6 to 14 aspirin per week; and 1.57 for more than 14 aspirin per week.
Conclusions
Regular, long-term aspirin use reduces risk of colorectal cancer. Non-aspirin NSAIDs appear to have a similar effect. However, a significant benefit of aspirin is not apparent until more than a decade of use, with maximal risk reduction at doses greater than 14 tablets per week. These results suggest that optimal chemoprevention for colorectal cancer requires long-term use of aspirin doses substantially higher than those recommended for prevention of cardiovascular disease, but the dose-related risk of gastrointestinal bleeding must also be considered.
doi:10.1001/jama.294.8.914
PMCID: PMC1550973  PMID: 16118381
21.  Vitamin E in the Primary Prevention of Rheumatoid Arthritis: The Women’s Health Study 
Arthritis and rheumatism  2008;59(11):1589-1595.
Background
Vitamin E supplements may reduce the risk of developing rheumatoid arthritis (RA) through antioxidant effects. While previous observational studies have investigated this question, no randomized trial data are available.
Methods
The Women’s Health Study is a randomized, double-blind, placebo-controlled trial designed to evaluate the benefits and risks of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer among 39,876 female health professionals age 45 years and older throughout the US, conducted between 1992 and 2004. After excluding women with self-reported RA at baseline, 39,144 women were included in the present study. The primary endpoint, definite RA, was confirmed using a connective tissue disease screening questionnaire (CSQ), followed by medical record review for ACR criteria.
Results
During an average follow-up of 10 years, 106 cases of definite RA occurred, 50 in the vitamin E group and 56 in the placebo group. Sixty-four (60%) RA cases were rheumatoid factor positive; 42 (40%) rheumatoid factor negative. There was no significant association between vitamin E and risk of definite RA (relative risk [RR], 0.89; 95% confidence interval, 0.61–1.31). There also were no significant risk reductions for either seropositive (RR, 0.64 (0.39–1.06)) or seronegative RA (RR 1.47 (0.79–2.72)).
Conclusion
600 IU every other day of vitamin E supplements are not associated with a significant reduction in the risk of developing RA among women in a randomized, double-blind, placebo-controlled trial.
doi:10.1002/art.24194
PMCID: PMC2927963  PMID: 18975365
rheumatoid arthritis; randomized controlled trial; vitamin E; antioxidants
22.  Discontinuation of low dose aspirin and risk of myocardial infarction: case-control study in UK primary care 
Objectives To evaluate the risk of myocardial infarction and death from coronary heart disease after discontinuation of low dose aspirin in primary care patients with a history of cardiovascular events.
Design Nested case-control study.
Setting The Health Improvement Network (THIN) database in the United Kingdom.
Participants Individuals aged 50-84 with a first prescription for aspirin (75-300 mg/day) for secondary prevention of cardiovascular outcomes in 2000-7 (n=39 513).
Main outcome measures Individuals were followed up for a mean of 3.2 years to identify cases of non-fatal myocardial infarction or death from coronary heart disease. A nested case-control analysis assessed the risk of these events in those who had stopped taking low dose aspirin compared with those who had continued treatment.
Results There were 876 non-fatal myocardial infarctions and 346 deaths from coronary heart disease. Compared with current users, people who had recently stopped taking aspirin had a significantly increased risk of non-fatal myocardial infarction or death from coronary heart disease combined (rate ratio 1.43, 95% confidence interval 1.12 to 1.84) and non-fatal myocardial infarction alone (1.63, 1.23 to 2.14). There was no significant association between recently stopping low dose aspirin and the risk of death from coronary heart disease (1.07, 0.67 to 1.69). For every 1000 patients, over a period of one year there were about four more cases of non-fatal myocardial infarction among patients who discontinued treatment with low dose aspirin (recent discontinuers) compared with patients who continued treatment.
Conclusions Individuals with a history of cardiovascular events who stop taking low dose aspirin are at increased risk of non-fatal myocardial infarction compared with those who continue treatment.
doi:10.1136/bmj.d4094
PMCID: PMC3139911  PMID: 21771831
23.  Aspirin and lung cancer risk in a cohort study of women: dosage, duration and latency 
British Journal of Cancer  2007;97(9):1295-1299.
Aspirin may reduce the risk of cancer at some sites but its effect at the lung is unclear. We prospectively examined associations between aspirin use and risk of lung cancer in 109 348 women in the Nurses' Health study from 1980 to 2004. During this time, 1360 lung cancers were documented in participants 36–82 years of age. Aspirin use and smoking were assessed every 2 years. Risk of lung cancer was a non-significant 16% lower for regular aspirin users of one or two tablets per week and a significant 55% higher for users of 15 or more tablets per week compared with women who never regularly used aspirin. Results were similar when limited to never smokers. For both the low and high quantity aspirin users, risk of lung cancer did not decline or increase with longer durations of use, and associations attenuated as the latency period between aspirin assessment and lung cancer diagnosis was lengthened. Our findings, together with those from previous clinical trials and prospective studies, do not provide consistent evidence that aspirin influences the development of lung cancer and further investigation is required with adjustment for smoking.
doi:10.1038/sj.bjc.6603996
PMCID: PMC2360462  PMID: 17895894
lung cancer; aspirin; cohort; women
24.  The association of cognitive performance with mental health and physical functioning strengthens with age: The Whitehall II cohort study 
Psychological medicine  2009;40(5):837-845.
Background
Cognitive performance has been associated with mental and physical health, but it is unknown whether the strength of these associations changes with ageing and with age-related social transitions, such as retirement. We examined whether cognitive performance predicted mental and physical health from midlife to early old age.
Methods
Participants were 5414 men and 2278 women from the Whitehall II cohort study followed for 15 years between 1991 and 2006. The age range included over the follow-up was from 40 to 75 years. Mental health and physical functioning were measured six times using SF-36 subscales. Cognitive performance was assessed three times using five cognitive tests assessing verbal and numerical reasoning, verbal memory, and phonemic and semantic fluency. Socioeconomic status and retirement were included as covariates.
Results
High cognitive performance was associated with better mental health and physical functioning. Mental health differences associated with cognitive performance widened with age from 39 to 76 years of age, while physical functioning differences widened only between 39 and 60 years but not after 60 years of age. Socioeconomic status explained part of the widening differences in mental health and physical functioning before the age of 60. Cognitive performance was more strongly associated with mental health in retired than non-retired participants, which contributed to the widening differences after 60 years of age.
Conclusions
The strength of cognitive performance in predicting mental and physical health may increase from midlife to early old age, and these changes may be related to socioeconomic status and age-related transitions, such as retirement.
doi:10.1017/S0033291709991024
PMCID: PMC3178658  PMID: 19719898
25.  Peripheral levels of fibrinogen, C-reactive protein, and plasma viscosity predict future cognitive decline in individuals without dementia 
Psychosomatic medicine  2009;71(8):901-906.
Objective
We aimed to determine whether circulating levels of the biomarkers C-reactive protein (CRP), fibrinogen, plasma viscosity, and haematocrit were associated with cognitive decline in middle-aged to elderly people.
Methods
Subjects consisted of 2,312 men and women aged 50 to 80 years participating in the Aspirin for Asymptomatic Atherosclerosis Trial, all of whom were free of symptomatic cardiovascular disease at baseline. Biomarker levels and cognitive ability were measured at baseline with cognition assessed in all subjects using the Mill Hill Vocabulary Test and in a subgroup of 504 persons using tests of memory, non-verbal reasoning, information processing speed, executive function, and mental flexibility. After 5 years, the five test battery was administered to all participants and scores were used to derive a general cognitive ability factor.
Results
Baseline CRP and fibrinogen levels were negatively associated with age and sex-adjusted follow-up scores on the majority of the cognitive tests, and the general cognitive ability factor (correlations -0.054 to -0.105, P < .05). In analyses adjusting for baseline cognitive scores, asymptomatic atherosclerotic disease, and cardiovascular risk factors, both markers predicted decline in several cognitive domains (excluding memory). Baseline plasma viscosity, but not hematocrit, was negatively associated with follow-up test scores for general cognitive ability, information processing speed and mental flexibility (correlations -0.050 to -0.098, P < .05) and with decline across the same domains (P < .05).
Conclusions
Raised circulating levels of CRP, fibrinogen, and elevated plasma viscosity predicted poorer subsequent cognitive ability and were associated with age-related cognitive decline in several domains, including general ability.
doi:10.1097/PSY.0b013e3181b1e538
PMCID: PMC2762963  PMID: 19661193
inflammation; rheology; cognition; cognitive decline

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