Vascular risk factors, alcohol intake, and cognitive decline

Since the therapeutic options currently available have demonstrated limited efficacy, the search for preventive strategies for cognitive decline and dementia is mandatory. A possible role of vascular and lifestyle-related factors was recently proposed for age-related changes of cognitive function, predementia syndromes, and cognitive decline of degenerative (Alzheimer’s disease, AD) or vascular origin. At present, cumulative evidence suggested that vascular risk factors may be important in the development of mild cognitive impairment (MCI), dementia, and AD. Among vascular-related factors, metabolic syndrome has been associated with the risk of cognitive decline and overall dementia. Moderate alcohol drinking has been proposed as a protective factor against MCI and dementia in several longitudinal studies, but contrasting findings also exist. However, in most cases, these were only observational studies, and results are awaited from large multicenter randomized clinical trials in older persons. At present, vascular risk factor management, lifestyle changes, and drugs could be employed together to delay the onset of dementia syndromes.     

Use of HRT and the subsequent risk of cancer

At least 20 million women in developed countries are estimated to be currently using hormone replacement therapy (HRT). Almost 100 epidemiological studies have reported on the relationship between the use of HRT and the risk of cancer of female reproductive organs, namely the breast, uterus or ovary. Cancer at these sites is common and there are a priori reasons why the use of hormonal therapy to 'replace' the endogenous production of ovarian hormones after the menopause might increase the risk of these cancers. The available evidence indicates that the risk of breast cancer or endometrial cancer is increased while women are using HRT, the risk increasing with increasing duration of use. Most of the evidence about these cancers relates to use of HRT preparations containing oestrogens alone. The limited evidence about combination therapy, with oestrogens and progestogens, suggests that, compared to oestrogens alone, the effect on the breast is similar, but the effect on the endometrium is diminished, the diminution in risk being greater the more days each month that progestogens are used. The effect of HRT on breast cancer wears off after use ceases and has disappeared largely, if not wholly, within 5 years, whereas the effects on endometrial cancer take longer to wear off, if at all. The breast and endometrial cancers that are diagnosed in HRT users are less aggressive clinically than cancers in never-users but, as yet, there is little reliable information about the relationship between use of HRT and mortality from these cancers. For other cancer sites, the existing data about the effects of HRT are inconclusive. The longer the period of use of HRT, the greater the excess incidence of cancer of the breast and endometrium is likely to be. Use of HRT for short periods of time should have little effect on the incidence of these cancers. The cumulative excess incidence in 1000 women who used HRT for 10 years, beginning at age 50, is estimated to be six for breast cancer, 42 for endometrial cancer in women with an intact uterus using oestrogen therapy alone and about 20 for endometrial cancer in women with an intact uterus using oestrogen-progestogen combinations. The estimate for combined therapy is based on small numbers and may well vary with the type of preparation used. The overall balance between the excess incidence of these cancers and other effects of HRT needs to be evaluated carefully and will require more reliable data than exist at present.     

Clinical Evaluation of Effects of Chronic Resveratrol Supplementation on Cerebrovascular Function,Cognition, Mood,Physical Function and General Well-Being in Postmenopausal Women—Rationale and Study Design

Background: This methodological paper presents both a scientific rationale and a methodological approach for investigating the effects of resveratrol supplementation on mood and cognitive performance in postmenopausal women. Postmenopausal women have an increased risk of cognitive decline and dementia, which may be at least partly due to loss of beneficial effects of estrogen on the cerebrovasculature. We hypothesise that resveratrol, a phytoestrogen, may counteract this risk by enhancing cerebrovascular function and improving regional blood flow in response to cognitive demands. A clinical trial was designed to test this hypothesis. Method: Healthy postmenopausal women were recruited to participate in a randomised, double-blind, placebo-controlled (parallel comparison) dietary intervention trial to evaluate the effects of resveratrol supplementation (75 mg twice daily) on cognition, cerebrovascular responsiveness to cognitive tasks and overall well-being. They performed the following tests at baseline and after 14 weeks of supplementation: Rey Auditory Verbal Learning Test, Cambridge Semantic Memory Battery, the Double Span and the Trail Making Task. Cerebrovascular function was assessed simultaneously by monitoring blood flow velocity in the middle cerebral arteries using transcranial Doppler ultrasound. Conclusion: This trial provides a model approach to demonstrate that, by optimising circulatory function in the brain, resveratrol and other vasoactive nutrients may enhance mood and cognition and ameliorate the risk of developing dementia in postmenopausal women and other at-risk populations.     

绝经与认知功能障碍

认知功能障碍泛指各种原因导致的各种程度的认知功能损害。老年女性出现认知功能的衰退不仅与年龄、遗传易感等因素相关,还可能与女性绝经后内源性雌激素缺乏有关。雌激素对于神经功能的保护作用已在诸多实验室研究和动物研究方面获得支持,但在临床应用激素补充治疗(hormone replacement therapy,HRT)时其疗效与预期并不完全一致。这可能与HRT启用的时机有关。目前认为,在围绝经期的窗口期开始HRT,会形成一个长期对痴呆的保护作用。     

IANA task force on nutrition and cognitive decline with aging

Cognitive impairment can be influenced by a number of factors. The potential effect of nutrition has become a topic of increasing scientific and public interest. In particular, there are arguments that nutrients (food and/or supplements) such as vitamins, trace minerals, lipids, can affect the risk of cognitive decline and dementia, especially in frail elderly people at risk of deficiencies. Our objective in this paper is to review data relating diet to risk of cognitive decline and dementia, especially Alzheimer's disease (AD). We chose to focus our statements on homocysteine-related vitamins (B-vitamins), antioxidant nutrients (vitamins E and C, carotenoids, flavonoids, enzymatic cofactors) and dietary lipids. Results of epidemiological studies may sometimes appeared conflicting; however, certain associations are frequently found. High intake of saturated and trans-unsaturated (hydrogenated) fats were positively associated with increased risk of AD, whereas intake of polyunsaturated and monounsaturated fats were protective against cognitive decline in the elderly in prospective studies. Fish consumption has been associated with lower risk of AD in longitudinal cohort studies. Moreover, epidemiologic data suggest a protective role of the B-vitamins, especially vitamins B9 and B12, on cognitive decline and dementia. Finally, the results on antioxidant nutrients may suggest the importance of having a balanced combination of several antioxidant nutrients to exert a significant effect on the prevention of cognitive decline and dementia, while taking into account the potential adverse effects of these nutrients. There is no lack of attractive hypotheses to support research on the relationships between nutrition and cognitive decline. It is important to stress the need to develop further prospective studies of sufficiently long duration, including subjects whose diet is monitored at a sufficiently early stage or at least before disease or cognitive decline exist. Meta analyses should be developed, and on the basis of their results the most appropriate interventional studies can be planned. These studies must control for the greatest number of known confounding factors and take into account the impact of the standard social determinants of food habits, such as the regional cultures, social status, and educational level.     

HRT and breast cancer

Research on hormone replacement therapy (HRT) in the 21st century has been dominated by the findings of the Women’s Health Initiative (WHI) and Million Women Study (MWS). Clinical practice has changed accordingly. Both studies confirm an increase in the risk of breast cancer among women using combined HRT (oestrogen and progestogen) when compared with women who have never used HRT. The risk among women using oestrogen-only preparations of HRT, according to the MWS, is increased, but to a lesser extent than for women using combined HRT. In contrast the WHI Study suggests that oestrogen alone is not associated with an increased risk of breast cancer. Despite these different findings most evidence-based guidelines from professional organizations still advise use of HRT only for the relief of menopausal symptoms and only short term. Routine use of unopposed oestrogen for women with a uterus is being discussed but is still not recommended. New data have also led to the recommendation that HRT is contraindicated for women who have had breast cancer. More research is needed on the contribution of progestogens to the increased risk of breast cancer and on the safety of different routes of administration of both oestrogen and progestogen.     

Prospective assessment of estrogen replacement therapy and cognitive functioning: atherosclerosis risk in communities study

Studies of humans have not confirmed the suggestion from animal studies that estrogen replacement therapy may have an inverse relation with cognitive function decline. Because many of these studies have been marred by design or methodological problems, such as a small sample size, failure to control for confounding variables, or the use of a cross-sectional design, the present study was conducted in a large cohort of middle-aged postmenopausal women participating in the Atherosclerosis Risk in Communities (ARIC) Study. The study population consisted of 2,859 women aged 48-67 years, whose cognitive function was tested at the second (1990-1992) and fourth (1996-1998) visits of the ARIC Study using three instruments: the Delayed Word Recall Test, Digit Symbol Subtest of the Wechsler Adult Intelligence Scale-Revised, and Word Fluency Test. After multiple adjustment, no consistent patterns of cognitive changes between the two cohort visits could be detected according to current use or duration of use of estrogen replacement therapy. Thus, the results of the present study do not support the hypothesis that estrogen replacement therapy may slow age-related cognitive decline, at least as it applies to relatively young postmenopausal women.     

Omega 3 fatty acids and cognitive health in older people

Oily fish and other sources of long-chain n-3 polyunsaturated fatty acids (n-3 LCPs) have been proposed as protective against dementia and age related cognitive impairment. The basic mechanisms underlying these proposed benefits have been postulated and experimental studies supporting the plausibility of the putative effects have been published. Observational epidemiological and case control studies also largely support a protective role of fish consumption on cognitive function with advancing age, albeit with important unexplained heterogeneity in findings. In this review we report the findings of the latest Cochrane review on the benefits of n-3 LCP supplementation on cognitive function among cognitively healthy older people and expand the review by including trials conducted with individuals with prevalent poor cognitive function or dementia. We identified seven relevant trials, four among cognitively healthy older people, and three among individuals with pre-existing cognitive decline or dementia, and overall conclude that there is no evidence to support the routine use of n-3 LCPs supplements for the prevention, or amelioration, of cognitive decline in later life. We identified several challenges in the design of intervention studies for the prevention of dementia and cognitive decline in older people that require careful consideration especially in recruitment and retention in long-term trials. Whether the lack of agreement in findings from mechanistic and observational data and from intervention studies reflects a real absence of benefit on cognitive function from n-3 LCP supplementation, or whether it reflects intrinsic limitations in the design of published studies remains open to question.     

Fruit, vegetables and prevention of cognitive decline or dementia: A systematic review of cohort studies

Background: Regular consumption of fruit and vegetables has been considered to be associated with a reduced risk of dementia and age-associated cognitive decline, although the association is currently unsupported by a systematic review of the literature. Methods: We searched Medline, Embase, Biosis, ALOIS, the Cochrane library, different publisher databases as well as bibliographies of retrieved articles. All cohort studies with a follow-up of 6 months or longer were included if they reported an association of Alzheimer's disease or cognitive decline in regard to the frequency of fruit and vegetables consumption. Findings: Nine studies with a total of 44 004 participants met the inclusion criteria. Six studies analyzed fruit and vegetables separately and five of them found that higher consumption of vegetables, but not fruit is associated with a decreased risk of dementia or cognitive decline. The same association was found by three further studies for fruit and vegetable consumption analytically combined. Conclusion: Increased intake of vegetables is associated with a lower risk of dementia and slower rates of cognitive decline in older age. Yet, evidence that this association is also valid for high fruit consumption is lacking.     

Dementing Illnesses in Rural Populations: The Need for Research and Challenges Confronting Investigators

Expansion of the world's elderly populations has increased concerns about aging-related medical disorders like Alzheimer's disease and other dementias. In the United States, one fourth of those older than age 65 and at greatest risk for developing dementia live in rural environments that may influence its manifestation. The objectives of this study were to determine the need for and potential benefits of further epidemiological research concerning dementia and similar disorders in rural U.S. populations and to identify pertinent methodological issues related to rural dementia research. This study employed a National Library of Medicine (MEDLINE) document search based on the key words "cognitive disorders," "dementia," "Alzheimer's disease," and "rural," followed by recovery of literature resources references in the bibliographies of selected articles. Nineteen studies focusing on dementia or related disorders in rural settings have been reported from around the world. While four of these were conducted in the United States, only one rural dementia prevalence study has been undertaken in this country. Because of methodological variability, comparisons of prevalence estimates between these rural studies, as well as with those from urban investigations, is difficult. Nonetheless, there is reason to believe that certain potentially dementing illnesses are more common in rural populations. There is also evidence to suggest that the screening instruments commonly used in such studies tend to misclassify rural elders as "false positive" dementia cases. Information regarding dementing disorders, particularly Alzheimer's disease, in rural populations is scarce. Preliminary observations that dementia may be more common in rural settings and that rural families are more likely to maintain their dementing elders in the community imply that further rural dementia research could yield important insights into the risk factors for these illnesses, the variables influencing their course, and the methods by which they can be more effectively managed. A determination of the reliability and validity of commonly used dementia screening instruments in rural populations would represent an important advancement in this area of research.     

Diabetes mellitus, dementia, and cognitive function in older persons

Dementia and cognitive decline are among the most common and most feared conditions of old age making the identification of modifiable risk factors for dementia an urgent public health priority. Recently, an increasing body of data suggests that type 2 diabetes mellitus, a common condition in older persons, is associated with the development of dementia and cognitive decline. A systematic review of the medical literature of the past 15 years identified 40 original-report articles in the English language pertaining to the relation of diabetes to dementia and cognitive function in older persons. Most, but not all, of these studies suggest a detrimental effect of diabetes on cognitive function. Current research efforts are aimed at understanding the underlying neurobiologic mechanisms whereby diabetes causes dementia and cognitive impairment in order to develop rational interventions to prevent this recently documented adverse consequence.     

The effect of hormone therapy on cognitive function in patients with breast cancer

Preclinical and clinical studies suggest that oestrogens have an important role in brain functioning and cognitive ability. Given that hormone therapies for breast cancer reduce oestrogen levels or block oestrogen receptors, it is conceivable that these agents also influence cognitive function. Several small studies have been conducted to address this issue, but many of them are methodologically insufficient. The negative effects of oophorectomy and luteinising hormone-releasing hormone (LHRH) analogues on verbal memory and working memory have been demonstrated the most consistently, albeit only in small studies. Anastrozole and tamoxifen also appear to exert some negative effect on cognition, but well-designed studies are lacking. No data are available on the influence of the aromatase inhibitors exemestane and letrozole on cognitive function. Raloxifene, a drug that has no obvious advantages over tamoxifen and will likely not be developed further for breast cancer treatment, has no negative influence on cognitive functioning. It remains unclear whether the observed effects are transient or permanent, and to what extent age, menopausal status and duration of therapy influence the severity of cognitive effects.     

B-vitamins and prevention of dementia

Elevated plasma homocysteine (Hcy) concentrations have been implicated with risk of cognitive impairment and dementia, but it is unclear whether low vitamin B12 or folate status is responsible for cognitive decline. Most studies reporting associations between cognitive function and Hcy or B-vitamins have used a cross-sectional or case-control design and have been unable to exclude the possibility that such associations are a result of the disease rather than being causal. The Hcy hypothesis of dementia has attracted considerable interest, as Hcy can be easily lowered by folic acid and vitamin B12, raising the prospect that B-vitamin supplementation could lower the risk of dementia. While some trials assessing effects on cognitive function have used folic acid alone, vitamin B12 alone or a combination, few trials have included a sufficient number of participants to provide reliable evidence. An individual-patient-data meta-analysis of all randomised trials of the effects on cognitive function and vascular risk of lowering Hcy with B-vitamins will maximise the power to assess the epidemiologically-predicted differences in risk. Among the twelve large randomised Hcy-lowering trials for prevention of vascular disease, data should be available on about 30 000 participants with cognitive function. The principal investigators of such trials have agreed to combine individual-participant data from their trials after their separate publication.     

Dietary Patterns,Cognitive Decline,and Dementia: A Systematic Review

Nutrition is an important modifiable risk factor that plays a role in the strategy to prevent or delay the onset of dementia. Research on nutritional effects has until now mainly focused on the role of individual nutrients and bioactive components. However, the evidence for combined effects, such as multinutrient approaches, or a healthy dietary pattern, such as the Mediterranean diet, is growing. These approaches incorporate the complexity of the diet and possible interaction and synergy between nutrients. Over the past few years, dietary patterns have increasingly been investigated to better understand the link between diet, cognitive decline, and dementia. In this systematic review we provide an overview of the literature on human studies up to May 2014 that examined the role of dietary patterns (derived both a priori as well as a posteriori) in relation to cognitive decline or dementia. The results suggest that better adherence to a Mediterranean diet is associated with less cognitive decline, dementia, or Alzheimer disease, as shown by 4 of 6 cross-sectional studies, 6 of 12 longitudinal studies, 1 trial, and 3 meta-analyses. Other healthy dietary patterns, derived both a priori (e.g., Healthy Diet Indicator, Healthy Eating Index, and Program National Nutrition Santé guideline score) and a posteriori (e.g., factor analysis, cluster analysis, and reduced rank regression), were shown to be associated with reduced cognitive decline and/or a reduced risk of dementia as shown by all 6 cross-sectional studies and 6 of 8 longitudinal studies. More conclusive evidence is needed to reach more targeted and detailed guidelines to prevent or postpone cognitive decline.     

Adjustment following surgical implantation of a penile prosthesis: a critical overview

The literature on postsurgical adjustment and/or satisfaction of patients and/or their partners following implantation of a penile prosthesis is reviewed. Only those studies that have systematically assessed psychological variables independent of surgical or functional outcome are included. It is reported that while transitory emotional problems were not uncommon, 64-100% of the implant recipients reported being at least fairly satisfied. Similar levels of satisfaction were reported for their partners when they were interviewed together or when patients responded for their partners. However, lower levels were reported when partners were interviewed separately. Satisfaction was reported to be associated with several variables, and high-risk populations were identified. It is important to interpret these conclusions with extreme caution because of the many serious methodological weaknesses contained in these studies. These methodological problems in the literature are reviewed, and recommendations for future research are presented.     

Smoking as a risk factor for dementia and cognitive decline: a meta-analysis of prospective studies

The authors assessed the association of smoking with dementia and cognitive decline in a meta-analysis of 19 prospective studies with at least 12 months of follow-up. Studies included a total of 26,374 participants followed for dementia for 2-30 years and 17,023 participants followed up for 2-7 years to assess cognitive decline. Mean study age was 74 years. Current smokers at baseline, relative to never smokers, had risks of 1.79 (95% confidence interval (CI): 1.43, 2.23) for incident Alzheimer's disease, 1.78 (95% CI: 1.28, 2.47) for incident vascular dementia, and 1.27 (95% CI: 1.02, 1.60) for any dementia. Compared with those who never smoked, current smokers at baseline also showed greater yearly declines in Mini-Mental State Examination scores over the follow-up period (effect size (beta)=-0.13, 95% CI: -0.18, -0.08). Compared with former smokers, current smokers at baseline showed an increased risk of Alzheimer's disease (relative risk=1.70, 95% CI: 1.25, 2.31) and an increased decline in cognitive abilities (effect size (beta)=-0.07, 95% CI: -0.11, -0.03), but the groups were not different regarding risk of vascular dementia or any dementia. The authors concluded that elderly smokers have increased risks of dementia and cognitive decline.     

The effect of hormone replacement therapy and route of administration on selected cardiovascular risk factors in post-menopausal women

BACKGROUND: There is increasing use of hormone replacement therapy (HRT) by post-menopausal women. Observational epidemiological studies have shown reductions in cardiovascular risk factors in HRT users in the USA, but no randomized controlled trials of HRT have been carried out in the primary practice setting. Previous studies of cardiovascular risk factors have shown a variety of responses according to type of progestagen and oral or topical administration. None has examined the effect of route using an identical progestagen. OBJECTIVES: Our aim was to establish differences, if any, in alteration in cardiovascular risk factors with HRT in post-menopausal women according to route of administration of HRT, oral, transdermal and implant, using first oestrogen alone then oestrogen plus norethisterone, or testosterone for implant. METHODS: Subjects were recruited by letter of invitation to women aged 50-65 years from lists in general practices local to the Charing Cross Hospital Lipid Clinic in West London. Their menopausal status was confirmed and they were randomized to one of three treatment groups or acted as controls. They attended for three visits; at baseline, HRT was initiated as oestrogen alone, oral or transdermal. At the 3-month visit, HRT with the progestagen, norethisterone, was given cyclically, continuously or transdermally until the final visit at 6 months. A separate group of women from the menopause clinic at Chelsea and Westminster Hospital were studied on oestrogen implant then on implanted oestrogen and testosterone. The outcome measures studied were the separate effects of the four regimes as compared with controls on lipoproteins, glucose, insulin, fibrinogen, factor VII and E-selectin, together with weight, waist:hip ratio and blood pressure. RESULTS: The continuous combined oestrogen-progestagen therapy had similar effects on cardiovascular risk factors as oestrogen with cyclical progestagen. All regimes lowered low-density lipoprotein cholesterol, the oral route being more potent than the parenteral; the effect of transdermal HRT was similar to the implant. Lp(a) was reduced only with the oral route. Reductions in factor VII and E-selectin were observed in both the oral and transdermal routes. There was no increase in body mass index, waist:hip ratio, blood pressure or glucose and insulin levels with any of the HRT regimes used. Systolic blood pressure was reduced with the transdermal route. CONCLUSIONS: This study supports the evidence that oestrogen-progestagen HRT, both oral and transdermal, although attenuating some of the benefit of oestrogen alone on fibrinogen and high-density lipoprotein, significantly reduces cardiovascular risk factors, which should diminish post-menopausal risk of coronary disease.     

Fatty acid intake and the risk of dementia and cognitive decline: a review of clinical and epidemiological studies

Dietary intake of fatty acids may be related to dementia and cognitive function through a number of plausible mechanisms, such as atherosclerosis and thrombosis, inflammation, via an effect on brain development and membrane functioning, or via accumulation of beta-amyloid. This review gives an overview of the few studies that have investigated the relationship between fatty acid intake (including the fatty acids from fish) and cognitive function or dementia and summarises the results from two Dutch population-based prospective studies: the Zutphen Elderly Study (n=476) and the Rotterdam Study (n=5,386). Additionally, limitations on dietary intake studies are discussed and possible mechanisms behind the investigated associations. Data from the Rotterdam Study showed that high intakes of the following nutrients were associated with an increased risk of dementia after adjustment for confounders: total fat (RR=2.4 (95%CI: 1.1-5.2)), saturated fat (RR=1.9 (95%CI: 0.9-4.0)), and cholesterol (RR=1.7 (95%CI: 0.9-3.2)). A high fish consumption, an important source of n-3 PUFAs, reduced the risk of dementia (RR=0.4 (95%CI: 0.2-0.9)). In the Zutphen Elderly Study a high linoleic acid intake was associated with cognitive impairment (OR=1.8 (95%CI: 1.0-3.0)). A high fish consumption tended to be inversely associated with cognitive impairment and decline (RR=0.5, 95%CI: 0.2-1.2). Since diet is a risk factor that is suitable for intervention these results are hopeful and potentially very important.     

Dairy constituents and neurocognitive health in ageing

Age-related cognitive decline (ARCD) and dementia are of increasing concern to an ageing population. In recent years, there has been considerable research focused on effective dietary interventions that may prevent or ameliorate ARCD and dementia. While a number of studies have considered the impact that dairy products may have on physiological health, particularly with regard to the metabolic syndrome and cardiovascular health, further research is currently needed in order to establish the impact that dairy products have in the promotion of healthy brain function during ageing. The present review considers the available evidence for the positive effects of dairy products on the metabolic syndrome and glucose regulation, with consideration of the implications for neurocognitive health. A literature search of current (September 2010) meta-analyses/reviews and original research regarding dairy products and cognition was conducted through SCOPUS using the following search terms for dairy consituents: dairy, milk, cheese, yoghurt, probiotics, whey protein, alpha lactalbumin, calcium, B-12, bioactive peptides and colostrinin (CLN). These search terms for dairy products were combined with the following search terms related to cognition and health: cognition, cognitive decline, dementia, Alzheimer's disease, metabolic syndrome, diabetes, insulin resistance and glucose regulation. Concerns regarding SFA and other fatty acids found in dairy products are also reviewed in relation to different forms of dairy products. The review also considers recent evidence for positive neurocognitive effects associated with bioactive peptides, CLN and proline-rich polypeptides, α-lactalbumin, vitamin B12, calcium and probiotics. Future directions for the extraction and purification of beneficial constituents are also discussed. It is concluded that low-fat dairy products, when consumed regularly as part of a balanced diet, may have a number of beneficial outcomes for neurocognitive health during ageing.