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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.  Migraine and cognitive decline among women: prospective cohort study 
Objective To evaluate the association between migraine and cognitive decline among women.
Design Prospective cohort study.
Setting Women’s Health Study, United States.
Participants 6349 women aged 65 or older enrolled in the Women’s Health Study who provided information about migraine status at baseline and participated in cognitive testing during follow-up. Participants were classified into four groups: no history of migraine, migraine with aura, migraine without aura, and past history of migraine (reports of migraine history but no migraine in the year prior to baseline).
Main outcome measures Cognitive testing was carried out at two year intervals up to three times using the telephone interview for cognitive status, immediate and delayed recall trials of the east Boston memory test, delayed recall trial of the telephone interview for cognitive status 10 word list, and a category fluency test. All tests were combined into a global cognitive score, and tests assessing verbal memory were combined to create a verbal memory score.
Results Of the 6349 women, 853 (13.4%) reported any migraine; of these, 195 (22.9%) reported migraine with aura, 248 (29.1%) migraine without aura, and 410 (48.1%) a past history of migraine. Compared with women with no history of migraine, those who experienced migraine with or without aura or had a past history of migraine did not have significantly different rates of cognitive decline in any of the cognitive scores: values for the rate of change of the global cognitive score between baseline and the last observation ranged from −0.01 (SE 0.04) for past history of migraine to 0.08 (SE 0.04) for migraine with aura when compared with women without any history of migraine. Women who experienced migraine were also not at increased risk of substantial cognitive decline (worst 10% of the distribution of decline). When compared with women without a history of migraine, the relative risks for the global score ranged from 0.77 (95% confidence interval 0.46 to 1.28) for women with migraine without aura to 1.17 (0.84 to 1.63) for women with a past history of migraine.
Conclusion In this prospective cohort of women, migraine status was not associated with faster rates of cognitive decline.
doi:10.1136/bmj.e5027
PMCID: PMC3414433  PMID: 22875950
4.  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
5.  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
6.  A TRIAL OF B VITAMINS AND COGNITIVE FUNCTION AMONG WOMEN AT HIGH RISK OF CARDIOVASCULAR DISEASE 
Background
High homocysteine levels may be neurotoxic and contribute to cognitive decline in older persons.
Objective
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.
Design
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.
Results
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.
Conclusions
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.
doi:10.3945/ajcn.2008.26404
PMCID: PMC3470481  PMID: 19064521
7.  A Randomised, Blinded, Placebo-Controlled Trial in Dementia Patients Continuing or Stopping Neuroleptics (The DART-AD Trial)  
PLoS Medicine  2008;5(4):e76.
Background
There have been increasing concerns regarding the safety and efficacy of neuroleptics in people with dementia, but there are very few long-term trials to inform clinical practice. The aim of this study was to determine the impact of long-term treatment with neuroleptic agents upon global cognitive decline and neuropsychiatric symptoms in patients with Alzheimer disease.
Methods and Findings
Design: Randomised, blinded, placebo-controlled parallel two-group treatment discontinuation trial.
Setting: Oxfordshire, Newcastle and Gateshead, London and Edinburgh, United Kingdom.
Participants: Patients currently prescribed the neuroleptics thioridazine, chlorpromazine, haloperidol trifluoperazine or risperidone for behavioural or psychiatric disturbance in dementia for at least 3 mo.
Interventions: Continue neuroleptic treatment for 12 mo or switch to an identical placebo.
Outcome measures: Primary outcome was total Severe Impairment Battery (SIB) score. Neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory (NPI).
Results: 165 patients were randomised (83 to continue treatment and 82 to placebo, i.e., discontinue treatment), of whom 128 (78%) commenced treatment (64 continue/64 placebo). Of those, 26 were lost to follow-up (13 per arm), resulting in 51 patients per arm analysed for the primary outcome. There was no significant difference between the continue treatment and placebo groups in the estimated mean change in SIB scores between baseline and 6 mo; estimated mean difference in deterioration (favouring placebo) −0.4 (95% confidence interval [CI] −6.4 to 5.5), adjusted for baseline value (p = 0.9). For neuropsychiatric symptoms, there was no significant difference between the continue treatment and placebo groups (n = 56 and 53, respectively) in the estimated mean change in NPI scores between baseline and 6 mo; estimated mean difference in deterioration (favouring continue treatment) −2.4 (95% CI −8.2 to 3.5), adjusted for baseline value (p = 0.4). Both results became more pronounced at 12 mo. There was some evidence to suggest that those patients with initial NPI ≥ 15 benefited on neuropsychiatric symptoms from continuing treatment.
Conclusions
For most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this benefit must be weighed against the side effects of therapy.
Trial registration: Cochrane Central Registry of Controlled Trials/National Research Register (#ISRCTN33368770).
In a randomized trial of patients with dementia, Clive Ballard and colleagues show that withdrawal of neuroleptics had no overall detrimental effect, and by some measures improved, functional and cognitive status.
Editors' Summary
Background
The number of people with dementia (currently 25 million worldwide) is expected to increase by 5 million each year. The risk of dementia, including Alzheimer disease, increases sharply with age: Alzheimer's Disease International estimates that 1.4% of people 65–69 have dementia, whereas almost a full quarter of those over the age of 85 years are affected. Almost all older dementia patients will experience, along with the cognitive and functional decline typical of the illness, some neuropsychiatric symptoms. These symptoms can include agitation, aggression, and psychosis, and are often devastating for the older patient and his or her family and caregiver. Managing these symptoms is often a prime concern for health-care providers and families. Neuroleptics (sometimes called antipsychotics) are the class of drugs often used to manage or control neuropsychiatric problems, but there have been questions about their safety and appropriateness. Safety concerns involve risk of stroke, parkinsonism, sedation, edema, and chest infections but also include a worsening of cognitive decline with prolonged use of neuroleptics.
Why Was the Study Done?
Previous studies on the effectiveness and safety of neuroleptics in older people have been short term. Ballard and colleagues wanted to study over a longer period of time the impact of neuroleptic drugs on elderly patients with dementia. Specifically, they wanted to know if being on a neuroleptic was associated with more cognitive decline than coming off the drug. They also wanted to investigate whether discontinuing the drug exacerbated any neuropsychiatric symptoms, Parkinson disease-like symptoms, or other functional, language, and cognition difficulties frequently associated with dementia.
What Did the Researchers Do and Find?
The researchers recruited older patients with Alzheimer disease from across England who had been on neuroleptics for at least three months. They randomised patients to one of two groups: the first group continued taking the same neuroleptic at the same dosage level while the second group was switched to an identical-looking placebo. The researchers assessed the patients' cognitive status and neuropsychiatric symptoms upon their entry into the study. Six and 12 months later the researchers assessed any cognitive decline and the level of neuropsychiatric and other problems that patients were experiencing.
At both 6 and 12 months, the researchers found that there were no differences between the two groups (continued treatment and placebo) in terms of cognitive decline. The placebo group may have had less cognitive decline, but this was not statistically significant. They also found no overall differences between the two groups in the change in the number of neuropsychiatric symptoms over these time periods. Patients with severe neuropsychiatric problems at the outset of the trial did better on continued neuroleptic therapy, but this advantage was not statistically significant. There was a significant decline on the verbal fluency language tests among the patients who continued on their neuroleptic.
What Do these Findings Mean?
The researchers report perhaps the first trial of this duration on continued versus withdrawn neuroleptic treatment among older dementia patients. The findings do not indicate any benefit of continuing neuroleptic therapies in older patients on either cognitive or neuropsychiatric outcomes. The researchers conclude that neuroleptics, with their known safety issues, should not be used as first-line treatment to manage problems such as agitation or aggression. For older dementia patients whose neuropsychiatric symptoms are not remedied by nonpharmaceutical treatments, the researchers advise caution. More studies are urgently needed to find better solutions to help older patients with dementia who have agitation, aggression, and psychosis.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050076.
Alzheimer's Disease International is an umbrella organisation of organisations worldwide
The Alzheimer's Research Trust in the UK is a charity funding research to cure or prevent dementias
The US National Institutes of Aging has information on Alzheimer Disease in English and Spanish
Two governmental regulatory agencies—the Medicines and Healthcare Products Regulatory Agency in the UK and the Food and Drug Administration in the US—offer information about antipsychotics in people with dementia
doi:10.1371/journal.pmed.0050076
PMCID: PMC2276521  PMID: 18384230
8.  Ten-year change in plasma amyloid β levels and late-life cognitive decline 
Archives of neurology  2009;66(10):1247-1253.
Background
Plasma levels of the amyloid β-peptides (Aβ) are potential biomarkers of early cognitive impairment and decline, and of Alzheimer disease (AD) risk.
Objective
To relate mid-life plasma Aβ measures, and ten-year change in plasma Aβ since mid-life, to later-life cognitive decline.
Design, setting, participants
Plasma Aβ-40 and Aβ-42 levels were measured in 481 Nurses’ Health Study participants in late mid-life (mean age=63.6 years) and again 10 years later (mean age=74.6 years). Cognitive testing also began 10 years after the initial blood draw. Participants completed three repeated telephone-based assessments (average span=4.1 years). Multivariable linear mixed effects models were used to estimate relations of mid-life plasma Aβ-40:Aβ-42 ratios and Aβ-42 levels to later-life cognitive decline, and to relate ten-year change in Aβ-40:Aβ-42 and Aβ-42 to cognitive decline.
Main Outcome Measures
The primary outcomes were: the Telephone Interview for Cognitive Status (TICS); a global score averaging all tests (TICS, immediate and delayed verbal recall, category fluency, and attention); and a verbal memory score averaging four tests of verbal recall.
Results
Higher mid-life plasma Aβ-40:Aβ-42 ratio was associated with worse later-life decline on the global score (p-trend=0.04). Furthermore, an increase in Aβ-40:Aβ-42 since mid-life predicted greater decline on the global score (p-trend=0.03) and the TICS (p-trend=0.02). There was no association between mid-life plasma Aβ-42 levels alone – or change in Aβ-42 since mid-life – and cognitive decline.
Conclusions
In this large community-dwelling sample, higher plasma Aβ-40:Aβ-42 ratios in late mid-life, and increases in Aβ-40:Aβ-42 ten years later, were significantly associated with greater decline in global cognition at late-life.
doi:10.1001/archneurol.2009.207
PMCID: PMC2761951  PMID: 19822780
Alzheimer disease; amyloid; mid-life; plasma assay; biomarker; cognitive function
9.  Long Term Effects on Cognitive Function of Postmenopausal Hormone Therapy Prescribed to Women Aged 50–55 Years 
JAMA internal medicine  2013;173(15):10.1001/jamainternmed.2013.7727.
Background
Postmenopausal hormone therapy with conjugated equine estrogens (CEE) may adversely affect older women’s cognitive function. It is not known whether this extends to younger women.
Methods
1,326 postmenopausal women, who had begun treatment in two randomized placebo-controlled clinical trials of hormone therapy when aged 50–55 years, were assessed with an annual telephone-administered cognitive battery that included measures of global (primary outcome) and domain-specific cognitive functions (verbal memory, attention, executive function, verbal fluency, and working memory). The clinical trials in which they participated had compared 0.625 mg CEE with or without 2.5 mg medroxyprogesterone acetate (MPA) over an average of 7.0 years. Cognitive testing was conducted an average of 7.2 years following the end of the trials, when women had mean age 67.2 years, and repeated one year later.
Results
Global cognitive function scores from women who had been assigned to CEE-based therapies were similar to those from women assigned to placebo: mean [95% confidence interval] intervention effect of 0.02 [−0.08,0.12]standard deviation units (p=0.66). Similarly, no overall differences were found for any individual cognitive domain (all p>0.15). Pre-specified subgroup analyses found some evidence that CEE-based therapies may have adversely affected verbal fluency among women who had prior hysterectomy or prior use of hormone therapy: mean treatment effects of −0.17 [−0.33, −0.02] and −0.25 [−0.42, −0.08], respectively, however this may be a chance finding. We are not able to address whether initiating hormone therapy during the menopause and maintaining therapy until any symptoms are passed affects cognitive function, either in the short or longer term.
Conclusions
CEE-based therapies produced no overall sustained benefit or risk to cognitive function when administered to postmenopausal women aged 50–55 years.
doi:10.1001/jamainternmed.2013.7727
PMCID: PMC3844547  PMID: 23797469
10.  Computerized Cognitive Training in Cognitively Healthy Older Adults: A Systematic Review and Meta-Analysis of Effect Modifiers 
PLoS Medicine  2014;11(11):e1001756.
Michael Valenzuela and colleagues systematically review and meta-analyze the evidence that computerized cognitive training improves cognitive skills in older adults with normal cognition.
Please see later in the article for the Editors' Summary
Background
New effective interventions to attenuate age-related cognitive decline are a global priority. Computerized cognitive training (CCT) is believed to be safe and can be inexpensive, but neither its efficacy in enhancing cognitive performance in healthy older adults nor the impact of design factors on such efficacy has been systematically analyzed. Our aim therefore was to quantitatively assess whether CCT programs can enhance cognition in healthy older adults, discriminate responsive from nonresponsive cognitive domains, and identify the most salient design factors.
Methods and Findings
We systematically searched Medline, Embase, and PsycINFO for relevant studies from the databases' inception to 9 July 2014. Eligible studies were randomized controlled trials investigating the effects of ≥4 h of CCT on performance in neuropsychological tests in older adults without dementia or other cognitive impairment. Fifty-two studies encompassing 4,885 participants were eligible. Intervention designs varied considerably, but after removal of one outlier, heterogeneity across studies was small (I2 = 29.92%). There was no systematic evidence of publication bias. The overall effect size (Hedges' g, random effects model) for CCT versus control was small and statistically significant, g = 0.22 (95% CI 0.15 to 0.29). Small to moderate effect sizes were found for nonverbal memory, g = 0.24 (95% CI 0.09 to 0.38); verbal memory, g = 0.08 (95% CI 0.01 to 0.15); working memory (WM), g = 0.22 (95% CI 0.09 to 0.35); processing speed, g = 0.31 (95% CI 0.11 to 0.50); and visuospatial skills, g = 0.30 (95% CI 0.07 to 0.54). No significant effects were found for executive functions and attention. Moderator analyses revealed that home-based administration was ineffective compared to group-based training, and that more than three training sessions per week was ineffective versus three or fewer. There was no evidence for the effectiveness of WM training, and only weak evidence for sessions less than 30 min. These results are limited to healthy older adults, and do not address the durability of training effects.
Conclusions
CCT is modestly effective at improving cognitive performance in healthy older adults, but efficacy varies across cognitive domains and is largely determined by design choices. Unsupervised at-home training and training more than three times per week are specifically ineffective. Further research is required to enhance efficacy of the intervention.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
As we get older, we notice many bodily changes. Our hair goes grey, we develop new aches and pains, and getting out of bed in the morning takes longer than it did when we were young. Our brain may also show signs of aging. It may take us longer to learn new information, we may lose our keys more frequently, and we may forget people's names. Cognitive decline—developing worsened thinking, language, memory, understanding, and judgment—can be a normal part of aging, but it can also be an early sign of dementia, a group of brain disorders characterized by a severe, irreversible decline in cognitive functions. We know that age-related physical decline can be attenuated by keeping physically active; similarly, engaging in activities that stimulate the brain throughout life is thought to enhance cognition in later life and reduce the risk of age-related cognitive decline and dementia. Thus, having an active social life and doing challenging activities that stimulate both the brain and the body may help to stave off cognitive decline.
Why Was This Study Done?
“Brain training” may be another way of keeping mentally fit. The sale of computerized cognitive training (CCT) packages, which provide standardized, cognitively challenging tasks designed to “exercise” various cognitive functions, is a lucrative and expanding business. But does CCT work? Given the rising global incidence of dementia, effective interventions that attenuate age-related cognitive decline are urgently needed. However, the impact of CCT on cognitive performance in older adults is unclear, and little is known about what makes a good CCT package. In this systematic review and meta-analysis, the researchers assess whether CCT programs improve cognitive test performance in cognitively healthy older adults and identify the aspects of cognition (cognitive domains) that are responsive to CCT, and the CCT design features that are most important in improving cognitive performance. A systematic review uses pre-defined criteria to identify all the research on a given topic; meta-analysis uses statistical methods to combine the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 51 trials that investigated the effects of more than four hours of CCT on nearly 5,000 cognitively healthy older adults by measuring several cognitive functions before and after CCT. Meta-analysis of these studies indicated that the overall effect size for CCT (compared to control individuals who did not participate in CCT) was small but statistically significant. An effect size quantifies the difference between two groups; a statistically significant result is a result that is unlikely to have occurred by chance. So, the meta-analysis suggests that CCT slightly increased overall cognitive function. Notably, CCT also had small to moderate significant effects on individual cognitive functions. For example, some CCT slightly improved nonverbal memory (the ability to remember visual images) and working memory (the ability to remember recent events; short-term memory). However, CCT had no significant effect on executive functions (cognitive processes involved in planning and judgment) or attention (selective concentration on one aspect of the environment). The design of CCT used in the different studies varied considerably, and “moderator” analyses revealed that home-based CCT was not effective, whereas center-based CCT was effective, and that training sessions undertaken more than three times a week were not effective. There was also some weak evidence suggesting that CCT sessions lasting less than 30 minutes may be ineffective. Finally, there was no evidence for the effectiveness of working memory training by itself (for example, programs that ask individuals to recall series of letters).
What Do These Findings Mean?
These findings suggest that CCT produces small improvements in cognitive performance in cognitively healthy older adults but that the efficacy of CCT varies across cognitive domains and is largely determined by design aspects of CCT. The most important result was that “do-it-yourself” CCT at home did not produce improvements. Rather, the small improvements seen were in individuals supervised by a trainer in a center and undergoing sessions 1–3 times a week. Because only cognitively healthy older adults were enrolled in the studies considered in this systematic review and meta-analysis, these findings do not necessarily apply to cognitively impaired individuals. Moreover, because all the included studies measured cognitive function immediately after CCT, these findings provide no information about the durability of the effects of CCT or about how the effects of CCT on cognitive function translate into real-life outcomes for individuals such as independence and the long-term risk of dementia. The researchers call, therefore, for additional research into CCT, an intervention that might help to attenuate age-related cognitive decline and improve the quality of life for older individuals.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001756.
This study is further discussed in a PLOS Medicine Perspective by Druin Burch
The US National Institute on Aging provides information for patients and carers about age-related forgetfulness, about memory and cognitive health, and about dementia (in English and Spanish)
The UK National Health Service Choices website also provides information about dementia and about memory loss
MedlinePlus provides links to additional resources about memory, mild cognitive impairment, and dementia (in English and Spanish)
doi:10.1371/journal.pmed.1001756
PMCID: PMC4236015  PMID: 25405755
11.  Seafood Types and Age-Related Cognitive Decline in the Women’s Health Study 
Background.
Seafood consumption may prevent age-related cognitive decline. However, benefits may vary by nutrient contents in different seafood types. We examined associations between total seafood consumption and cognitive decline and whether these associations differ by seafood types.
Methods.
We conducted a prospective cohort study of 5,988 women (mean age, 72 years) from the Women’s Health Study who self-reported seafood intake at Women’s Health Study baseline and also participated in telephone assessments of general cognition, verbal memory, and category fluency administered 5.6 years after Women’s Health Study baseline and 2 and 4 years thereafter. Primary outcomes were standardized composite scores of global cognition and verbal memory.
Results.
After adjusting for potential confounders, different amounts of total seafood consumption were not associated with changes in global cognition (p = .56) or verbal memory (p = .29). Considering seafood types, however, compared with women consuming less than once-weekly tuna or dark-meat finfish, those with once-weekly or higher consumption had significantly better verbal memory (0.079 standard units; p < .01) after 4 years—a difference comparable to that for women 2.1 years apart in age. There was also a statistically nonsignificant suggestion of better global cognition (p = .13) with once-weekly or higher tuna or dark-meat fish consumption. No significant associations were observed for light-meat finfish or shellfish.
Conclusions.
The relation of seafood to cognition may depend on the types consumed. Total consumption levels of seafood were unrelated to cognitive change. However, consumption of tuna and dark-meat fish once weekly or higher was associated with lower decline in verbal memory for a period of 4 years.
doi:10.1093/gerona/glt037
PMCID: PMC3779629  PMID: 23554464
Cognition; Epidemiology; Nutrition.
12.  Fasting plasma insulin, c-peptide and cognitive change in older men without diabetes: results from the Physicians’ Health Study II 
Neuroepidemiology  2010;34(4):200-207.
Background
Type 2 diabetes has been associated with diminished late-life cognition; less is known about relations of insulin levels and insulin secretion to cognitive change among persons without diabetes. We examined prospectively relations of fasting insulin levels and insulin secretion to cognitive decline, among healthy, community-dwelling older men without diabetes.
Methods
Fasting plasma insulin and c-peptide (insulin secretion) levels were measured in 1,353 non-diabetic men, aged 60–92 years (mean=71.3), in the Physicians’ Health Study II who participated in cognitive testing an average of 3.3 years later. Two assessments were administered 2 years apart (range=1.5–4.0) using telephone-based tests (general cognition, verbal memory, and category fluency). Primary outcomes were the Telephone interview for Cognitive Status (TICS), global cognition (averaging all tests) and verbal memory (averaging four verbal tests). Multivariable linear regression models were used to estimate relations of insulin and c-peptide to cognitive decline.
Results
Higher fasting insulin was associated with worse decline on all tests, after adjustment. Findings were statistically significant for the TICS and category fluency: e.g., the multivariable-adjusted mean difference (95% CI) in decline for men with the highest vs. lowest insulin levels was −0.62 (−1.15, −0.09) points on the TICS (p-trend=0.04); this difference was similar to that between men 7 years apart in age. Similarly, there was worse decline across all tests with increasing c-peptide, but findings were statistically significant only for global score (p-trend=0.03).
Conclusions
Higher fasting insulin and greater insulin secretion in older men may be related to overall cognitive decline, even in the absence of diabetes.
doi:10.1159/000289351
PMCID: PMC2883838  PMID: 20197703
insulin; c-peptide; cognitive decline; dementia; diabetes
13.  Fasting Plasma Insulin, C-Peptide and Cognitive Change in Older Men without Diabetes: Results from the Physicians’ Health Study II 
Neuroepidemiology  2010;34(4):200-207.
Background
Type 2 diabetes has been associated with diminished late-life cognition; less is known about relations of insulin levels and insulin secretion to cognitive change among persons without diabetes. We examined prospectively relations of fasting insulin levels and insulin secretion to cognitive decline among healthy, community-dwelling older men without diabetes.
Methods
Fasting plasma insulin and C-peptide (insulin secretion) levels were measured in 1,353 nondiabetic men, aged 60–92 years (mean = 71.3 years), in the Physicians’ Health Study II, who participated in cognitive testing an average of 3.3 years later. Two assessments were administered 2 years apart (range = 1.5–4.0 years) using telephone-based tests (general cognition, verbal memory and category fluency). Primary outcomes were the Telephone Interview for Cognitive Status (TICS), global cognition (averaging all tests) and verbal memory (averaging 4 verbal tests). Multivariable linear regression models were used to estimate the relations of insulin and C-peptide to cognitive decline.
Results
Higher fasting insulin was associated with a greater decline on all tests, after adjustment. Findings were statistically significant for the TICS and category fluency, e.g. the multivariable-adjusted mean difference (95% CI) in decline for men with the highest versus lowest insulin levels was −0.62 (−1.15, −0.09) points on the TICS (p for trend = 0.04); this difference was similar to that between men 7 years apart in age. Similarly, there was a greater decline across all tests with increasing C-peptide, but the findings were statistically significant only for the global score (p for trend = 0.03).
Conclusions
Higher fasting insulin and greater insulin secretion in older men may be related to overall cognitive decline, even in the absence of diabetes.
doi:10.1159/000289351
PMCID: PMC2883838  PMID: 20197703
Insulin; C-Peptide; Cognitive decline; Dementia; Diabetes
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.  Mediterranean diet and cognitive decline in women with cardiovascular disease or risk factors 
Background
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.
Objectives
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jand.2012.02.023
PMCID: PMC3378990  PMID: 22709809
cognitive decline; vascular disease; hypertension; Mediterranean diet; longitudinal study
16.  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
17.  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
18.  Exposure to Particulate Air Pollution and Cognitive Decline in Older Women 
Archives of internal medicine  2012;172(3):219-227.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1001/archinternmed.2011.683
PMCID: PMC3622279  PMID: 22332151
19.  Predicting cognitive decline 
Neurology  2013;80(14):1300-1306.
Objective:
Our aim was to compare 2 Framingham vascular risk scores with a dementia risk score in relation to 10-year cognitive decline in late middle age.
Methods:
Participants were men and women with mean age of 55.6 years at baseline, from the Whitehall II study, a longitudinal British cohort study. We compared the Framingham general cardiovascular disease risk score and the Framingham stroke risk score with the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score that uses risk factors in midlife to estimate risk of late-life dementia. Cognitive tests included reasoning, memory, verbal fluency, vocabulary, and global cognition, assessed 3 times over 10 years.
Results:
Higher cardiovascular disease risk and higher stroke risk were associated with greater cognitive decline in all tests except memory; higher dementia risk was associated with greater decline in reasoning, vocabulary, and global cognitive scores. Compared with the dementia risk score, cardiovascular and stroke risk scores showed slightly stronger associations with 10-year cognitive decline; these differences were statistically significant for semantic fluency and global cognitive scores. For example, cardiovascular disease risk was associated with −0.06 SD (95% confidence interval [CI] = −0.08, −0.05) decline in the global cognitive scores over 10 years whereas dementia risk was associated with −0.03 SD (95% CI = −0.04, −0.01) decline (difference in β coefficients = 0.03; 95% CI = 0.01, 0.05).
Conclusions:
The CAIDE dementia and Framingham risk scores predict cognitive decline in late middle age but the Framingham risk scores may have an advantage over the dementia risk score for use in primary prevention for assessing risk of cognitive decline and targeting of modifiable risk factors.
doi:10.1212/WNL.0b013e31828ab370
PMCID: PMC3656460  PMID: 23547265
20.  Decline in renal functioning is associated with longitudinal decline in global cognitive functioning, abstract reasoning and verbal memory 
Nephrology Dialysis Transplantation  2012;28(7):1810-1819.
Background
Decreased estimated glomerular filtration rate (eGFR) and higher serum creatinine (sCR) levels have been associated with longitudinal decline in global mental status measures. Longitudinal data describing change in multiple domains of cognitive functioning are needed in order to determine which specific abilities are most affected in individuals with impaired renal function.
Methods
We conducted a 5-year longitudinal study with 590 community-living individuals (mean age 62.1 years, 60.2% female, 93.2% white, 11.4% with diabetes mellitus, mean eGFR 78.4 mL/min/1.73 m²) free from dementia, acute stroke and end-stage renal disease. To measure longitudinal change-over-time, cognitive performance measures were regressed on eGFR adjusting for baseline eGFR and cognitive performance, comorbidity and vascular risk factors. Outcome measures were scores from 17 separate tests of cognitive abilities that were used to index 5 theoretically relevant domains: verbal episodic memory, visual-spatial organization and memory, scanning and tracking, working memory and similarities (abstract reasoning).
Results
Declines in eGFR values were associated with cognitive declines, when adjusted for eGFR and cognitive function scores at baseline. Change in renal functioning over time was related to change observed in global cognitive ability [b = 0.21SD decline per unit ln(eGFR), 95% CI: 0.04–0.38, P = .018], verbal episodic memory [b = 0.28 SD decline per unit ln(eGFR), 95% CI: 0.02–0.54, P = 0.038] and abstract reasoning [b = 0.36 SD decline per unit ln(eGFR), 95% CI: 0.04–0.67, P = 0.025]. Decline in cognitive functioning in association with declining renal functioning was observed despite statistical adjustment for demographic variables and CVD risk factors and the exclusion of persons with dementia or a history of acute stroke.
Conclusions
Early detection of mild to moderate kidney disease is an important public health concern with regard to cognitive decline.
doi:10.1093/ndt/gfs470
PMCID: PMC3707524  PMID: 23166308
cardiovascular disease; chronic kidney disease; cognitive performance; estimated glomerular filtration rate; renal disease
21.  Impact of smoking on cognitive decline in early old age: the Whitehall II cohort study 
Archives of General Psychiatry  2012;69(6):627-635.
Context
Smoking is a possible risk factor for dementia although its impact may have been underestimated in elderly populations due to the shorter lifespan of smokers.
Objective
To examine the association between smoking history and cognitive decline in the transition from midlife to old age.
Design, Setting, and Participants
Data are from 5099 men and 2137 women in the Whitehall II study, mean age 56 years (range=44–69 years) at the first cognitive assessment (1997–1999), repeated over 2002–2004 and 2007–2009.
Main Outcome Measures
The cognitive test battery was composed of tests of memory, vocabulary, executive function (composed of one reasoning and two fluency tests), and a global cognitive score summarising performance across all five tests. Smoking status was assessed over the entire study period. Linear mixed models were used to assess the association between smoking history and 10-year cognitive decline, expressed as z-scores.
Results
In men, 10-year cognitive decline in all tests except vocabulary among never smokers ranged from a quarter to a third of the baseline standard deviation. Faster cognitive decline was observed among current smokers compared to never smokers in men [mean difference in 10-year decline in global cognition=−0.09 (95%CI:−0.15;−0.03) and executive function=−0.11 (−0.17;−0.05)]. Recent ex-smokers had greater decline in executive function (−0.08 (−0.14;−0.02)) while the decline in long-term ex-smokers was similar to that among never smokers. In analyses that additionally took drop-out and death into account, these differences were 1.2 to 1.5 times larger. In women, cognitive decline did not vary as a function of smoking status.
Conclusions
Compared to never smokers, middle-aged male smokers experienced faster cognitive decline in global cognition and executive function. In ex-smokers with at least 10-year cessation there were no adverse effects on cognitive decline.
doi:10.1001/archgenpsychiatry.2011.2016
PMCID: PMC3675806  PMID: 22309970
Adult; Aged; Cognition Disorders; etiology; physiopathology; Cohort Studies; Female; Great Britain; Humans; Male; Middle Aged; Neuropsychological Tests; Smoking; adverse effects; Time Factors
22.  Phobic anxiety and cognitive performance over 4 years among community-dwelling older women in the Nurses’ Health Study 
Objective
To examine the relation of phobic anxiety to late-life cognitive trajectory.
Design
Prospective cohort.
Setting
Nurses’ Health Study – U.S. registered nurses.
Participants
16,351 women among whom phobic anxiety symptoms were assessed in 1988 (mean age=63 years).
Measurements
Beginning a decade after phobic anxiety ascertainment (mean age=74 years), three assessments of general cognition, word and paragraph immediate and delayed recall, category fluency, and attention/working memory were administered over an average of 4.4 years; global cognitive and verbal memory composite scores were generated from the component tests. General linear models of response profiles were used to evaluate relations of phobic anxiety to initial cognitive performance and subsequent change.
Results
Higher phobic anxiety was associated with poorer initial performance: e.g., comparing women with the highest anxiety to those with no/minimal symptoms, the multivariate-adjusted mean difference (95% confidence interval) in scores was −0.10 (−0.13,−0.06) standard units for the global score summarizing all tests, and −0.08 (−0.11,−0.04) standard units for verbal memory (summarizing 4 word- and paragraph-recall tasks). Mean differences between extreme categories of phobic anxiety were equal to those for participants aged 1.5–2 years apart: i.e., cognitively equivalent to being about two years older. There were no relations of phobic anxiety to subsequent cognitive change.
Conclusions
Higher mid-life phobic anxiety was related to worse later-life overall cognition and verbal memory. Yet, profiles of poorer cognition with higher anxiety remained parallel over time, suggesting phobic anxiety may impose impact on cognition earlier in life, rather than ongoing impact in later-life.
doi:10.1016/j.jagp.2013.01.050
PMCID: PMC3516630  PMID: 23567369
23.  Treatment for Schistosoma japonicum, Reduction of Intestinal Parasite Load, and Cognitive Test Score Improvements in School-Aged Children 
Background
To determine whether treatment of intestinal parasitic infections improves cognitive function in school-aged children, we examined changes in cognitive testscores over 18 months in relation to: (i) treatment-related Schistosoma japonicum intensity decline, (ii) spontaneous reduction of single soil-transmitted helminth (STH) species, and (iii) ≥2 STH infections among 253 S. japonicum-infected children.
Methodology
Helminth infections were assessed at baseline and quarterly by the Kato-Katz method. S. japonicum infection was treated at baseline using praziquantel. An intensity-based indicator of lower vs. no change/higher infection was defined separately for each helminth species and joint intensity declines of ≥2 STH species. In addition, S. japonicum infection-free duration was defined in four categories based on time of schistosome re-infection: >18 (i.e. cured), >12 to ≤18, 6 to ≤12 and ≤6 (persistently infected) months. There was no baseline treatment for STHs but their intensity varied possibly due to spontaneous infection clearance/acquisition. Four cognitive tests were administered at baseline, 6, 12, and 18 months following S. japonicum treatment: learning and memory domains of Wide Range Assessment of Memory and Learning (WRAML), verbal fluency (VF), and Philippine nonverbal intelligence test (PNIT). Linear regression models were used to relate changes in respective infections to test performance with adjustment for sociodemographic confounders and coincident helminth infections.
Principal Findings
Children cured (β = 5.8; P = 0.02) and those schistosome-free for >12 months (β = 1.5; P = 0.03) scored higher in WRAML memory and VF tests compared to persistently infected children independent of STH infections. A decline vs. no change/increase of any individual STH species (β:11.5–14.5; all P<0.01) and the joint decline of ≥2 STH (β = 13.1; P = 0.01) species were associated with higher scores in WRAML learning test independent of schistosome infection. Hookworm and Trichuris trichiura declines were independently associated with improvements in WRAML memory scores as was the joint decline in ≥2 STH species. Baseline coinfection by ≥2 STH species was associated with low PNIT scores (β = −1.9; P = 0.04).
Conclusion/Significance
Children cured/S. japonicum-free for >12 months post-treatment and those who experienced declines of ≥2 STH species scored higher in three of four cognitive tests. Our result suggests that sustained deworming and simultaneous control for schistosome and STH infections could improve children's ability to take advantage of educational opportunities in helminth-endemic regions.
Author Summary
Parasitic worm infections are associated with cognitive impairment and lower academic achievement for infected relative to uninfected children. However, it is unclear whether curing or reducing worm infection intensity improves child cognitive function. We examined the independent associations between: (i) Schistosoma japonicum infection-free duration, (ii) declines in single helminth species, and (iii) joint declines of ≥2 soil-transmitted helminth (STH) infections and improvements in four cognitive tests during18 months of follow-up. Enrolled were schistosome-infected school-aged children among whom coinfection with STH was common. All children were treated for schistosome infection only at enrolment with praziquantel. Children cured or schistosome-free for >12 months scored higher in memory and verbal fluency tests compared to persistently infected children. Likewise, declines of single and polyparasitic STH infections predicted higher scores in three of four tests. We conclude that reducing the intensity of certain helminth species and the frequency of multi-species STH infections may have long-term benefits for affected children's cognitive performance. The rapidity of schistosome re-infection and the ubiquity of concurrent multi-species infection highlight the importance of sustained deworming for both schistosome and STH infections to enhance the learning and educational attainment of children in helminth-endemic settings.
doi:10.1371/journal.pntd.0001634
PMCID: PMC3341324  PMID: 22563514
24.  Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients 
BMJ : British Medical Journal  2002;324(7329):71-86.
Objective
To determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular events.
Design
Collaborative meta-analyses (systematic overviews).
Inclusion criteria
Randomised trials of an antiplatelet regimen versus control or of one antiplatelet regimen versus another in high risk patients (with acute or previous vascular disease or some other predisposing condition) from which results were available before September 1997. Trials had to use a method of randomisation that precluded prior knowledge of the next treatment to be allocated and comparisons had to be unconfounded—that is, have study groups that differed only in terms of antiplatelet regimen.
Studies reviewed
287 studies involving 135 000 patients in comparisons of antiplatelet therapy versus control and 77 000 in comparisons of different antiplatelet regimens.
Main outcome measure
“Serious vascular event”: non-fatal myocardial infarction, non-fatal stroke, or vascular death.
Results
Overall, among these high risk patients, allocation to antiplatelet therapy reduced the combined outcome of any serious vascular event by about one quarter; non-fatal myocardial infarction was reduced by one third, non-fatal stroke by one quarter, and vascular mortality by one sixth (with no apparent adverse effect on other deaths). Absolute reductions in the risk of having a serious vascular event were 36 (SE 5) per 1000 treated for two years among patients with previous myocardial infarction; 38 (5) per 1000 patients treated for one month among patients with acute myocardial infarction; 36 (6) per 1000 treated for two years among those with previous stroke or transient ischaemic attack; 9 (3) per 1000 treated for three weeks among those with acute stroke; and 22 (3) per 1000 treated for two years among other high risk patients (with separately significant results for those with stable angina (P=0.0005), peripheral arterial disease (P=0.004), and atrial fibrillation (P=0.01)). In each of these high risk categories, the absolute benefits substantially outweighed the absolute risks of major extracranial bleeding. Aspirin was the most widely studied antiplatelet drug, with doses of 75-150 mg daily at least as effective as higher daily doses. The effects of doses lower than 75 mg daily were less certain. Clopidogrel reduced serious vascular events by 10% (4%) compared with aspirin, which was similar to the 12% (7%) reduction observed with its analogue ticlopidine. Addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone. Among patients at high risk of immediate coronary occlusion, short term addition of an intravenous glycoprotein IIb/IIIa antagonist to aspirin prevented a further 20 (4) vascular events per 1000 (P<0.0001) but caused 23 major (but rarely fatal) extracranial bleeds per 1000.
Conclusions
Aspirin (or another oral antiplatelet drug) is protective in most types of patient at increased risk of occlusive vascular events, including those with an acute myocardial infarction or ischaemic stroke, unstable or stable angina, previous myocardial infarction, stroke or cerebral ischaemia, peripheral arterial disease, or atrial fibrillation. Low dose aspirin (75-150 mg daily) is an effective antiplatelet regimen for long term use, but in acute settings an initial loading dose of at least 150 mg aspirin may be required. Adding a second antiplatelet drug to aspirin may produce additional benefits in some clinical circumstances, but more research into this strategy is needed.
What is already known on this topicAntiplatelet therapy is effective for short term treatment of patients with suspected acute myocardial infarction and unstable anginaLong term treatment is beneficial for patients who have had a myocardial infarction, stroke, or transient ischaemic attackDaily aspirin doses of 75-325 mg are effectiveWhat this study addsAntiplatelet therapy protects against vascular events among patients with stable angina, intermittent claudication, and (if oral anticoagulants are unsuitable) atrial fibrillationAntiplatelet therapy can be started promptly during acute presumed ischaemic stroke and continued long termDaily aspirin doses of 75-150 mg seem to be as effective as higher doses for long term treatments (and clopidrogel is an appropriate alternative for patients with a contraindication to aspirin)Short term addition of a glycoprotein IIb/IIIa antagonist to aspirin prevents vascular events in patients having percutaneous coronary intervention and those with unstable angina but causes increased bleeding
PMCID: PMC64503  PMID: 11786451
25.  Effect of multivitamin and multimineral supplementation on cognitive function in men and women aged 65 years and over: a randomised controlled trial 
Nutrition Journal  2007;6:10.
Background
Observational studies have frequently reported an association between cognitive function and nutrition in later life but randomised trials of B vitamins and antioxidant supplements have mostly found no beneficial effect. We examined the effect of daily supplementation with 11 vitamins and 5 minerals on cognitive function in older adults to assess the possibility that this could help to prevent cognitive decline.
Methods
The study was carried out as part of a randomised double blind placebo controlled trial of micronutrient supplementation based in six primary care health centres in North East Scotland. 910 men and women aged 65 years and over living in the community were recruited and randomised: 456 to active treatment and 454 to placebo. The active treatment consisted of a single tablet containing eleven vitamins and five minerals in amounts ranging from 50–210 % of the UK Reference Nutrient Intake or matching placebo tablet taken daily for 12 months. Digit span forward and verbal fluency tests, which assess immediate memory and executive functioning respectively, were conducted at the start and end of the intervention period. Risk of micronutrient deficiency at baseline was assessed by a simple risk questionnaire.
Results
For digit span forward there was no evidence of an effect of supplements in all participants or in sub-groups defined by age or risk of deficiency. For verbal fluency there was no evidence of a beneficial effect in the whole study population but there was weak evidence for a beneficial effect of supplementation in the two pre-specified subgroups: in those aged 75 years and over (n 290; mean difference between supplemented and placebo groups 2.8 (95% CI -0.6, 6.2) units) and in those at increased risk of micronutrient deficiency assessed by the risk questionnaire (n 260; mean difference between supplemented and placebo groups 2.5 (95% CI -1.0, 6.1) units).
Conclusion
The results provide no evidence for a beneficial effect of daily multivitamin and multimineral supplements on these domains of cognitive function in community-living people over 65 years. However, the possibility of beneficial effects in older people and those at greater risk of nutritional deficiency deserves further attention.
doi:10.1186/1475-2891-6-10
PMCID: PMC1872030  PMID: 17474991

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