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A Randomized Trial of Beta Carotene Supplementation and Cognitive Function in MenThe Physicians' Health Study II
Abstract
Oxidative stress contributes to brain aging. Antioxidant treatment, especially over the long term, might confer cognitive benefits.
We added cognitive testing to the Physicians' Health Study II (PHSII), a randomized trial of beta carotene and other vitamin supplements for chronic disease prevention. The PHSII is a continuation of the Physicians' Health Study (PHS), which had randomized male participants to low-dose aspirin and beta carotene. Participants include those continuing their original beta carotene assignment from the PHS, begun in 1982, and newer recruits randomized as of 1998. The beta carotene arm (50 mg, alternate days) was terminated; follow-up is ongoing for the remaining arms. Near the close of the beta carotene arm, we interviewed 5956 participants older than 65 years to assess general cognition, verbal memory, and category fluency. The primary end point was a global score averaging all tests (using z scores); the secondary end point was a verbal memory score combining results of 4 tests. We compared mean cognition among those assigned to beta carotene vs placebo. We separately examined new recruits and continuing participants.
Among 1904 newly recruited subjects (mean treatment duration, 1 year), cognition was similar across treatment assignments. Among 4052 continuing participants from the PHS (mean treatment duration, 18 years), the mean global score was significantly higher in the beta carotene group than in the placebo group (mean difference in z scores, 0.047 standard units; P = .03). On verbal memory, men receiving long-term beta carotene supplementation also performed significantly better than the placebo group (mean difference in z scores, 0.063; P = .007).
We did not find an impact of short-term beta carotene supplementation on cognitive performance, but long-term supplementation may provide cognitive benefits.
... The studies were published from 1997 to 2023 and conducted in seven countries: the United States, Germany, France, Switzerland, the United Kingdom, China, and the Netherlands. Nine studies were conducted in both sexes [28,29,[33][34][35][36][37][38][39], whereas two studies were exclusively conducted in males [30,40] and five in females [31,32,[41][42][43]. The ages of all the participants ranged from 30 to 100 years (mean 53.2 ± 13.6). ...
... The systematic review included studies that utilized a wide variety of cognitive test batteries (Figure 3), such as the MMSE [30,33,35,36], TICS [40,42], MoCA [32], and SIB [35] for global cognition. Memory was assessed at different levels (lexical and semantic memory, through verbal fluency tests [34,38], the EBMT [40,42], the CFT [29,40,42], the COWAT [35], and the WFT [34,36]; working memory and speed processing, through the digit span test which includes the FDST [30,37,38], CERAD WL [29], ONB [32], and DSST [29,36]; episodic memory, with RI-48 [37,38] and FOME [30]; and verbal memory, with the CVLT [30] and ISLT [32]), whereas visual memory/visual perception was evaluated using the BVRT [30]. ...
... The systematic review included studies that utilized a wide variety of cognitive test batteries (Figure 3), such as the MMSE [30,33,35,36], TICS [40,42], MoCA [32], and SIB [35] for global cognition. Memory was assessed at different levels (lexical and semantic memory, through verbal fluency tests [34,38], the EBMT [40,42], the CFT [29,40,42], the COWAT [35], and the WFT [34,36]; working memory and speed processing, through the digit span test which includes the FDST [30,37,38], CERAD WL [29], ONB [32], and DSST [29,36]; episodic memory, with RI-48 [37,38] and FOME [30]; and verbal memory, with the CVLT [30] and ISLT [32]), whereas visual memory/visual perception was evaluated using the BVRT [30]. The KAI, BAT, and WAIS-III/R tests were administered for Total Intellectual Quotient and Intelligence [28,35,41]. ...
β-carotene is a powerful antioxidant and dietary precursor of vitamin A whose role in maintaining mental health and cognitive performance, either alone or in combination with other dietary compounds, has been a topic of recent research. However, its effectiveness is still unclear. This systematic review, conducted according to the PRISMA guideline and assisted by the MySLR platform, addressed this issue. A total of 16 eligible original research articles were identified. Dietary intake or β-carotene serum levels were associated with improved measures of cognitive function in 7 out of 10 epidemiological studies included. In intervention studies, β-carotene consumption alone did not promote better cognitive function in the short term, but only in a long-term intervention with a mean duration of 18 years. However, all but one intervention study suggested the beneficial effects of β-carotene supplementation at doses ranging from 6 mg to 50 mg per day in combination with a multicomplex such as vitamin E, vitamin C, zinc, or selenium for a period of 16 weeks to 20 years. Despite the current limitations, the available evidence suggests a potential association between β-carotene dietary/supplementary intake and the maintenance of cognitive function. The β-carotene most probably does not act alone but in synergy with other micronutrients.
... There is evidence suggesting that carotenoids, due to their anti-inflammatory and antioxidant properties, may help prevent Alzheimer's disease (AD) and cognitive decline. Long-term studies have shown that consuming carotenoids in the diet may protect memory and cognitive functions [157][158][159][160]. For instance, a 5-year prospective study involving 960 participants found a link between consuming lutein/zeaxanthin and β-carotene and a reduction in cognitive dysfunction [158]. ...
... The study, which lasted for 18 years, involved over 4000 participants over 56 years of age. The report also shows that annual β-carotene supplementation is not sufficient to improve global performance or verbal memory [160]. Similar results were found in the Nurse's Health Study [238]. ...
Alzheimer’s disease (AD) is characterized by, among other things, dementia and a decline in cognitive performance. In AD, dementia has neurodegenerative features and starts with mild cognitive impairment (MCI). Research indicates that apoptosis and neuronal loss occur in AD, in which oxidative stress plays an important role. Therefore, reducing oxidative stress with antioxidants is a natural strategy to prevent and slow down the progression of AD. Carotenoids are natural pigments commonly found in fruits and vegetables. They include lipophilic carotenes, such as lycopene, α- and β-carotenes, and more polar xanthophylls, for example, lutein, zeaxanthin, canthaxanthin, and β-cryptoxanthin. Carotenoids can cross the blood–brain barrier (BBB) and scavenge free radicals, especially singlet oxygen, which helps prevent the peroxidation of lipids abundant in the brain. As a result, carotenoids have neuroprotective potential. Numerous in vivo and in vitro studies, as well as randomized controlled trials, have mostly confirmed that carotenoids can help prevent neurodegeneration and alleviate cognitive impairment in AD. While carotenoids have not been officially approved as an AD therapy, they are indicated in the diet recommended for AD, including the consumption of products rich in carotenoids. This review summarizes the latest research findings supporting the potential use of carotenoids in preventing and alleviating AD symptoms. A literature review suggests that a diet rich in carotenoids should be promoted to avoid cognitive decline in AD. One of the goals of the food industry should be to encourage the enrichment of food products with functional substances, such as carotenoids, which may reduce the risk of neurodegenerative diseases.
... Two intervention studies (ATBC, CARET) involving individuals at high risk of developing lung cancer (current and previous heavy smokers, workers exposed to asbestos) concluded that supplementation with high doses of β-carotene over several years leads to an increase the incidence of lung cancer (Heinonen et al. 1994). In other studies, in which high doses of β-carotene were supplemented to apparently healthy individuals, not detrimental effects or even lower mortality in some cases were observed (Kamangar et al. 2006;Grodstein et al. 2007). Among the reasons that can be added to explain the different results are differences in the volunteer's characteristics and habits (mainly exposure to lung carcinogens such as tobacco smoke or asbestos that can lead to the formation of detrimental compounds), dosage, formulation of the supplements or plasma levels of β-carotene (Veeramachaneni and Wang 2009). ...
... • β-carotene have primarily antioxidant effects on lipids under stress but do not significantly affect the regulation of p53 gene expression(wawrzyniak et al. 2013) study on rodents • reduction of adiposity via the carotenoid cleavage oxygenases BCMo1 (amengual et al. 2011) Human clinical trials • Positive effect of long-term supplementation of β-carotene (50 mg every other day) on cognitive function in men.(Grodstein et al. 2007). • skin health benefits and treatment of erythropoietic protoporphyria(Zerres and stahl 2020). ...
Gut microbiota plays a crucial role in regulating the response to immune checkpoint therapy, therefore modulation of the microbiome with bioactive molecules like carotenoids might be a very effective strategy to reduce the risk of chronic diseases. This review highlights the bio-functional effect of carotenoids on Gut Microbiota modulation based on a bibliographic search of the different databases. The methodology given in the preferred reporting items for systematic reviews and meta-analyses (PRISMA) has been employed for developing this review using papers published over two decades considering keywords related to carotenoids and gut microbiota. Moreover, studies related to the health-promoting properties of carotenoids and their utilization in the modulation of gut microbiota have been presented. Results showed that there can be quantitative changes in intestinal bacteria as a function of the type of carotenoid. Due to the dependency on several factors, gut microbiota continues to be a broad and complex study subject. Carotenoids are promising in the modulation of Gut Microbiota, which favored the appearance of beneficial bacteria, resulting in the protection of villi and intestinal permeability. In conclusion, it can be stated that carotenoids may help to protect the integrity of the intestinal epithelium from pathogens and activate immune cells.
... Other cohort studies also found that higher intakes of carotenoid-rich dietary patterns [41] and β-carotene [42,43] were associated with better objective cognitive function. A long-term RCT on β-carotene-the Physicians' Health Study II (n = 4052)-showed that participants who received 50 mg supplementation for 18 years had better cognitive performance compared with the placebo group [44]. In addition, a meta-analysis of RCTs on the effects of carotenoids on cognition suggested that carotenoid supplementation may have cognitive benefits [45]. ...
Purpose of the Review
Age-related cognitive decline is an important global challenge. Substantial evidence suggests that diet may prevent or delay cognitive aging.
This narrative review examines recent literature on how dietary factors influence cognitive function, with a focus on subjective cognitive decline (SCD).
Recent Findings
Higher intakes of flavonoids, carotenoids, and plant-based protein were associated with lower odds of SCD. Berries, citrus fruits and juices, carotenoid-rich and green leafy vegetables, and beans/legumes were among the foods with the strongest inverse associations with SCD. Healthy dietary patterns, such as the Mediterranean and MIND diet, may be beneficial for maintaining subjective cognitive function.
Summary
Healthy choice of diet may play a role in lowering the risk of late-life SCD.
... Functional foods are well characterized by their natural properties of health promotion, and disease prevention in addition to numerous nutritional values [1]. One of the most consumed functional foods is honey which has been defined as a natural product produced by honeybees via a regurgitation mechanism of the plant parts [2]. There are different types of honey depend on plant from which bees collect nectar, acacia Honey is rich in phenolic compounds, which act as natural antioxidants and have promising effect in the treatment of cardiovascular diseases. ...
Background: The most serious and common adverse side effect associated with anticoagulant is increased risk of bleeding, both non-major
and major bleeding events. Risk of bleeding is dependent on the class of anticoagulant agent used, patient's age, and pre-existing health
conditions. Drugs derived from plants as green medicine is believed to be safe and dependable, compared with costly synthetic drugs that
have adverse effects. Honey has been used since ancient times for its nutritional and therapeutic value, Acacia honey is available worldwide
and it is inexpensive in compare to anti-thrombotic and thrombolytic agent. And has anticoagulant activity for treatment these problems.
Materials and Methods: In this study 100 normal blood samples from normal individuals with age range (18-30) years, 50% male and
50% female. PT and APTT tests were done before adding acacia honey by mixture patient plasma with normal plasma (as controls) and
after adding acacia honey with different concentrations (10% and 25%).
Results: the results were analyzed by using SPSS and showed that the acacia honey has a strong statistically significant (p= 0.000) in all
concentrations in both PT and APTT tests.
Conclusion: this study approved that acacia honey has a strong anticoagulant effect; so acacia honey can be used as a supplementary
anticoagulant agent to improve and/ or prevent thrombosis and cardiovascular diseases.
Keywords: Natural Acacia Honey; Coagulation; PT and APTT; Sudanese healthy individuals
List of abbreviations: PT: Prothrombin Time; APTT: Activated Partial Thromboplastin Time; DVT: Deep Vein Thrombosis; PPP:
Platelet poor plasma; BV: Blood Vessel; VWD: Von willebrand disease
... One of the most important antioxidative and nutritive factor is glutathione, which participate in signalling and stress prevention in plants (Foyer and Noctor, 2005). Grodstein et al. (2007) emphasized antioxidative function of β-carotene. The aim of experiment was to compare ecological and organic production from the point of potential to improve grain quality of maize, soybean and spelt, based on content of antioxidants. ...
Ecological cropping includes combination of different crops at the same field and application of organic and mineral fertilizers, according to plant requirements. Organic cropping includes application of allowed organic fertilizers. Trial was conducted during 2012. In ecological production maize and soybean were grown as: single crops (SC), in alternating rows (AR) and alternating strips (3 rows of each crop-AS). Fertilization regimes included: urea, Ofert (organic fertilizer), Uniker (microbiological fertilizer) and control. Organic production in trial included spelt, soybean and maize. Fertilization regimes were: DCM EKO-MIX 1 (F1), DIX 10 N (F2) and control. After harvest, grain yield, mass of 1000 grains, and content of phenolics, glutathione, phytate and β-carotene were determined in grain. In ecological production the highest yields and 1000 grain weight were obtained in Uniker treatment, as well as with AR cropping in both crops, with two times higher values in soybean, in relation to control. Generally, soybean grain had higher levels of phytate, phenolics and β-carotene, compared to maize. In organic production differences in yield parameters were insignificant. Uniker show the highest impact on phytate and β-carotene accumulation in grain of both crops in ecological production, and the same trend was noticed in F1 treatment in organic production. The content of phenolics and glutathione varied among fertilization treatments, but the highest values were obtained in AR cropping. Lower level of phytate and higher level of β-carotene achieved in crops from organic production indicated higher nutritional quality of crops produced in this system.
... Their cognitive memory was better compared to the men treated with a placebo. The benefits can be attributed to the early age of starting to consume it and/or the long period of using it [145]. β-carotene along with Vitamin E can prevent lipid peroxidation [146]. ...
Aging is a natural process that leads to time-related changes and a decrease in cognitive abilities, executive functions, and attention. In neuronal aging, brain cells struggle to respond to oxidative stress. The structure, function, and survival of neurons can be mediated by different pathways that are sensitive to oxidative stress and age-related low-energy states. Mitochondrial impairment is one of the most noticeable signs of brain aging. Damaged mitochondria are thought to be one of the main causes that feed the inflammation related to aging. Also, protein turnover is involved in age-related impairments. The brain, due to its high oxygen usage, is particularly susceptible to oxidative damage. This review explores the mechanisms underlying neuronal cell rearrangement during aging, focusing on morphological changes that contribute to cognitive decline and increased susceptibility to neurodegenerative diseases. Potential therapeutic approaches are discussed, including the use of antioxidants (e.g., Vitamin C, Vitamin E, glutathione, carotenoids, quercetin, resveratrol, and curcumin) to mitigate oxidative damage, enhance mitochondrial function, and maintain protein homeostasis. This comprehensive overview aims to provide insights into the cellular and molecular processes of neuronal aging and highlight promising therapeutic avenues to counteract age-related neuronal deterioration.
... A double-blind, controlled study revealed that prolonged intake of β-carotene (50 milligrams each day) played a role in sustaining cognitive function within a healthy general population. Participants showed significant positive changes in verbal memory, cognitive status, telephone interviews, and overall scores after an average of 18 years of treatment (53). Lutein and zeaxanthin, carotenoids with anti-inflammatory and antioxidant effects, have been connected with cognitive functions related to recall, processing quickness, focus, and logical thinking (49). ...
Objective
This study investigates the relationship between the Composite Dietary Antioxidant Index (CDAI) and cognitive function among elderly individuals, aiming to understand how increased antioxidant intake affects cognitive abilities in an aging population.
Methods
Utilizing data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014, we analyzed a sample of 2,516 participants aged 60 and above. Cognitive performance was assessed using the CERAD Word Learning and Recall Test, the Animal Fluency Test, and the Digit Symbol Substitution Test. Multivariable regression models were adjusted for demographic, dietary, and health-related factors to explore the association between CDAI scores and cognitive outcomes.
Results
The regression analyses showed a statistically significant positive association between higher CDAI scores and cognitive performance across several tests. Specifically, increments in CDAI were associated with increased scores in the CERAD Word Learning Test: Score 1 (β = 0.04, 95% CI [0.03, 0.06]), Score 2 (β = 0.04, 95% CI [0.02, 0.05]), Score 3 (β = 0.04, 95% CI [0.02, 0.06]), and the Delayed Recall Test (β = 0.04, 95% CI [0.01, 0.06]). Additionally, significant improvements were observed in the Animal Fluency Test (β = 0.19, 95% CI [0.14, 0.24]) and the Digit Symbol Test (β = 0.55, 95% CI [0.39, 0.71]). Subgroup analyses further highlighted that higher CDAI scores conferred more pronounced cognitive benefits in women, individuals aged 80 and above, Non-Hispanic Black people, and those with lower educational levels, suggesting that dietary antioxidants might be particularly beneficial in these groups.
Conclusion
An antioxidant-rich diet may represent a viable intervention to mitigate age-related cognitive decline, supporting cognitive health in the elderly. These results underscore the potential public health implications of dietary recommendations aimed at increasing antioxidant consumption among older adults. Further studies are necessary to confirm these findings and to investigate the underlying mechanisms in detail.
... Recently, beta-carotene has been shown to have a protective effect against oxidative stress and reduce AD risk .One study evaluated the effects of a beta-carotene-rich diet versus supplements on the risk of developing AD and found that it could significantly reduce its risk [17]. Several studies have shown that the carotene in fruits and vegetables can protect brain tissue from free radical damage, thereby improving cognitive function and memory [55]. Fat-soluble vitamins A, D, and E are considered antioxidants with potential benefits. ...
Background
Mild cognitive impairment (MCI) and Alzheimer’s disease (AD) are significant neurodegenerative disorders with increasing prevalence worldwide. Lifestyle and dietary factors, including micronutrients, have been suggested as modifiable risk factors for disease development. This study aims to investigate the association between micronutrients and cognitive ability in these diseases.
Methods
A cross-sectional study involving 105 participants with MCI and AD was conducted. Dietary assessments were performed using a validated food frequency questionnaire (FFQ), and micronutrient intake was calculated based on nutrient content. Disease severity was evaluated using the Functional Assessment Staging Tool (FAST). Statistical analyses, including correlation coefficients and multiple regression models, were employed to examine the association between micronutrients and disease progression.
Results
The results revealed significant correlations between disease severity and several micronutrients, including omega-3 fatty acids (B = -0.2, P = 0.01), carotenoids (B = -0.19, P = 0.02), dietary antioxidant compounds, including vitamins A, C, D, E (B = -0.19, P = 0.02), selenium (B = -0.17, P = 0.03), alpha-carotene (B = -0.16, P = 0.04), beta-carotene (B = -0.17, P = 0.03), and lycopene (B = -0.16, P = 0.04). Multivariate regression analysis showed that higher intake of omega-3 fatty acids was associated with slower disease progression. Furthermore, the levels of these micronutrients declined in advanced stages of the disease.
Conclusion
Omega-3 fatty acids and carotenoids may affect the cognitive ability and disease progression. Further longitudinal studies are warranted to establish causality and explore the therapeutic implications of these findings for the prevention and management of MCI and AD.
... These diverse mechanisms underscore the potential health benefits associated with β-carotene consumption. Moreover, emerging evidence suggests a plausible connection between β-carotene and neurodegenerative diseases, including cognitive decline, PD, and Alzheimer's disease, underscoring its relevance in maintaining neurological health (17,(22)(23)(24)(25)(26). Recent studies utilizing the NHANES database have reported an inverse correlation between increased dietary β-carotene intake and the risk of cognitive decline in elderly individuals (27). ...
Background
The existing evidence concerning the correlation between dietary β-carotene intake and Parkinson’s disease (PD) is currently deemed insufficient. Thus, this research aims to investigate the relationship between dietary β-carotene intake and both the prevalence of PD and all-cause mortality within the US (United States) population.
Methods
The research employed cross-sectional analysis and cohort studies utilizing data from 16,852 participants in the National Health and Nutrition Examination Survey (NHANES) spanning from 2001 to 2018. Weighted logistic regression, weighted cox regression, restricted cubic splines (RCS), subgroup analysis, and sensitivity analyses were employed to validate the research objectives.
Results
Among all eligible subjects, the mean age was 59.62 ± 11.77 years, with a prevalence of PD at 1.82% overall, with 43.88% in males. In the fully adjusted model, dietary β-carotene intake exhibited a negative association with PD prevalence [odds ratio (OR) = 0.95; 95% confidence interval (CI): 0.90 ~ 0.997; p = 0.040]. Utilizing RCS analysis, a negative linear correlation between dietary β-carotene intake and PD prevalence was observed (non-linear p = 0.857). Furthermore, after controlling for multiple variables, dietary β-carotene intake was inversely associated with all-cause mortality [Hazard ratios (HR) = 0.98; 95% CI: 0.97 ~ 0.99; p = 0.002], with RCS curves indicating a negative linear relationship (nonlinear: p = 0.082). Comparable patterns of association were noted in subgroup analyses, and consistent findings were derived from additional sensitivity analyses.
Conclusion
The cross-sectional and cohort study reveals a significant negative correlation between dietary β-carotene intake and both the prevalence of PD and all-cause mortality in the general population. This suggested that supplementing with dietary β-carotene might have certain benefits for reducing the prevalence of PD and all-cause mortality. However, further rigorously designed expected studies are needed to establish the causal relationship between them.
... study evaluated the effects of a betacarotene-rich diet versus supplements on the risk of developing AD and found that it could signi cantly reduce its risk [30]. Several studies have shown that the carotene in fruits and vegetables can protect brain tissue from free radical damage, thereby improving cognitive function and memory [31]. Fat-soluble vitamins A, D, and E are considered antioxidants with potential bene ts. ...
Background: Mild cognitive impairment (MCI) and Alzheimer's disease (AD) are significant neurodegenerative disorders with increasing prevalence worldwide. Lifestyle and dietary factors, including micronutrients, have been suggested as modifiable risk factors for disease development. This study aims to investigate the association between micronutrients and cognitive ability in these diseases.
Methods: A cross-sectional, randomized controlled study was conducted, involving 105 participants with MCI and AD. Dietary assessments were performed using a validated food frequency questionnaire, and micronutrient intake was calculated based on nutrient content. Disease severity was evaluated using the Functional Assessment Staging Tool (FAST). Statistical analyses, including correlation coefficients and multiple regression models, were employed to examine the association between micronutrients and disease progression.
Results: The results revealed significant correlations between disease severity and several micronutrients, including omega-3 fatty acids (B = -0.2, P = 0.01), carotenoids (B = -0.19, P = 0.02), antioxidants (B = -0.19, P = 0.02), selenium (B = -0.17, P = 0.03), alpha-carotene (B = -0.16, P = 0.04), beta-carotene (B = -0.17, P = 0.03), and lycopene (B = -0.16, P = 0.04). Multivariate regression analysis showed that higher intake of omega-3 fatty acids was associated with slower disease progression. Furthermore, the levels of these micronutrients declined in advanced stages of the disease.
Conclusion: Omega-3 fatty acids, carotenoids, and antioxidants may affect the cognitive ability and disease progression. Further longitudinal studies are warranted to establish causality and explore the therapeutic implications of these findings for the prevention and management of MCI and AD.
... Functional foods are well characterized by their natural properties of health promotion, and disease prevention in addition to numerous nutritional values [1]. One of the most consumed functional foods is honey which has been defined as a natural product produced by honeybees via a regurgitation mechanism of the plant parts [2]. There are different types of honey depend on plant from which bees collect nectar, acacia Honey is rich in phenolic compounds, which act as natural antioxidants and have promising effect in the treatment of cardiovascular diseases. ...
... The presence of ß-carotene in palm oil is not only aesthetically undesirable but also gives rise to difficulty in controlling the color of final products where palm oil is part of their composition [3][4][5][6][7]. Although it contributes to preventing oxidative stress and improving brain and eyes health [8][9][10][11][12][13][14][15], ß-carotene has also been found to increase the risk of cancer and heart disease in smokers and those who drink alcohol [16,17]. Therefore, the removal of ß-carotene from palm oil is a prerequisite for many industries such as food industry [18] and for cosmetics and biodiesel production [19][20][21]. ...
Three silica-smectite based composites with different structures denoted CSS1, CSS2 and CSS3 were used to adsorb palm
oil β-carotene via batch tests. The optimal conditions were 2% (w/w), 40 min and 95 °C for adsorbent dosage, contact time,
and temperature respectively. The bleaching capacity was found to be 64% for CSS1, 79% for CSS2 and 92% for CSS3. R 2
and Root Mean Square Deviation values indicated that equilibrium data were described well by Freundlich isotherm while
the second-order and intraparticle diffusion fitted well the kinetic data, The activation energy values were less than 10 kJ/
mol for all adsorbents and the enthalpy change ranged from 13.8 to 23.0 kJ/mol, pointing to a physical adsorption and an
endothermic process. In addition, as the temperature increased, from 60 to 95 °C, the Gibbs free energy ΔG decreased,
(− 964.20 to − 2441.30 J/mol for CSS1), (− 1717.50 to − 7175.90 J/mol for CSS2) and (− 2510.30 to − 3476.90 J/mol
for CSS3) revealing the spontaneous character of the process at higher temperature. The positive values of entropy change
(57.5≤ΔS≤87.6 J/mol.K) ΔS suggested an increase in the randomness at the adsorbent-palm oil interface, related to the
redistribution of energy between the β-carotene molecules and the adsorbent. Each of the three composites behaved as a
good adsorbent, but CSS3 outperformed CSS2 and CSS1.
Keywords Silica-smectite based composites · β-carotene · Adsorption · Kinetic · Equilibrium · Thermodynamics
... Researchers conducting a randomized trial called the Physicians' Health Study II administered either a placebo or 50 mg of β-carotene to a group of 5,956 men aged 65 and above. The study revealed that long-term supplementation (at least 15 years) resulted in cognitive improvements (11). ...
Dietary supplements (DS) are manufactured products consisting of one or more dietary ingredients; they are intended to supplement the diet and provide additional nutrients or other beneficial compounds that are lacking or insufficient in a regular diet. Dietary supplements containing antioxidant compounds have been shown to have positive effects in various (pato)physiological processes, i.e., any condition that is fundamentally redox imbalanced (cardiovascular diseases, cancer, aging, intense exercise). The most common antioxidants in dietary supplements are clearly antioxidant micronutrients such as vitamin C, vitamin E, zinc, and selenium, but also various secondary plant compounds, including polyphenols and carotenoids. The dosage of antioxidants administered through dietary supplements may not always be optimal, so some dietary interventions through supplementation with antioxidant compounds have been shown to have an effect that it is limited, or completely absent. Therefore, any dietary supplementation should be done only under appropriate guidance from health care professionals to ensure that it is safe, effective, and appropriate for the individual's condition and needs.
... One study on isotretinoin that has already been published in cognitively healthy subjects found that isotretinoin may have dose-dependent improvements in hippocampalbased learning [223]. Furthermore, a 1 year treatment of beta carotene (a provitamin A carotenoid) in individuals older than 65 years resulted in cognitive benefits, but short-term administration of beta carotene had no impact [224]. One potential hurdle in utilizing vitamin A or retinoids for AD is the potential negative side effect. ...
Alzheimer's disease (AD) is an age-associated neurodegenerative disease. As the population ages, the increasing prevalence of AD threatens massive healthcare costs in the coming decades. Unfortunately, traditional drug development efforts for AD have proven largely unsuccessful. A geroscience approach to AD suggests that since aging is the main driver of AD, targeting aging itself may be an effective way to prevent or treat AD. Here, we discuss the effectiveness of geroprotective interventions on AD pathology and cognition in the widely utilized triple-transgenic mouse model of AD (3xTg-AD) which develops both β-amyloid and tau pathologies characteristic of human AD, as well as cognitive deficits. We discuss the beneficial impacts of calorie restriction (CR), the gold standard for geroprotective interventions, and the effects of other dietary interventions including protein restriction. We also discuss the promising preclinical results of geroprotective pharmaceuticals, including rapamycin and medications for type 2 diabetes. Though these interventions and treatments have beneficial effects in the 3xTg-AD model, there is no guarantee that they will be as effective in humans, and we discuss the need to examine these interventions in additional animal models as well as the urgent need to test if some of these approaches can be translated from the lab to the bedside for the treatment of humans with AD.
... Long-term supplementation with 50 mg of β-carotene every other day for 18 years has also been shown to provide psychological beneficial results to an otherwise healthy population (n = 4,052 males, Physicians' Health Study II) (Grodstein et al., 2007). The role of carotenoids and their variants in diabetes, obesity, and some other metabolic diseases is also becoming more widely recognized (Mullan et al., 2017;Leermakers et al., 2016). ...
Carotenoids are isoprenoids that are extensively dispersed in foods that have always been part of the human diet. Certain carotenoids can be transformed into retinoids with vitamin A activity, which is needed for humans. Additionally , they are far more flexible, since they may be found in foods not just as sources of vitamin A, and also as natural colors, antioxidants, and health-promoting substances. Functional foods provide health advantages in addition to basic nourishment. They can be found in a variety of forms, including whole, fortified, enriched, or enhanced meals. A flood of information about the health advantages of functional foods has been supplied by several epidemiological research. This review discusses the factor for healthy and sustainable usage of carotenoid-rich ingredients for the design of functional food products primarily intended for health promotion. Furthermore, data on sources, intakes, and variables influencing bioavailability are summarized.
... Moreover, beta carotene has neuromodulatory actions that occur via the acetylcholinesterase inhibitory actions [27]. It also possesses an anti-oxidant role in the prevention of neurovascular disorders [27,31] and reduces neurovascular complications [32]. In addition, carotenoids improve the quality of life in chronic pancreatitis and associated pain disorders via free radical scavenging actions [33]. ...
Beta carotene is a natural anti-oxidant agent, and it inhibits the matrix metalloprotease (MMP) activity. Diabetic neuropathic pain (DNP) is produced by cellular oxidative stress. The role of the beta carotene effect in diabetic neuropathic pain is not explored yet. The present study is designed for the evaluation of the palm oil mill effluent-derived beta carotene (PBC) effect in DNP in zebrafish. The DNP was induced by the intraperitoneal administration of streptozotocin (STZ). Blood glucose levels of above 15 mM were considered to be diabetic conditions. The zebrafish were exposed to test compound PBC (25, 50, and 100 µM), pregabalin (PG: 10 μM), and an MMP-13 inhibitor (CL-82198; 10 μM) for 10 consecutive days from day 11. The neuralgic behavioral parameters, i.e., temperature test, acetic acid test, and fin clip test were assessed on day 0 and the 7th, 14th, and 21st days. On the 22nd day, the blood glucose and MMP-13 levels and brain thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), and MMP-13 activity levels were estimated. The treatment of PBC ameliorated the DNP-associated behavioral and biochemical changes. The results are similar to those of PG and CL-82198 treatments. Hence, the PBC possesses a potentially ameliorative effect against DNP due to its potential anti-oxidant, anti-lipid peroxidation, and MMP-13 inhibitory actions.
... A randomized trial study of 4052 participants reported that the participants had a higher global score in the β-carotene intake group than in the control group. In the verbal memory test, men with durable beta carotene replenishment also had significantly better scores than the control group [40]. Another survey of 298 participants also found that serum β-carotene was significantly associated with cognitive function [44]. ...
This study aims to examine the relationships of dietary α-carotene and β-carotene intake with cognitive function. The data were selected from the National Health and Nutrition Examination Survey (NHANES) 2011–2014. A total of 2009 participants were included in this analysis. Dietary α-carotene and β-carotene intake were averaged by two 24-h dietary recalls. The Consortium to Establish a Registry for Alzheimer’s Disease Word Learning subset (CERAD W-L), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST) were used to evaluate cognitive function. Logistic regression and restricted cubic spline models were applied to explore the associations of dietary α-carotene and β-carotene intake with cognitive performance. After adjusting for all confounding factors, compared with individuals in the lowest quartile of β-carotene dietary intake, those in the highest quartile had lower risks of both CERAD W-L decline [odds ratio (OR) = 0.63, 95% confidence interval (CI): 0.44–0.90] and AFT decline (OR = 0.66, 95% CI: 0.47–0.94). In addition, the third quartile of β-carotene dietary intake had a significantly decreased risk of lower DSST (OR = 0.67, 95% CI: 0.48–0.83). Compared with the lowest quartile of α-carotene intake, the OR of AFT decline in the highest intake quartile was 0.66 (95% CI: 0.46, 0.94). For males, both dietary α-carotene and β-carotene intake were associated with a decreased risk of AFT decline (OR = 0.42, 95% CI: 0.25–0.71; OR = 0.51, 95% CI: 0.30–0.85, respectively). For females, dietary α-carotene intake was associated with a decreased risk of CERAD W-L decline (OR = 0.55, 95% CI: 0.33–0.91) and dietary β-carotene intake was associated with decreased risks of both CERAD W-L and AFT decline (OR = 0.37, 95% CI: 0.21–0.64; OR = 0.58, 95% CI: 0.37–0.91, respectively). Our results suggested that higher dietary α-carotene and β-carotene intake had inverse effects on cognitive function decline among older adults.
... β-carotene improves cognitive function in addition to its antioxidant activity. Long-term intake of β-carotene for 15 years or more may slow down age-related cognitive decline, but short-term intake has no significant effect (Grodstein et al., 2007;Kristine, 2007). It also helps to improve skin health, which is likely due to its antioxidant effects (Stahl and Sies, 2012). ...
Carotenoids are the colored compounds that prominently occur in fruits, vegetables, flowers, algae, fungi, yeast, and marine organisms. The coloration of carotenoids is mainly due to varieties of conjugated double bonds, which act as a light-absorbing chromophores. β-Carotene, α-Carotene, Lycopene, Astaxanthin, Lutein, Zeaxanthin, β-Cryptoxanthin, α-Cryptoxanthin, γ-Carotene and Fucoxanthin are the common carotenoids of the human diet. This review aimed at providing scientific evidence supporting the benefits of nutritional carotenoid intake on gut microbiota modulation in different disease models. Carotenoids have some beneficial effects on human health, and it is due to the activity of pro-vitamin A and antioxidant function. Although mechanisms are under investigation, studies suggest that carotenoid intake may reduce the risk of cancer, cardiovascular disease, eye disease, haematological disease, immune stimulants, and improve cognitive function. Recent studies have shown that carotenoids can modulate gut microbiota composition associated with host health. The human gut harbors a complex community of over 100 trillion microbial cells, influencing human physiology, metabolism, nutrition, and immune function. The combination of extrinsic (lifestyle and medication) and intrinsic (host genetics, immune and metabolic regulations) factors shapes the gut microbiota. Diet is a crucial modifiable factor influencing gut microbiota composition, indicating the potential for therapeutic dietary strategies to manipulate microbial diversity, design, and stability.
... Like lutein, β-carotene is a strong antioxidant, but unlike lutein, it can be converted to vitamin A 25 . Although long term supplementation of adult humans with β-carotene provided benefits in verbal memory and cognition global score 26 , its role in brain development has not been reported. Lutein intake is associated with positive outcomes in brain health. ...
Nutrition during the first years of life has a significant impact on brain development. This study characterized differences in brain maturation from birth to 6 months of life in infant macaques fed formulas differing in content of lutein, β-carotene, and other carotenoids using Magnetic Resonance Imaging to measure functional connectivity. We observed differences in functional connectivity based on the interaction of diet, age and brain networks. Post hoc analysis revealed significant diet-specific differences between insular-opercular and somatomotor networks at 2 months of age, dorsal attention and somatomotor at 4 months of age, and within somatomotor and between somatomotor-visual and auditory-dorsal attention networks at 6 months of age. Overall, we found a larger divergence in connectivity from the breastfeeding group in infant macaques fed formula containing no supplemental carotenoids in comparison to those fed formula supplemented with carotenoids. These findings suggest that carotenoid formula supplementation influences functional brain development.
... Carotenoid supplement studies confirm a direct effect of carotenoids on brain function. Improved cognitive performance was observed after 3-18 months supplementation with -carotene [79], lutein and docosahexaenoic acid [80], lutein and zeaxanthin [81,82], as well as lutein, meso-zeaxanthin, and zeaxanthin [83,84]. Supplementation with lutein and zeaxanthin increased visual processing speeds in young adults [85] and altered brain activation patterns in older adults [86,87]. ...
Background
Oxidative stress contributes to pathogenesis and progression of Alzheimer’s disease (AD). Higher levels of the dietary antioxidants— carotenoids and tocopherols— are associated with better cognitive functions and lower risk for AD, and lower levels of multiple carotenoids are found in serum and plasma of patients with AD. Although brains donated by individuals with mild cognitive impairment had significantly lower levels of lutein and beta-carotene, previous investigators found no significant difference in carotenoid levels of brains with AD and cognitively normal brains.
Objective
This study tested the hypothesis that micronutrients are significantly lower in donor brains with AD than in healthy elderly brains.
Methods
Samples of donor brains with confirmed AD or verified health were dissected into grey and white matter, extracted with organic solvents and analyzed by HPLC.
Results
AD brains had significantly lower levels of lutein, zeaxanthin, anhydrolutein, retinol, lycopene, and alpha-tocopherol, and significantly increased levels of XMiAD, an unidentified xanthophyll metabolite. No meso-zeaxanthin was detected. The overlapping protective roles of xanthophylls, carotenes, α- and γ-tocopherol are discussed.
Conclusion
Brains with AD had substantially lower concentrations of some, but not all, xanthophylls, carotenes, and tocopherols, and several-fold higher concentrations of an unidentified xanthophyll metabolite increased in AD (XMiAD).
... A study by Grodstein et al. found that beta-carotene supplementation had no significant impact on cognition in the short term, but was associated with better verbal memory and overall better global cognitive scores in the long-term [100]. A cross-sectional study found that plasma vitamin C and beta-carotene were significantly lower in individuals with dementia as compared to the control group [101]. ...
Background and Objectives: Alzheimer’s disease (AD) is the most common form of dementia, with the risk of developing it attributed to non-modifiable and modifiable factors. Currently, there is no cure for AD. A plant-based diet may protect against cognitive decline, due to the effects of plant-based nutrients such as vitamins, antioxidants, and fiber. The aim of the review is to summarize current literature on plant-based nutrients and their impact on cognition. Materials and Methods: A search was conducted on PubMed for clinical and murine studies, using combinations of the following words: “Alzheimer’s disease”, “dementia”, “cognition”, “plant-based diet”, “mild cognitive impairment”, “vitamin B”, “vitamin C”, “vitamin E, “beta carotene”, “antioxidants”, “fiber”, “vitamin K”, “Mediterranean diet”, “vitamin D”, and “mushrooms”. Results and Conclusions: A diet rich in vitamin B and antioxidants can benefit the cognitive functions of individuals as shown in randomized clinical trials. Vitamin K is associated with improved cognition, although large randomized controlled trials need to be done. Fiber has been shown to prevent cognitive decline in animal studies. Vitamin D may contribute to cognitive health via anti-inflammatory processes. Several medical organizations have recommended a plant-based diet for optimizing cognitive health and potentially helping to prevent dementia.
... The latter permits lutein to adopt a more apolar orientation in the membrane, potentially protecting its OH groups from the water interface (McNulty et al. 2007). Carotenoids, including lutein, were also found to have a human health benefit for cognitive functions in the brain (Grodstein et al. 2007;Johnson et al. 2008;Eggersdorfer and Wyss 2018), to be important for visual and cognitive development in infants (Hammond 2008;Henriksen and Chan 2014), to reduce the risk of coronary heart disease and stroke (Leermakers et al. 2016) and to reduce the probability of cardiovascular disorders (Pashkow et al. 2008). ...
The green algae Tetraspora sp. CU2551 was previously identified as a strain with high potential for biohydrogen production; however, its algal biomass characteristics changed from green to reddish orange within 43 days of biohydrogen production. The crude pigments were extracted, partially purified, and characterized by chemical determination. The present study focused on elucidating the carotenoid composition of the selected green alga Tetraspora sp. CU2551. The pigment extract was partially purified and fractionated using thin layer chromatography, and yielded two major and two minor carotenoid bands. The fractions were confirmed by high-performance liquid chromatography with a diode array detector (HPLC–DAD) before being identified and confirmed using Liquid Chromatograph-Quadrupole Time of Flight-Mass Spectrometry (LC-QTOF-MS). The spectral data of these fractions revealed four sub-fractions of interest that were lutein, canthaxanthin, neochrome, and β-carotene, which had percentages in the crude extracts of 30.57%, 25.47%, 7.89%, and 0.71%, respectively. Lutein and canthaxanthin were found to be the major carotenoid pigments present. Our findings in this present study are the first reporting of Tetraspora sp. CU2551 as a potential alternate source for carotenoid pigment production.
... The precursor of vitamin A, the β-carotene, is found in yellow, orange, and green leafy fruits and vegetables (e.g., carrots, spinach, lettuce, tomatoes, sweet potatoes, broccoli, cantaloupe, pumpkin) and has positive effects against oxidative stress and neurodegeneration [105,106]. Indeed, low β-carotene plasma concentrations have been found in people with AD [107] and PD [108] compared with healthy controls. These findings have recently been confirmed by an in vitro study demonstrating that β-carotene reduces oxidative stress and pro-inflammatory cytokines in mononuclear cells of people with AD [109]. ...
Aging induces substantial remodeling of glia, including density, morphology, cytokine expression, and phagocytic capacity. Alterations of glial cells, such as hypertrophy of lysosomes, endosomes and peroxisomes, and the progressive accumulation of lipofuscin, lipid droplets, and other debris have also been reported. These abnormalities have been associated with significant declines of microglial processes and reduced ability to survey the surrounding tissue, maintain synapses, and recover from injury. Similarly, aged astrocytes show reduced capacity to support metabolite transportation to neurons. In the setting of reduced glial activity, stressors and/or injury signals can trigger a coordinated action of microglia and astrocytes that may amplify neuroin-flammation and contribute to the release of neurotoxic factors. Oxidative stress and proteotoxic aggregates may burst astrocyte-mediated secretion of pro-inflammatory cytokines, thus activating microglia, favoring microgliosis, and ultimately making the brain more susceptible to injury and/or neurodegeneration. Here, we discuss the contribution of microglia and astrocyte oxidative stress to neuroinflammation and neurodegeneration, highlight the pathways that may help gain insights into their molecular mechanisms, and describe the benefits of antioxidant supplementation-based strategies.
... However, a recent meta-analysis [43] exploring the effect of antioxidants vitamins on cognitive functioning of non-demented older people indicated that only two studies specifically report some favorable effects upon cognitive functioning for β-carotene and for vitamin C intake in cognitively normal older adults. Specifically, in a large randomized controlled trial, namely 'Physician Health Study', a long-term supplementation (i.e., mean treatment duration, 18 years) with β-carotene (i.e., 50 mg on alternate days) in men older than 65 years was associated with improved global cognition [44]. Furthermore, vitamin C was not associated with cognitive changes over time in women of ≥65 years of age with cardiovascular disease, but showed a protective effect against new cardiovascular events [45]. ...
Simple Summary
Alzheimer’s disease currently represents one of the major challenges of modern society in relation to social and medical costs. As people age, they often experience mild changes in cognitive functioning that may be due to an initial degeneration of cerebral networks. Advances in neurobiology research including antioxidants intake and brain capacity to resist damage is relevant in order to support elderly people in the adoption of healthy lifestyles able to counteract dementia onset.
Abstract
Here we performed a narrative review highlighting the effect of brain/cognitive reserve and natural/synthetic antioxidants in exerting a neuroprotective effect against cognitive deterioration during physiological and pathological aging. Particularly, we discussed pathogenesis of Alzheimer’s disease, brain and cognitive reserve as means of resilience towards deterioration, and evidence from the literature about antioxidants’ role in sustaining cognitive functioning in the preclinical phase of dementia. During aging, the effects of disease-related brain changes upon cognition are reduced in individuals with higher cognitive reserve, which might lose its potential with emerging cognitive symptoms in the transitional phase over the continuum normal aging-dementia (i.e., Mild Cognitive Impairment). Starting from this assumption, MCI should represent a potential target of intervention in which antioxidants effects may contribute—in part—to counteract a more severe brain deterioration (alongside to cognitive stimulation) causing a rightward shift in the trajectory of cognitive decline, leading patients to cross the threshold for clinical dementia later.
... Carotenoids and their metabolites have been implicated as having functions in human health and providing protection in various ROS-induced disorders. These roles include but are not limited to cognitive functions [133][134][135], cancer prevention [131,136], immune stimulation/modulation [137], fertility [138,139] and genomic impacts on transcription and translation [140]. ...
It is estimated that the prevalence rate of Alzheimer’s disease (AD) will double by the year 2040. Although currently available treatments help with symptom management, they do not prevent, delay the progression of, or cure the disease. Interestingly, a shared characteristic of AD and other neurodegenerative diseases and disorders is oxidative stress. Despite profound evidence supporting the role of oxidative stress in the pathogenesis and progression of AD, none of the currently available treatment options address oxidative stress. Recently, attention has been placed on the use of antioxidants to mitigate the effects of oxidative stress in the central nervous system. In preclinical studies utilizing cellular and animal models, natural antioxidants showed therapeutic promise when administered alone or in combination with other compounds. More recently, the concept of combination antioxidant therapy has been explored as a novel approach to preventing and treating neurodegenerative conditions that present with oxidative stress as a contributing factor. In this review, the relationship between oxidative stress and AD pathology and the neuroprotective role of natural antioxidants from natural sources are discussed. Additionally, the therapeutic potential of natural antioxidants as preventatives and/or treatment for AD is examined, with special attention paid to natural antioxidant combinations and conjugates that are currently being investigated in human clinical trials.
... 106 In this sense, a long-term β-carotene supplementation with 50 mg on alternate days maintained cognitive performance in a healthy population. 107 Regarding the effects of carotenoids on cancer, there is evidence that lycopene is related to prostate cancer, because it has been found in high concentrations within the prostate gland, 108 reporting an inverse association between prostate cancer and lycopene intake. 109 In this same line, a metaanalysis of 42 epidemiological studies found that dietary lycopene consumption was significantly and inversely correlated with prostate cancer. ...
The current increased industrial food production has led to a significant rise in the amount of food waste generated. These food wastes, especially fruit and vegetable byproducts, are good sources of natural pigments, such as anthocyanins, betalains, carotenoids, and chlorophylls, with both coloring and health-related properties. Therefore, recovery of natural pigments from food wastes is important for both economic and environmental reasons. Conventional methods that are used to extract natural pigments from food wastes are time-consuming, expensive, and unsustainable. In addition, natural pigments are sensitive to high temperatures and prolonged processing times that are applied during conventional treatments. In this sense, the present review provides an elucidation of the latest research on the extraction of pigments from the agri-food industry and how their consumption may improve human health.
... However, the evidence that supports this theory has only been able to correlate ageing with oxidative damage and many of the experiments involving manipulations have produced variable effects (Blackett & Hall, 1981;Morley & Trainor, 2001). Clinical studies with single antioxidant supplements such as beta carotene, vitamin A, Vitamin C and Vitamin E have demonstrated that single antioxidants do not protect against chronic diseases including heart disease and cancer (Bjelakovic et al., 2007;Grodstein et al., 2007;Lee et al., 2005). One plausible reason for these results might be that antioxidants work best in combination with other micronutrients, other antioxidants or phytochemicals and supplementation with a single antioxidant may not produce the same effect. ...
Evaluation of nutritionally enhanced biofortified dietary interventions that increase lifespan may uncover cost-effective and sustainable approaches for treatment of age-related morbidities and increasing healthy life expectancy. In this study, we report that anthocyanin rich, high yielding crossbred blue wheat prolongs lifespan of Drosophila melanogaster in different dietary contexts. In addition to functioning as an antioxidant rich intervention, the biofortified blue wheat also works through modulating expression of DR pathway genes including AMPK alpha, SREBP, PEPCK and Cry. Supplementation with blue- or purple-colored wheat provided better protection against paraquat-induced oxidative stress than control diet and increased survivability of flies in which superoxide dismutase 2 was knocked down conditionally in adults. Lastly, our findings indicate that supplementing biofortified blue wheat formulated diet prevented the decrease in lifespan and cardiac structural pathologies associated with intake of high fat diet. Overall, our findings indicate that plant-based diets formulated with biofortified cereal crops promote healthy ageing and delay progression of diseases that are exacerbated by accumulation of oxidative damage.
... The Physicians' Health Study II evaluated β-carotene supplementation in the short (50 mg on alternate days for 12 months) and long term (50 mg on alternate days for 18 years) in relation to cognitive functions. The men who received the supplementation had slightly better cognition than the placebo group, and this supplementation must be at least for 15 years (Grodstein et al., 2007). ...
Carotenoids are lipophilic natural yellow to red pigments found in fruits and vegetables. The chemical molecules of these bioactive compounds comprise an extensive chain of conjugated double bonds responsible for the color and their reactivity and antioxidant activity, which are related to several health benefits. The mechanisms of action of the dietary carotenoids will be presented in this chapter considering the existent scientific evidence based on experimental protocols using in vitro assays, animal models, and clinical trials.
... There are numerous studies in the literature investigating possible effects of vitamin supplements intake on cognitive function and on the prevention of cognitive decline and AD, although there are no definitive conclusions. For example, analyses of data from the Physicians' Health Study and Physicians' Health Study II (n = 4052) reported no significant effects on cognitive function with beta-carotene (provitamin A) treatment in the short-term and beneficial effect with longer-term (18-year) administration [320]. In general, studies of vitamin B on cognition have shown mixed results. ...
Multiple factors combined are currently recognized as contributors to cognitive decline. The main independent risk factor for cognitive impairment and dementia is advanced age followed by other determinants such as genetic, socioeconomic, and environmental factors, including nutrition and physical activity. In the next decades, a rise in dementia cases is expected due largely to the aging of the world population. There are no hitherto effective pharmaceutical therapies to treat age-associated cognitive impairment and dementia, which underscores the crucial role of prevention. A relationship among diet, physical activity, and other lifestyle factors with cognitive function has been intensively studied with mounting evidence supporting the role of these determinants in the development of cognitive decline and dementia, which is a chief cause of disability globally. Several dietary patterns, foods, and nutrients have been investigated in this regard, with some encouraging and other disappointing results. This review presents the current evidence for the effects of dietary patterns, dietary components, some supplements, physical activity, sleep patterns, and social engagement on the prevention or delay of the onset of age-related cognitive decline and dementia.
... It was found that beta carotene treatment for a long duration will decrease cognitive impairment and improves verbal memory in men (Grodstein et al., 2007). Many investigations have been proven the beneficial effect of carotene in the treatment of AD (Polidori and Stahl, 2009;Balez et al., 2016). ...
... It was found that beta carotene treatment for a long duration will decrease cognitive impairment and improves verbal memory in men (Grodstein et al., 2007). Many investigations have been proven the beneficial effect of carotene in the treatment of AD (Polidori and Stahl, 2009;Balez et al., 2016). ...
... It was found that beta carotene treatment for a long duration will decrease cognitive impairment and improves verbal memory in men (Grodstein et al., 2007). Many investigations have been proven the beneficial effect of carotene in the treatment of AD (Polidori and Stahl, 2009;Balez et al., 2016). ...
... In animal models, supplementation with VA leads to improvement of cognitive abilities related to a decrease of hippocampal function in those with VAD [33]. In humans, the evidence of supplementation with VA or derivate (betacarotene) is scarce and not conclusive [34,35]. Further studies are needed to identify the cause of LSR and their treatment, to avoid adverse health outcomes in OA. ...
Background
Vitamin A (VA) provides neuroprotection against oxidative stress and brain inflammation. VA deficiency (VAD) increases the risk of neurodegeneration in animal models, but results are inconclusive in humans: particularly in the older adult (OA) population which is at higher risk for micronutrient deficiencies and cognitive impairment.
Objective
To estimate the association between serum retinol levels and cognitive function (CF) in older Mexican adults.
Methods
Cross-sectional study with 803 adults aged ≥60 years with fasting blood sample from the southern region of Mexico, collected in summer of 2015. Low serum retinol (LSR) was defined if serum retinol ≤20 µg/dl. CF was evaluated using Semantic Verbal Fluency Test (SVFT). Mild cognitive impairment (MCI) was defined using normative values for SVFT. Linear and logistic regression models were used to estimate the association of LSR with CF and MCI, respectively.
Results
Prevalence of MCI was 9.35% and LSR 3.36%. OA with LSR evoked less words in the SVFT (β = −2.8, CI95% −4.6, −0.9) and had higher probability of MCI (OR = 2.7, CI95% 0.9, 7.7). Associations remained significant when considered IL-6.
Conclusion
Frequency of LSR in older Mexican adults was low, but strongly associated with MCI. This result suggests that VA plays a role in maintaining CF in the elderly population. Since VAD is a reversible condition, further studies are needed in order to identify the main causes of LSR and prevent MCI in populations which are at higher risk for malnutrition.
Trial registration: ClinicalTrials.gov identifier: NCT04820465.
The modern Western diet is dominated by ultra-processed food (UPF), which is increasingly linked to adverse health outcomes. Previous reviews have already identified problematic components of UPF, such as added fats and sugars. Therefore, the aim of this review was to provide a nuanced understanding of another ubiquitous component of UPF, food additives, and to explore any potential health risks associated with their consumption, as well as strategies for mitigating those risks. To provide real-world contextualization, we first quantified the food additive profile a person would be exposed to when consuming a popular UPF, the burger. Here we show that the selected burgers contain up to thirty-six different additives, primarily emulsifiers, thickeners, preservatives, and colours. While some reviewed additives, such as resistant starch and natural colours, have beneficial effects, the majority have a deleterious effect on health. However, limitations of current studies and gaps in government regulations complicate the assessment of the long-term health implications of a diet high in food additives. This review underscores the need for greater transparency in food labelling and a re-valuation of food additive safety standards. It advocates for both elimination of certain food additives and reformulation strategies to mitigate potential health risks associated with UPF consumption. However, since elimination poses multiple challenges, reformulation may be a more realistic strategy. This could include fortification with fibre, replacing synthetic colours with natural colours, and reducing the use of preservatives by utilising advancements in hurdle technology.
Carotenoids, fat-soluble pigments richly found in fruits and vegetables, selectively accumulate in diverse anatomical compartments, including the brain, contributing significantly to early-life neurodevelopment and neural conservation. Experimental evidence has established a correlation between diminished levels of specific carotenoids and the onset of Alzheimer’s disease. Furthermore, research posits that the incorporation of certain carotenoids into the diet holds promise in the prevention and treatment of various human illnesses, including cancer, alcoholic liver disease, and ophthalmological, cardiovascular, and neurological disorders. These beneficial effects stem from the antioxidative, anti-inflammatory, and antiapoptotic properties of carotenoids. While an expanding body of research underscores the favorable outcomes linked to carotenoid consumption, certain facets warrant additional analysis. Challenges to their restricted bioavailability and potential prooxidant impact necessitate a comprehensive understanding to precisely outline the optimal influence of carotenoids on overall well-being. In this chapter, we provide a comprehensive review regarding the impact of various carotenoids, such as α/β-carotenes, lycopene, crocin, crocetin, fucoxanthin, β-cryptoxanthin, astaxanthin, lutein, and zeaxanthin, on cognitive function. Furthermore, it elucidates different delivery systems and explores their implications in dementia and AD. It then delves into their intricate signaling pathways and interactions within the food matrix, contributing to the academic exploration of their multifaceted roles.
Many countries across the globe are experiencing aging populations, which brings into question the fitness and capacity of these populations. Rates of neurodegenerative diseases worldwide are increasing, even after adjusting for increasing lifespans. This worrying trend motivates taking steps in the population to prevent dementia. This review summarizes the work on lifestyle medicine based prevention of dementia and cognitive decline using multiple modalities and interventions. Our results bring hope to those seeking to stay cognitively healthy in advanced age through combinations of diet, exercise, and mindfulness based interventions. Leveraging cheap and scalable interventions is an important strategy for alleviating the expected tide of neurodegenerative illnesses. This review covers the potential lifestyle and dietary interventions which can alleviate Alzheimer's disease burden, paving the way for population level preventative approaches for neurodegenerative disease.
Carotenoids are natural products found in photosynthetic organisms such as plants, algae, and some bacteria species. Humans and animals cannot synthesize carotenoids, and they obtain these molecules through their diet. The common structure of carotenoids contains conjugated double bonds that provide color formation in the visible spectrum, at 400–500 nm. In photosynthetic organisms, carotenoids contribute to color formation for various purposes, such as sex selection, protection from predators, and light-harvesting to increase the spectral range of photosynthesis. The conjugated double bonds not only provide color formation but also provide antioxidant properties to carotenoid molecules. Studies have shown that carotenoids are capable of scavenging free radicals and reactive oxygen species, as well as quenching singlet oxygen molecules. The antioxidant power of carotenoids results in several health benefits. These include anticancer, neuroprotective, and anti-atherosclerotic activities. This chapter aims to review the antioxidant activities and health benefits of major carotenoids, beginning with their structure and synthesis, and also discussing their natural sources.
Given the health risks associated with synthetic colorants, natural pigments have emerged as a promising alternative. These renewable choices not only provide health benefits but also offer valuable technical and sensory properties to food systems. The effective application of natural colorants, however, requires the optimization of processing conditions, exploration of new sources, and development of novel formulations to ensure stability and maintain their inherent qualities. Several natural pigment sources have been explored to achieve the broad color range desired by consumers. The purpose of this review is to explore the current advances in the obtention and utilization of natural pigments derived from by-products, which possess health-enhancing properties and are extracted through environmentally friendly methods. Moreover, this review provides new insights into the extraction processes, applications, and bioactivities of different types of pigments.
Recent research has been exploring the link between vitamin deficiencies and the pathogenesis of neurodegenerative ailments such as cognition impairment, dementia, and Alzheimer’s disease (AD). Lipophilic vitamins A, D, E and K, offer a range of health benefits, including antioxidant, anti-inflammatory, and neuroprotective characteristics, which are crucial for sustaining nerve myelination and neurotransmission in different brain functions. The neuroprotective role of lipophilic vitamins has been demonstrated by a number of preclinical and clinical studies, with a special focus on early-detection of AD. Such experimental and clinical investigations offer an important cost-effective strategy for the management of neurodegenerative disorders with different dietary supplements and nutraceuticals containing lipophilic vitamins. While the aetiology of AD is still elusive, experimental studies and histopathology of human brain has suggested a reduction in brain volume, oligomerisation and subsequent stabilisation of Aβ fibrils, coupled with phagocyte elimination, as the primary mechanism involved in the reduction of oxidative stress. This,in turn, slows the progression of cognitive decline. However, the underlying mechanisms of action of lipophilic vitamins are complex, and further studies are needed to bridge the gap in our knowledge. This book chapter offers an overview of the pathogenesis of AD and proposed usage of lipophilic vitamins, as well as the distribution these agents in nature. The physiological functions of each vitamin have been discussed in detail, supplemented with information to their biologically active metabolites and purported mechanisms of action. Finally, keeping in mind the novel delivery systems and advancements in the delivery of drugs into the brain, a section on nanotechnological interventions, as well as key challenges and future perspectives have also been addressed.
Carotenoids represent a large group of well-known substances, mainly due to their nature as pigments and their beneficial effects on human health. These compounds are found naturally in microorganisms and plants but are not produced by humans, who must consume them through their diet. However, the mere intake of foods containing even large quantities of carotenoids is insufficient to guarantee their optimum absorption and, therefore, the desired beneficial effects. Due to their physicochemical characteristics, carotenoids are poorly stable and mostly insoluble in polar solvents like water. The conservation and improvement of their properties have become crucial objectives for the nutraceutical and functional food sector. Increasingly innovative delivery systems are being tested and developed. In this context, chitosan, a polysaccharide derived from the deacetylation of chitin, available in the exoskeleton of crustaceans and insects and the cell wall of some fungi and marine microalgae, has proved to be highly advantageous. In this review, we summarize the main characteristics of carotenoids, their benefits on human health, and their bioaccessibility and bioavailability for humans. We analyze the most recent carotenoid delivery systems, focusing on the potential of chitosan in preserving and enhancing the beneficial effects of these valuable pigments.
Field experiments were conducted to study possible influence of cropping system on the antioxidant component of Garden egg fruits during the wet and dry seasons of year 2014 and 2015 G represented maize and garden egg respectively. The treatments were arranged in a randomized complete block design in a split plot arrangement and replicated three times. Time of introduction was assigned at the main plot while population density ratios were allotted at the sub plot treatments. Population ratio had significant effects on both the number of Garden egg fruits/plot and fruit yield with the values significantly deceasing linearly as Maize population increases in the crop mixtures. Number of fruits/plant and fruit yield were highest in both seasons in sole crop with values being superior to other population ratios in the crop mixtures. The effects of cropping system under different population ratios on the antioxidant components of Garden egg fruits varied appreciably depending on the antioxidant component under study. Increasing the population densities of both crops to full population increases the phenolic content of Garden egg fruits while sole Garden egg gave the lowest phenolic content. The reverse was the case in flavonoid component. Plants under the population ratio 100M: 25G had the highest value of 2.2 diphenyl-1-picrylhydrazyl (DPPH) at both growing seasons.
Background
For decades, evidence from observational studies and randomized controlled trials has converged to suggest associations of dietary components, foods, and dietary patterns with dementia. With population aging and a projected exponential expansion of people living with dementia, formulating nutritional strategies for dementia prevention has become a research hotspot.
Objective
This review aimed to summarize available data on the roles of specific dietary components, food groups, and dietary patterns in dementia prevention among the elderly.
Method
Database search was carried out using PubMed, the Cochrane Library, EMBASE, and Medline.
Results
Polyphenols, folate, vitamin D, omega-3 fatty acids, and β-carotene might decrease the risk of dementia. Consumption of green leafy vegetables, green tea, fish, and fruits is recommended. However, saturated fat, a diet rich in both dietary copper and saturated fat, aluminum from drinking water, and heavy drinking might increase dementia risk. Healthy dietary patterns, especially the Mediterranean diet, were proven to bring more cognitive benefits than single dietary components.
Conclusion
We discussed and summarized the evidence on the roles of dietary components and patterns in dementia prevention among the elderly and found that some factors were closely associated with dementia risk in elderly. This may pave the way for the identification of dietary components and patterns as new therapeutic targets for dementia prevention in the elderly population.
Ageing is a universal decline of physiological functions accompanied by an increase in risks of developing morbidity, diseases, and death. Calorie restriction (CR) without malnutrition has been shown to improve lifespan from simple model organisms to mammals, and extensive research over the past decades have identified several universally conserved signalling pathways by which CR regulates lifespan. More recently, emerging evidence has suggested that modulation of intake levels of macronutrients and micronutrients can also impact healthspan and lifespan in model organisms. These findings propose potentially promising and cost-effective approaches to promote healthy ageing and longevity in humans through personalised nutrition. In this review, we summarise the mechanisms by which CR promotes healthspan and longevity, focusing on the mitochondrial reactive oxygen species (ROS) and several universally conserved geroprotective nutrient-sensing pathways (insulin/insulin-like growth factor (IGF-1), AMP-activated protein kinase (AMPK), mTOR). We further discuss the accumulating data supporting that changes in dietary pattern, levels of nutrient intake (both macronutrient and micronutrient) and functional foods can impact healthspan through acting on the key components of nutrient-sensing and immunoprotective pathways, providing fundamental support for future research and development of anti-ageing diets and dietary regimes.
β-Carotene is a natural antioxidant that has an indispensable effect on the growth and immunity of the human body. For intracellular and in vitro detection of β-carotene, N-doped carbon quantum dots (O-CDs) were prepared by co-heating carbonization of 1,5-naphthalenediamine and nitric acid in ethanol solvent for 2 h at 200 °C. O-CDs have longer wavelength orange light emission, with an optimal excitation peak of 470 nm and an optimal emission peak of 590 nm. According to the principle of the internal filtering effect on which the detection system is based, O-CDs present a good linear relationship with β-carotene within a wide range of 0-2000 μM, and the R2 coefficient of the linear regression equation is 0.999. In addition, O-CDs showed targeting of lysosomes in cell imaging and could be used to detect intracellular lysosomal movement. These experiments show that O-CDs can be used for in vivo and in vitro detection of β-carotene and can serve as a potential substitute to commercial lysosome targeting probes.
The wave of individuals impacted by dementia continues to rise rapidly as worldwide lifespan increases. Dietary strategies to slow cognitive decline and prolong time to clinical dementia remain understudied, but with potentially powerful public health consequences. Indeed, previously conducted large, randomized, placebo-controlled trials of micronutrients remain an under-leveraged resource to study changes in cognitive performance. As a motivating example, we highlight an ancillary report from the Physicians' Health Study, where subjects randomized to β-carotene (a provitamin A carotenoid) had a more attenuated change in longitudinal global cognitive performance and verbal memory, as compared to subjects randomized to placebo. Despite mechanistic evidence from cell and animal studies supporting a vitamin A-mediated role in the biology associated with cognition, limited follow-up work has been conducted. We argue that dietary factors (including provitamin A) deserve a second look, leveraging multi-omic approaches, to elucidate how they may mitigate cognitive decline and dementia risk.
Most alternative treatments are to be taken by mouth; less often they must be applied externally as creams. These modalities include, for instance, dietary supplements, homeopathic remedies, or herbal medicines. In this chapter, I discuss prominent examples from these categories. As there are many more, I focus on those that are best-known.
Étude des déterminants nutritionnels (nutriments, aliments et alimentation globale) du vieillissement en bonne santé. Analyse dans la cohorte SU.VI.MAX 2. Nous avons investigué les déterminants nutritionnels d'un modèle multidimensionnel du vieillissement en bonne santé (VBS) dans la cohorte SU.VI.MAX, qui contient des données nutritionnelles collectées en 1994-96, et des données de santé collectées en 2007-09. Les déterminants étudiés étaient une supplémentation en antioxydants, et la qualité globale de l'alimentation. Un objectif supplémentaire était d'étudier le rôle du statut plasmatique en vitamine D pour la santé cognitive.Il n’y avait pas d’effet global de la supplémentation en antioxydants. Dans des analyses stratifiés, un effet bénéfique était observé chez les hommes et les ceux avec un statut sérique bas en vitamine C ou en zinc, ou avec une consommation faible de fruits et légumes. De plus, le VBS était associé à une bonne adéquation aux recommandations nutritionnelles françaises et aux apports nutritionnels conseillés. Nous avons également identifié un rôle bénéfique d'une typologie alimentaire a posteriori ‘saine’ chez ceux avec un faible apport énergétique. Enfin, nous avons observé une relation entre un bon statut plus élevé en vitamine D et de meilleures performances de la mémoire à court terme et de travail chez les ceux ayant un niveau d'éducation faible.Nos résultats supportent un rôle bénéfique d'un apport équilibré en nutriments antioxydants, et d'une bonne adéquation aux recommandations nutritionnelles françaises et aux apports nutritionnels conseillés pour le VBS. De plus, ils soulignent l’importance de présenter à la fois une bonne qualité alimentaire et un apport adéquat en énergie. Enfin, nos résultats supportent, en partie, un rôle bénéfique d'un bon statut en vitamine D pour la santé cognitive.
The main goal of the present work was to access the ability of high internal phase emulsions (HIPEs) to encapsulate β-carotene. The carotenoid loading capacity of the HIPEs was around 20-fold higher when OSA-starch/chitosan complexes were used than when only OSA-starch was used. This impact could be mainly assigned to the capacity of the former HIPEs to trap carotenoid caystals in a stable form. The OSA-starch/chitosan complexes were shown to absorb on the oil droplets interface and form a 3D network in the aqueous phase, which helped to prevent droplet coalescence induced by β-carotene crystal. The incorporation of β-carotene within the oil droplets enhanced its resistance to chemical degradation when exposed to heat, ultraviolet radiation, or gastrointestinal conditions. Our results provide information that may aid the design and development of edible soft solids containing high carotenoid levels, which may be applied in food and pharmaceutical industry.
Carotenoids possess strong anti-inflammatory and antioxidant actions in addition to a plethora of other properties. These actions of carotenoids are primarily due to their structure which dictate their functions. Because of their protective potential in disease states, carotenoids are associated with prevention and/or treatment of various neurological diseases. In this chapter, the role(s) of carotenoids in various neurological diseases such as Alzheimer’s disease, vascular dementia, Lewy body dementia, mild cognitive impairment, neurological trauma, brain tumor, schizophrenia, depression, Parkinson’s disease and multiple sclerosis, have been reviewed. A number of studies report associations of low levels of carotenoids with higher likelihood of neurological diseases. Other investigations describe beneficial and protective effects of pharmacological or dietary interventions which lead to enhancement of carotenoids levels in the body. However, further validation of these beneficial actions is required both in clinical and animal studies. Development of good animal models of neurological diseases will help.
Cross-sectional studies have shown that the dysregulation of one-carbon metabolism is associated with cognitive impairment. However, the findings of longitudinal studies investigating this association have been inconsistent. This study investigated the prospective associations between cognitive decline and the levels of folate, vitamin B(12) and homocysteine both at baseline and over course of the study period.
A total of 607 (83%) elderly individuals were selected from a group of 732 elderly individuals without dementia at baseline and followed over a 2.4-year study period. The Mini-Mental State Examination (MMSE) was administered to the subjects, and the serum levels of folate, vitamin B(12) and homocysteine were assayed both at baseline and at follow-up examinations. Covariates included demographic data, disability, depression, alcohol consumption, physical activity, vascular risk factors, serum creatinine level, vitamin intake, and apolipoprotein E genotype.
Cognitive decline was associated with decreasing quintiles of folate at baseline, a relative decline in folate and an increase in homocysteine across the two examinations after adjustment for relevant covariates.
These results suggest that folate and homocysteine are involved in the etiology of cognitive decline in the elderly.
Lung cancer and cardiovascular disease are major causes of death in the United States. It has been proposed that carotenoids and retinoids are agents that may prevent these disorders.
We conducted a multicenter, randomized, double-blind, placebo-controlled primary prevention trial -- the Beta Carotene and Retinol Efficacy Trial -- involving a total of 18,314 smokers, former smokers, and workers exposed to asbestos. The effects of a combination of 30 mg of beta carotene per day and 25,000 IU of retinol (vitamin A) in the form of retinyl palmitate per day on the primary end point, the incidence of lung cancer, were compared with those of placebo.
A total of 388 new cases of lung cancer were diagnosed during the 73,135 person-years of follow-up (mean length of follow-up, 4.0 years). The active-treatment group had a relative risk of lung cancer of 1.28 (95 percent confidence interval, 1.04 to 1.57; P=0.02), as compared with the placebo group. There were no statistically significant differences in the risks of other types of cancer. In the active-treatment group, the relative risk of death from any cause was 1.17 (95 percent confidence interval, 1.03 to 1.33); of death from lung cancer, 1.46 (95 percent confidence interval, 1.07 to 2.00); and of death from cardiovascular disease, 1.26 (95 percent confidence interval, 0.99 to 1.61). On the basis of these findings, the randomized trial was stopped 21 months earlier than planned; follow-up will continue for another 5 years.
After an average of four years of supplementation, the combination of beta carotene and vitamin A had no benefit and may have had an adverse effect on the incidence of lung cancer and on the risk of death from lung cancer, cardiovascular disease, and any cause in smokers and workers exposed to asbestos.
Atherosclerosis and thrombosis may lead to cognitive impairment through cerebral infarcts or white matter hyperintensities. Oxidative stress is now seen as a major contributor to the process of atherogenesis. High intake of polyunsaturated fatty acids, e.g., linoleic acid, or low intake of antioxidants can increase oxidative stress. High intake of n-3 polyunsaturated fatty acids and its main source, fish, may reduce the risk of thrombosis. Little is known, however, about the relation between these dietary factors and cognitive function. The authors investigated this relation with data derived from a cohort of men, aged 69-89 years, who were participants in the Zutphen Elderly Study. The 30-point Mini-Mental State Examination was used to assess cognitive impairment in 1990 (score < or = 25 in 153/476 men, 32%) and cognitive decline from 1990 to 1993 (drop > 2 points in 51/342 men, 15%). Food intake was estimated in 1985 and 1990 by the cross-check dietary history method. High linoleic acid intake was associated with cognitive impairment after adjustment for age, education, cigarette smoking, alcohol consumption, and energy intake (odds ratio (OR) for highest vs. lowest tertile = 1.76, 95% confidence interval (CI) 1.04-3.01). Intake of n-3 polyunsaturated fatty acids was not associated with cognitive impairment, whereas high fish consumption tended to be inversely associated with cognitive impairment (OR = 0.63, 95% CI 0.33-1.21) and cognitive decline (OR = 0.45, 95% CI 0.17-1.16). Intakes of beta-carotene, vitamins C and E, and flavonoids were not inversely associated with cognitive impairment or decline. This study raises the possibility that high linoleic acid intake is positively associated with cognitive impairment and high fish consumption inversely associated with cognitive impairment.
Evidence of the importance of the B vitamins folic acid, vitamin B-12, and vitamin B-6 for the well-being and normal function of the brain derives from data showing neurologic and psychologic dysfunction in vitamin deficiency states and in cases of congenital defects of one-carbon metabolism. The status of these vitamins is frequently inadequate in the elderly and recent studies have shown associations between loss of cognitive function or Alzheimer disease and inadequate B vitamin status. The question that arises is whether these B vitamin inadequacies contribute to such brain malfunctions or result from aging and disease. From a theoretical standpoint, these inadequacies could give rise to impairment of methylation reactions that are crucial to the health of brain tissue. In addition or perhaps instead, these inadequacies could result in hyperhomocysteinemia, a recently identified risk factor for occlusive vascular disease, stroke, and thrombosis, any of which may result in brain ischemia. Advances in the understanding of this putative relation between inadequate vitamin status and loss of cognitive function in the elderly are likely to be slow and may depend on the outcomes of both prospective studies and longitudinal studies in which nutritional intervention is provided before cognitive decline occurs.
Vitamin A and its derivatives, the retinoids, have been implicated recently in the synaptic plasticity of the hippocampus and might therefore play a role in associated cognitive functions. Acting via transcription factors, retinoids can regulate gene expression via their nuclear receptors [retinoic acid receptors (RARs) and retinoid X receptors]. In a series of experiments, the present study investigated the possible role of age-related downregulation of retinoid-mediated transcription events in the cognitive decline seen in aged mice. We observed that the brain (and hippocampal) levels of retinoid receptors and the expression of specific associated target genes were restored to presenescent (adult) levels in aged mice after acute administration (150 microg/kg, s.c.) of retinoic acid (RA). These effects of RA, however, could be abolished by the coadministration of an RAR antagonist. RA was also demonstrated to alleviate the age-related deficit in the CA1 long-term potentiation efficacy of aged mice in vivo. Moreover, RA was found to alleviate completely the performance deficit of aged mice to the control level in a two-stage spatial discrimination paradigm designed to assess relational memory. This promnesic effect of RA was again susceptible to abolition by RAR antagonist treatment. The parallel molecular, cellular, and behavioral correlates associated with the decrease of retinoid receptor expression and its normalization demonstrated here suggest that the fine regulation of retinoid-mediated gene expression is fundamentally important to optimal brain functioning and higher cognition. Specifically, a naturally occurring dysregulation of retinoid-mediated molecular events might be a potential etiological factor for cognitive deterioration during senescence.
Oxidative processes have been suggested as elements in the development of Alzheimer disease (AD), but whether dietary intake of vitamin E and other antioxidant nutrients prevents its development is unknown.
To examine whether intake of antioxidant nutrients, vitamin E, vitamin C, and beta carotene is associated with incident AD.
Prospective study, conducted from 1993 to 2000, of individuals selected in a stratified random sample of community-dwelling residents. The 815 residents 65 years and older were free of AD at baseline and were followed up for a mean of 3.9 years. They completed food frequency questionnaires an average of 1.7 years after baseline.
Incident AD diagnosed in clinical evaluations with standardized criteria.
Increasing vitamin E intake from foods was associated with decreased risk of developing AD after adjustment for age, education, sex, race, APOE epsilon 4, and length of follow-up. Relative risks (95% confidence intervals [CIs]) from lowest to highest quintiles of intake were 1.00, 0.71 (0.24-2.07), 0.62 (0.26-1.45), 0.71 (0.27-1.88), and 0.30 (0.10-0.92) (P for trend =.05). The protective association of vitamin E was observed only among persons who were APOE epsilon 4 negative. Adjustment for other dietary factors reduced the protective association. After adjustment for baseline memory score, the risk was 0.36 (95% CI, 0.11-1.17). Intake of vitamin C, beta carotene, and vitamin E from supplements was not significantly associated with risk of AD.
This study suggests that vitamin E from food, but not other antioxidants, may be associated with a reduced risk of AD. Unexpectedly, this association was observed only among individuals without the APOE epsilon 4 allele.
Laboratory findings have suggested that oxidative stress may contribute to the pathogenesis of Alzheimer disease. Therefore, the risk of Alzheimer disease might be reduced by intake of antioxidants that counteract the detrimental effects of oxidative stress.
To determine whether dietary intake of antioxidants is related to risk of Alzheimer disease.
The Rotterdam Study, a population-based, prospective cohort study conducted in the Netherlands.
A total of 5395 participants who, at baseline (1990-1993), were aged at least 55 years, free of dementia, and noninstitutionalized and had reliable dietary assessment. Participants were reexamined in 1993-1994 and 1997-1999 and were continuously monitored for incident dementia.
Incidence of Alzheimer disease, based on Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) criteria and National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer Disease and Related Disorders Association (NINCDS-ADRDA) criteria, associated with dietary intake of beta carotene, flavonoids, vitamin C, and vitamin E.
After a mean follow-up of 6 years, 197 participants developed dementia, of whom 146 had Alzheimer disease. When adjustments were made for age, sex, baseline Mini-Mental State Examination score, alcohol intake, education, smoking habits, pack-years of smoking, body mass index, total energy intake, presence of carotid plaques, and use of antioxidative supplements, high intake of vitamin C and vitamin E was associated with lower risk of Alzheimer disease (rate ratios [RRs] per 1-SD increase in intake were 0.82 [95% confidence interval [CI], 0.68-0.99] and 0.82 [95% CI, 0.66-1.00], respectively). Among current smokers, this relationship was most pronounced (RRs, 0.65 [95% CI, 0.37-1.14] and 0.58 [95% CI, 0.30-1.12], respectively) and also was present for intake of beta carotene (RR, 0.49 [95% CI, 0.27-0.92]) and flavonoids (RR, 0.54 [95% CI, 0.31-0.96]). The associations did not vary by education or apolipoprotein E genotype.
High dietary intake of vitamin C and vitamin E may lower the risk of Alzheimer disease.
The present prospective study investigated whether elevated total serum homocysteine concentration is a risk factor for cognitive decline. The outcomes were compared to the possible relation between cognition and vitamin B12 or folic acid. Cognitive performance of 144 normal aging individuals (aged 30-80 years) was tested at baseline and after six years of follow-up. Domains of cognitive function addressed were cognitive speed (Letter-Digit Coding test), attention and information processing (Stroop test) and verbal learning and memory (Word Learning Test Total; Delayed Recall). Serum concentrations of homocysteine, folic acid and vitamin B12 were determined. Serum concentrations of homocysteine correlated negatively with cognitive performance on the Word Learning tests at baseline, independent of age, sex, education level or folic acid concentration. Homocysteine concentration at baseline correlated negatively with cognitive performance on the Stroop and Word Learning tests during the whole six-year follow-up period. The folic acid concentration correlated to the Delayed Recall test at baseline only and no correlations were observed for vitamin B12. Thus, while a relation between vitamin B12 or folic acid and cognition was almost absent, elevated homocysteine concentrations were associated with prolonged lower cognitive performance in this normal aging population.
The ageing of the human brain is a cause of cognitive decline in the elderly and the major risk factor for Alzheimer's disease. The time in life when brain ageing begins is undefined. Here we show that transcriptional profiling of the human frontal cortex from individuals ranging from 26 to 106 years of age defines a set of genes with reduced expression after age 40. These genes play central roles in synaptic plasticity, vesicular transport and mitochondrial function. This is followed by induction of stress response, antioxidant and DNA repair genes. DNA damage is markedly increased in the promoters of genes with reduced expression in the aged cortex. Moreover, these gene promoters are selectively damaged by oxidative stress in cultured human neurons, and show reduced base-excision DNA repair. Thus, DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a programme of brain ageing that starts early in adult life.
The Women's Health Initiative Memory Study (WHIMS) previously reported that estrogen plus progestin therapy does not protect cognition among women aged 65 years or older. The effect of estrogen-alone therapy, also evaluated in WHIMS, on cognition has not been established for this population.
To determine whether conjugated equine estrogen (CEE) alters global cognitive function in older women and to compare its effect with CEE plus medroxyprogesterone acetate (CEE plus MPA).
A randomized, double-blind, placebo-controlled ancillary study of the Women's Health Initiative (WHI), WHIMS evaluated the effect of CEE on incidence of probable dementia among community-dwelling women aged 65 to 79 years with prior hysterectomy from 39 US academic centers that started in June 1995. Of 3200 eligible women free of probable dementia enrolled in the WHI, 2947 (92.1%) were enrolled in WHIMS. Analyses were conducted on the 2808 women (95.3%) with a baseline and at least 1 follow-up measure of global cognitive function before the trial's termination on February 29, 2004.
Participants received 1 daily tablet containing either 0.625 mg of CEE (n = 1387) or matching placebo (n = 1421).
Global cognitive function measured annually with the Modified Mini-Mental State Examination (3MSE).
During a mean follow-up of 5.4 years, mean (SE) 3MSE scores were 0.26 (0.13) units lower than among women assigned to CEE compared with placebo (P =.04). For pooled hormone therapy (CEE combined with CEE plus MPA), the mean (SE) decrease was 0.21 (0.08; P =.006). Removing women with dementia, mild cognitive impairment, or stroke from the analyses lessened these differences. The adverse effect of hormone therapy was more pronounced among women with lower cognitive function at baseline (all P<.01). For women assigned to CEE compared with placebo, the relative risk of having a 10-unit decrease in 3MSE scores (>2 SDs) was estimated to be 1.47 (95% confidence interval, 1.04-2.07).
For women aged 65 years or older, hormone therapy had an adverse effect on cognition, which was greater among women with lower cognitive function at initiation of treatment.
Deficiencies in folate and vitamin B12 have been associated with neurodegenerative disease.
To examine the association between rates of age-related cognitive change and dietary intakes of folate and vitamin B12.
Prospective study performed from 1993 to 2002.
Geographically defined biracial community in Chicago, Ill.
A total of 3718 residents, 65 years and older, who completed 2 to 3 cognitive assessments and a food frequency questionnaire.
Change in cognitive function measured at baseline and 3-year and 6-year follow-ups, using the average z score of 4 tests: the East Boston Tests of immediate and delayed recall, the Mini-Mental State Examination, and the Symbol Digit Modalities Test.
High folate intake was associated with a faster rate of cognitive decline in mixed models adjusted for multiple risk factors. The rate of cognitive decline among persons in the top fifth of total folate intake (median, 742 microg/d) was more than twice that of those in the lowest fifth of intake (median, 186 microg/d), a statistically significant difference of 0.02 standardized unit per year (P = .002). A faster rate of cognitive decline was also associated with high folate intake from food (P for trend = .04) and with folate vitamin supplementation of more than 400 microg/d compared with nonusers (beta = -.03, P<.001). High total B12 intake was associated with slower cognitive decline only among the oldest participants.
High intake of folate may be associated with cognitive decline in older persons. These unexpected findings call for further study of the cognitive implications of high levels of dietary folate in older populations.
Mild cognitive impairment is a transitional state between the cognitive changes of normal aging and early Alzheimer's disease.
In a double-blind study, we evaluated subjects with the amnestic subtype of mild cognitive impairment. Subjects were randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo for three years. The primary outcome was clinically possible or probable Alzheimer's disease; secondary outcomes were cognition and function.
A total of 769 subjects were enrolled, and possible or probable Alzheimer's disease developed in 212. The overall rate of progression from mild cognitive impairment to Alzheimer's disease was 16 percent per year. As compared with the placebo group, there were no significant differences in the probability of progression to Alzheimer's disease in the vitamin E group (hazard ratio, 1.02; 95 percent confidence interval, 0.74 to 1.41; P=0.91) or the donepezil group (hazard ratio, 0.80; 95 percent confidence interval, 0.57 to 1.13; P=0.42) during the three years of treatment. Prespecified analyses of the treatment effects at 6-month intervals showed that as compared with the placebo group, the donepezil group had a reduced likelihood of progression to Alzheimer's disease during the first 12 months of the study (P=0.04), a finding supported by the secondary outcome measures. Among carriers of one or more apolipoprotein E epsilon4 alleles, the benefit of donepezil was evident throughout the three-year follow-up. There were no significant differences in the rate of progression to Alzheimer's disease between the vitamin E and placebo groups at any point, either among all patients or among apolipoprotein E epsilon4 carriers.
Vitamin E had no benefit in patients with mild cognitive impairment. Although donepezil therapy was associated with a lower rate of progression to Alzheimer's disease during the first 12 months of treatment, the rate of progression to Alzheimer's disease after three years was not lower among patients treated with donepezil than among those given placebo.
The Physicians' Health Study is a randomized, double-blind, placebo-controlled trial designed to determine whether low-dose aspirin (325 mg every other day) decreases cardiovascular mortality and whether beta carotene reduces the incidence of cancer. The aspirin component was terminated earlier than scheduled, and the preliminary findings were published. We now present detailed analyses of the cardiovascular component for 22,071 participants, at an average follow-up time of 60.2 months. There was a 44 percent reduction in the risk of myocardial infarction (relative risk, 0.56; 95 percent confidence interval, 0.45 to 0.70; P < 0.00001) in the aspirin group (254.8 per 100,000 per year as compared with 439.7 in the placebo group). A slightly increased risk of stroke among those taking aspirin was not statistically significant; this trend was observed primarily in the subgroup with hemorrhagic stroke (relative risk, 2.14; 95 percent confidence interval, 0.96 to 4.77; P = 0.06). No reduction in mortality from all cardiovascular causes was associated with aspirin (relative risk, 0.96; 95 percent confidence interval, 0.60 to 1.54). Further analyses showed that the reduction in the risk of myocardial infarction was apparent only among those who were 50 years of age and older. The benefit was present at all levels of cholesterol, but appeared greatest at low levels. The relative risk of ulcer in the aspirin group was 1.22 (169 in the aspirin group as compared with 138 in the placebo group; 95 percent confidence interval, 0.98 to 1.53; P = 0.08), and the relative risk of requiring a blood transfusion was 1.71. This trial of aspirin for the primary prevention of cardiovascular disease demonstrates a conclusive reduction in the risk of myocardial infarction, but the evidence concerning stroke and total cardiovascular deaths remains inconclusive because of the inadequate numbers of physicians with these end points.
Background:
It has been suggested that increased intake of various antioxidant vitamins reduces the incidence rates of vascular disease, cancer, and other adverse outcomes.
Methods:
20,536 UK adults (aged 40-80) with coronary disease, other occlusive arterial disease, or diabetes were randomly allocated to receive antioxidant vitamin supplementation (600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene daily) or matching placebo. Intention-to-treat comparisons of outcome were conducted between all vitamin-allocated and all placebo-allocated participants. An average of 83% of participants in each treatment group remained compliant during the scheduled 5-year treatment period. Allocation to this vitamin regimen approximately doubled the plasma concentration of alpha-tocopherol, increased that of vitamin C by one-third, and quadrupled that of beta-carotene. Primary outcomes were major coronary events (for overall analyses) and fatal or non-fatal vascular events (for subcategory analyses), with subsidiary assessments of cancer and of other major morbidity.
Findings:
There were no significant differences in all-cause mortality (1446 [14.1%] vitamin-allocated vs 1389 [13.5%] placebo-allocated), or in deaths due to vascular (878 [8.6%] vs 840 [8.2%]) or non-vascular (568 [5.5%] vs 549 [5.3%]) causes. Nor were there any significant differences in the numbers of participants having non-fatal myocardial infarction or coronary death (1063 [10.4%] vs 1047 [10.2%]), non-fatal or fatal stroke (511 [5.0%] vs 518 [5.0%]), or coronary or non-coronary revascularisation (1058 [10.3%] vs 1086 [10.6%]). For the first occurrence of any of these "major vascular events", there were no material differences either overall (2306 [22.5%] vs 2312 [22.5%]; event rate ratio 1.00 [95% CI 0.94-1.06]) or in any of the various subcategories considered. There were no significant effects on cancer incidence or on hospitalisation for any other non-vascular cause.
Interpretation:
Among the high-risk individuals that were studied, these antioxidant vitamins appeared to be safe. But, although this regimen increased blood vitamin concentrations substantially, it did not produce any significant reductions in the 5-year mortality from, or incidence of, any type of vascular disease, cancer, or other major outcome.
OBJECTIVES: To study the relation between serum levels of carotenoids and white matter lesions (WMLs) on magnetic resonance imaging (MRI).
DESIGN: Evaluation of cross-sectional data from a cohort study.
SETTING: The Rotterdam Scan Study.
PARTICIPANTS: Two hundred and three nondemented older persons, age 60 to 90, from the Rotterdam Scan Study.
MEASUREMENTS: Serum levels of carotenoids were determined. WMLs on MRIs were rated separately into periventricular and subcortical WMLs. Odds ratios (ORs) for the presence of severe WMLs (upper decile) were calculated per standard deviation (SD) increase in serum carotenoid level and per SD increase in overall carotenoid serum level. Effect modification by smoking status was studied through stratified analyses.
RESULTS: Increasing levels of all the separate carotenoids were associated with less severe periventricular WMLs, which reached statistical significance for the overall carotenoid serum level (OR 0.4 per SD; 95% confidence interval (CI) = 0.2–0.9). We found no association between carotenoid levels and the presence of severe subcortical WMLs (OR 1.2 per SD; 95% CI = 0.7–2.0). The association of carotenoid levels with severe periventricular WMLs was more marked in those who ever smoked (OR 0.1 per SD; 95% CI = 0.0–0.9) than in those who had never smoked (OR 0.9 per SD; 95% CI = 0.4–2.1).
CONCLUSIONS: These findings are compatible with the view that high levels of carotenoids may protect against WMLs in the periventricular region, in particular in smokers. Longitudinal studies with repeated measurements of both carotenoids and WMLs are necessary to explore this hypothesis further.
Hippocampal long-term potentiation (LTP) and long-term depression (LTD) are the most widely studied forms of synaptic plasticity thought to underlie spatial learning and memory. We report here that RARβ deficiency in mice virtually eliminates hippocampal CA1 LTP and LTD. It also results in substantial performance deficits in spatial learning and memory tasks. Surprisingly, RXRγ null mice exhibit a distinct phenotype in which LTD is lost whereas LTP is normal. Thus, while retinoid receptors contribute to both LTP and LTD, they do so in different ways. These findings not only genetically uncouple LTP and LTD but also reveal a novel and unexpected role for vitamin A in higher cognitive functions.
Objectives
To examine the ability of the total score and individual items from the Mini-Mental State Examination in predicting the development of Alzheimer disease (AD) across a 3- and 6-year period in a population-based sample, and to describe the longitudinal changes in these measures across the same follow-up periods.Design
Prospective follow-up of a community-based cohort, with 3 times of testing across a 6-year period. At each time of measurement, participants were clinically examined by physicians to identify demented and nondemented participants according to Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, criteria.Participants
The study population consisted of all participants who were nondemented at the first follow-up and participated in the second follow-up examination. Among those, 459 remained nondemented and 73 developed AD during the second follow-up period.Results
Baseline differences in the total Mini-Mental State Examination score and the delayed memory item were seen 6 years before eventual dementia diagnosis (P<.01). Analysis of the longitudinal changes showed no differences in the rate of decline for the incident AD or nondemented group between time 1 and time 2 (P>.10). However, the incident AD group exhibited precipitous declines in 8 of the 10 subscales between time 2 and time 3, the point at which they were clinically diagnosed (P<.01). Logistic regression analyses showed that only the delayed memory item was a significant predictor of who would develop AD, independent of age, sex, and years of education, at both of the first 2 times of measurement (P<.001).Conclusions
The diagnosis of AD is preceded by a long preclinical phase in which deficits in memory performance are most common. These deficits remain relatively stable up until the time that a dementia diagnosis can be rendered.
Retinoic add (RA) induced differentiation of SH-SY5Y neuroblastoma cells is associated with more than a tenfold induction of total Alzheimer's disease βA4 amyloid protein precursor (APP) mRNA as analyzed by Northern blot hybridisation. Sl nuelease protection experiments reveal that the splicing pattern of these differentiated cells is altered in favor of APP695 mRNA, coding for the shortest amyloidogenic βA4 amyloid precursor protein. Induction of differentiation of SH-SY5Y cells with NGF leads to a fivefold increase of total APP mRNA without change in the splicing pattern. This suggests that RA but not NGF induces factor(s) which are responsible for an APP hnRNA splicing favoring APP695 mRNA.
Basic research and observational studies suggest vitamin E or vitamin C may reduce the risk of cardiovascular disease. However, few long-term trials have evaluated men at initially low risk of cardiovascular disease, and no previous trial in men has examined vitamin C alone in the prevention of cardiovascular disease.
To evaluate whether long-term vitamin E or vitamin C supplementation decreases the risk of major cardiovascular events among men.
The Physicians' Health Study II was a randomized, double-blind, placebo-controlled factorial trial of vitamin E and vitamin C that began in 1997 and continued until its scheduled completion on August 31, 2007. There were 14,641 US male physicians enrolled, who were initially aged 50 years or older, including 754 men (5.1%) with prevalent cardiovascular disease at randomization.
Individual supplements of 400 IU of vitamin E every other day and 500 mg of vitamin C daily.
A composite end point of major cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular disease death).
During a mean follow-up of 8 years, there were 1245 confirmed major cardiovascular events. Compared with placebo, vitamin E had no effect on the incidence of major cardiovascular events (both active and placebo vitamin E groups, 10.9 events per 1000 person-years; hazard ratio [HR], 1.01 [95% confidence interval {CI}, 0.90-1.13]; P = .86), as well as total myocardial infarction (HR, 0.90 [95% CI, 0.75-1.07]; P = .22), total stroke (HR, 1.07 [95% CI, 0.89-1.29]; P = .45), and cardiovascular mortality (HR, 1.07 [95% CI, 0.90-1.28]; P = .43). There also was no significant effect of vitamin C on major cardiovascular events (active and placebo vitamin E groups, 10.8 and 10.9 events per 1000 person-years, respectively; HR, 0.99 [95% CI, 0.89-1.11]; P = .91), as well as total myocardial infarction (HR, 1.04 [95% CI, 0.87-1.24]; P = .65), total stroke (HR, 0.89 [95% CI, 0.74-1.07]; P = .21), and cardiovascular mortality (HR, 1.02 [95% CI, 0.85-1.21]; P = .86). Neither vitamin E (HR, 1.07 [95% CI, 0.97-1.18]; P = .15) nor vitamin C (HR, 1.07 [95% CI, 0.97-1.18]; P = .16) had a significant effect on total mortality but vitamin E was associated with an increased risk of hemorrhagic stroke (HR, 1.74 [95% CI, 1.04-2.91]; P = .04).
In this large, long-term trial of male physicians, neither vitamin E nor vitamin C supplementation reduced the risk of major cardiovascular events. These data provide no support for the use of these supplements for the prevention of cardiovascular disease in middle-aged and older men.
clinicaltrials.gov Identifier: NCT00270647.
In the economically developed world, folate deficiency is one of the commonest vitamin deficiencies. Several reports suggest a higher prevalence of various psychiatric disorders in elderly people with folate deficiency. There is interest in whether dietary supplements of folic acid (an artificial chemical analogue of naturally occurring folates) can improve cognitive function of people at risk of cognitive decline associated with ageing or dementia, whether by affecting homocysteine metabolism or through other mechanisms. Eight trials met the criteria for inclusion. It was not possible to pool the data because the trials studied different populations, tested folic acid in different doses, and used different outcome measures. There were two trials of folic acid in conjunction with B12. The analysis showed significant benefit of folic acid over placebo in some measures of cognition in a long-term trial recruiting elderly people with high homocysteine levels from a general population. In one pilot trial, 1 mg/day of folic acid was associated with significant improvement in behavioural response to cholinesterase inhibitors in people with Alzheimer's disease.
Two brief screening tests, the Short Portable Mental Status Questionnaire (SPMSQ) and the East Boston Memory Test (EBMT), were included in a population questionnaire administered to 3,811 persons 65 years of age and older. A detailed clinical evaluation was then administered to 467 persons (drawn from high, medium and low performers on the EBMT) to determine who was cognitively impaired and the disorders that were responsible for that cognitive impairment. The results showed that the EBMT was better at enriching the population of the poor performance group with persons who had Alzheimer's disease (AD). It had a lower refusal rate among non-proxy respondents: 2% for the EMBT versus 9% for the SPMSQ. The sensitivity and positive predictive value were also higher for the EBMT than the SPMSQ when the diagnosis of interest was AD. However, there were persons with AD in all strata of performance on both the EBMT and the SPMSQ, emphasizing the importance of selecting persons from all performance strata in multistage community studies of AD.
The Physicians' Health Study is a randomized, double-blind, placebo-controlled trial using a 2 x 2 factorial design to test the effects of low-dose aspirin on risk of cardiovascular disease and beta-carotene supplementation on the incidence of cancer. To evaluate self-reported compliance with assigned treatment, we measured serum thromboxane B2, which is decreased after aspirin use, and plasma beta-carotene in samples of study participants drawn from three geographic locations in three different time periods. Thromboxane B2 levels were markedly lower in those assigned to aspirin (median = 63.5 pg/mL) than in those given aspirin placebo (median = 3,600 pg/mL, P less than .0001). Similarly, those assigned to beta-carotene had significantly higher levels (median = 1,176 ng/mL) than those given placebo (median = 306 ng/mL, P less than .0001). In addition, there was a highly significant positive correlation between levels of these biochemical markers and the self-reports of compliance (r = 0.65 for thromboxane B2 and r = 0.69 for beta-carotene, P less than .0001). These findings support the validity of the self-reported compliance in the Physicians' Health Study.
To evaluate the interval between the onset of detectable cognitive impairment and clinical diagnosis in individuals with probable Alzheimer's disease (AD), and to identify the pattern of the earliest changes in cognition in probable AD.
Longitudinal follow-up of a community-based cohort sample. In 1976 through 1978, a screening neuropsychological examination was administered to Framingham Study participants. These subjects were then followed up prospectively for development of probable AD for up to 13 years.
This study was conducted at a community-based center for epidemiologic research.
The surveillance sample consisted of 1045 participants in the Framingham Study aged 65 to 88 years who were free of dementia at the time of the neuropsychological screening examination.
Scores on a group of neuropsychological tests were entered into a series of age- and education-adjusted multiple regression procedures, with the presence or absence of probable AD as the outcome variable.
Considered individually, most of the screening neuropsychological measures were significantly related to later AD diagnosis. When stepwise regression procedures were employed, only measures of verbal memory and immediate auditory attention span remained significantly related to AD diagnosis. Of note, subjects later diagnosed with probable AD performed at higher levels than normal subjects on the Digit Span test at initial screening. Regression results were essentially unchanged even when the AD sample was restricted to those individuals for whom the screening examination preceded the clinical onset of dementia by 7 years or more.
These findings support previous contentions that a "preclinical phase" of detectable cognitive deficits can precede the clinical diagnosis of probable AD by many years, and they also support the hypothesis that problems with secondary verbal memory are among the first signs of AD.
Free radicals are produced in the body as by products of normal metabolism and as a result of exposure to radiation and some environmental pollutants. Because they are highly reactive, they can damage cellular components and are implicated in a variety of diseases. Free radicals are normally neutralized by efficient systems in the body that include the antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) and the nutrient-derived antioxidant small molecules (vitamin E, vitamin C, carotenes, flavonoids, glutathione, uric acid, and taurine). In healthy individuals, a delicate balance exists between free radicals and antioxidants. In some pathologic conditions such as diabetes, and in critically ill patients, oxidative stress causes the level of antioxidants to fall below normal. Antioxidant supplements for such conditions are expected to be of benefit. As a preventive measure against certain diseases, the best approach for healthy individuals is to regularly consume adequate amounts of antioxidant-rich foods, eg, fruits and vegetables.
To determine the validity of the Dementia Questionnaire (a semistructured informant interview) for the diagnosis of dementia.
Comparison of dementia status determined by a telephone-administered informant questionnaire with the criterion standard of clinical diagnosis established by examination and laboratory studies.
Gerontology Research Center, the Baltimore Longitudinal Study of Aging.
Volunteer cohort of 42 men and 32 women aged 68 to 97 years. Subjects were selected from strata defined by Blessed Information Memory Concentration Test scores, with oversampling of borderline scores (3 to 10).
Sensitivity and specificity of the Dementia Questionnaire in comparison with the criterion standard of clinical diagnosis. SECONDARY OUTCOME MEASURE: Interrater reliability (kappa coefficient).
Sensitivity and specificity for dementia were 100% and 90%, respectively. Most false-positive findings were from subjects with cognitive impairment that did not meet criteria for dementia (Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition. Interrater reliability was high (kappa = 0.83).
The Dementia Questionnaire can be used effectively in research studies to screen for dementia.
The effects of antioxidants tocopherols and ascorbic acid were tested on the survival of hippocampal and striatal neurones in dissociated culture. Alpha- and gamma-tocopherol increased the number of surviving neurones in a concentration-dependent manner. Significant effect was observed at concentrations of 10(-8)-10(-6) M. Furthermore, the promoting effect of alpha-tocopherol on neuronal survival was markedly enhanced in the presence of ascorbic acid (2 x 10(-6) M). These results indicate that tocopherols and ascorbic acid support the survival of cultured neurones by protecting them from oxidative attack.
Long-term potentiation (LTP) of synaptic transmission in the hippocampus is thought to be one of the cellular mechanisms underlying learning and memory. Recent evidence in literature suggests the involvement of free radicals in impeding LTP maintenance. In the present study, the effects of alpha-tocopherol, a major lipid-soluble antioxidant which could prevent lipid peroxidation, were examined on the excitatory post-synaptic potentials (EPSPs) of CA1 neurons in guinea pig hippocampal slices. alpha-Tocopherol phosphate disodium salt (0.2 mM applied for 5 min) induced a slowly developing long-lasting increase of the EPSP, without significantly changing the membrane potential, the input resistance and the ability to generate action potentials. No significant changes in the fast and the slow inhibitory post-synaptic potentials (IPSPs) were observed during the alpha-tocopherol-induced LTP of the EPSP. 2-Amino-5-phosphonovalerate (APV) did not block the induction of this LTP. L-Ascorbic acid (Na salt, 3-10 mM), a water-soluble antioxidant, failed to produce any significant enhancement in the EPSP. These results indicate that alpha-tocopherol can induce LTP of the EPSP in guinea pig hippocampal CA1 neurons. The activation of N-methyl-D-aspartate (NMDA) receptors does not appear to be necessary for this action of alpha-tocopherol. Whether the LTP-inducing action of this agent is related to its antioxidant property is unclear.
It has been suggested that the activity of the enzyme responsible for the synthesis of acetylcholine, choline acetyltransferase (ChAT), is substantially reduced in the neocortex and hippocampus of Alzheimer's and other aging brains. d-alpha-Tocopherol (vitamin E), a free radical scavenger fat-soluble vitamin, was utilized in the present study to determine whether its supplementation in aging and ethylcholine mustard aziridinium (AF64A)-lesioned rats would improve the cholinergic hypofunction. Vitamin E (given 24 h and 15 min prior to AF64A administration) significantly (P < 0.01) reversed the effect of AF64A in hippocampal choline acetyltransferase activity, but it did not cause any change of this enzyme activity in other brain regions (striatum and frontal cortex), nor did it cause any significant change after 30-day daily treatment in AF64A-lesioned rats. Furthermore, vitamin E (50 mg/kg, i.p. for 30-day treatment) significantly (P < 0.01) partially restored the enzyme activity in striatum of aging (20-28 month old) rats. The present result indicates that vitamin E can partly restore the hypofunction of the cholinergic system in aging and partly prevent the toxicity in AF64A-lesioned rats.
Clones of the rat pheochromocytoma cell line PC12 were selected for their resistance to amyloid beta protein (A beta). These A beta-resistant cells also survive higher concentrations of exogenously applied peroxides than the parent cells. A beta triggers intracellular H2O2 accumulation in the parent PC12 cells but not in the A beta-resistant cells. The absence of H2O2 accumulation in A beta-resistant cells is not attributable to differences in A beta binding to the cell surface. However, the mRNA and protein levels of catalase and glutathione peroxidase, as well as the corresponding enzyme activities, are highly elevated in A beta-resistant clones. These activities correlate well with the increased resistance of cells to A beta or peroxides. Finally, cells transfected with catalase and glutathione peroxidase are also more resistant to A beta toxicity. These results indicate that increased antioxidant enzyme activities in A beta-resistant cells account for at least part of their resistance to A beta and substantiate further the role of H2O2 in A beta toxicity.
Observational studies suggest that people who consume more fruits and vegetables containing beta carotene have somewhat lower risks of cancer and cardiovascular disease, and earlier basic research suggested plausible mechanisms. Because large randomized trials of long duration were necessary to test this hypothesis directly, we conducted a trial of beta carotene supplementation.
In a randomized, double-blind, placebo-controlled trial of beta carotene (50 mg on alternate days), we enrolled 22,071 male physicians, 40 to 84 years of age, in the United States; 11 percent were current smokers and 39 percent were former smokers at the beginning of the study in 1982. By December 31, 1995, the scheduled end of the study, fewer than 1 percent had been lost to follow-up, and compliance was 78 percent in the group that received beta carotene.
Among 11,036 physicians randomly assigned to receive beta carotene and 11,035 assigned to receive placebo, there were virtually no early or late differences in the overall incidence of malignant neoplasms or cardiovascular disease, or in overall mortality. In the beta carotene group, 1273 men had any malignant neoplasm (except nonmelanoma skin cancer), as compared with 1293 in the placebo group (relative risk, 0.98; 95 percent confidence interval, 0.91 to 1.06). There were also no significant differences in the number of cases of lung cancer (82 in the beta carotene group vs. 88 in the placebo group); the number of deaths from cancer (386 vs. 380), deaths from any cause (979 vs. 968), or deaths from cardiovascular disease (338 vs. 313); the number of men with myocardial infarction (468 vs. 489); the number with stroke (367 vs. 382); or the number with any one of the previous three end points (967 vs. 972). Among current and former smokers, there were also no significant early or late differences in any of these end points.
In this trial among healthy men, 12 years of supplementation with beta carotene produced neither benefit nor harm in terms of the incidence of malignant neoplasms, cardiovascular disease, or death from all causes.
Antioxidants have been implicated in processes related to atherosclerosis, aging, and selective neuronal damage, all of which may ultimately affect cognitive function. In a sample of older persons, the authors examined the cross-sectional relation between cognitive function and dietary intake of beta-carotene and vitamins C and E. The data were derived from 5,182 community participants aged 55-95 years in the population-based Rotterdam Study in the period 1990 to 1993. Dietary intake was estimated from a semi-quantitative food frequency questionnaire and categorized into five levels of intake. Cognitive function was measured with the 30-point Mini-Mental State Examination (MMSE) and characterized as unimpaired (> 25 points) or impaired (< or = 25 points). Logistic regression analysis was used to estimate the odds ratio (OR) and 95% confidence interval (CI) for cognitive impairment. After adjustment for age, education, sex, smoking, total caloric intake, and intake of other antioxidants, a lower intake of beta-carotene was associated with impaired cognitive function (< 0.9 mg vs. > or = 2.1 mg intake, OR = 1.9, 95% CI 1.2-3.1; p for trend < 0.04). There was no association between cognitive function and intake of vitamins C and E. These cross-sectional observations are compatible with the view that beta-carotene-rich foods may protect against cognitive impairment in older people. The finding could also reflect unmeasured confounding, measurement error, or a change in food habits that resulted from rather than preceded the onset of cognitive impairment.
The goal of this study was to project the future prevalence and incidence of Alzheimer's disease in the United States and the potential impact of interventions to delay disease onset.
The numbers of individuals in the United States with Alzheimer's disease and the numbers of newly diagnosed cases that can be expected over the next 50 years were estimated from a model that used age-specific incidence rates summarized from several epidemiological studies, US mortality rates, and US Bureau of the Census projections.
in 1997, the prevalence of Alzheimer's disease in the United States was 2.32 million (range: 1.09 to 4.58 million); of these individuals, 68% were female. It is projected that the prevalence will nearly quadruple in the next 50 years, by which time approximately 1 in 45 Americans will be afflicted with the disease. Currently, the annual number of new incident cases in 360,000. If interventions could delay onset of the disease by 2 years, after 50 years there would be nearly 2 million fewer cases than projected; if onset could be delayed by 1 year, there would be nearly 800,000 fewer prevalent cases.
As the US population ages, Alzheimer's disease will become an enormous public health problem. interventions that could delay disease onset even modestly would have a major public health impact.
Age-related changes in nutrition can affect the nutritional status of the elderly in a number of ways. Food intake is affected by socio-economic, physiological and pathological factors. The major physiological age-related change is the decrease in the energy requirement due to a reduction in lean body mass and a reduction in physical activity leading to a compensatory decrease in macro- and micronutrient intake of approximately 30% by the age of 80 years. Morbidity and some types of medication, smoking and alcohol consumption also affect the absorption and metabolism of vitamins. The plasma levels of fat-soluble vitamins and carotenoids tend to increase with age with the exception of vitamin D, while certain water-soluble vitamin levels decrease, particularly vitamin B6 and vitamin B12. Many epidemiological studies have examined the vitamin intake and the plasma concentrations of large elderly populations in many regions of the world, but few have specifically determined the incidence of vitamin deficiencies. The criteria for defining deficiency varies between studies making it difficult to compare data from different studies. In the SENECA Study on European elderly evidence for biochemical vitamin deficiency was found in 47% for vitamin D, 23.3% for vitamin B6, 2.7% for vitamin B12 and 1.1% for vitamin E.
To assess the balance of benefits and risks of supplementation with beta-carotene, vitamin E, vitamin C, and multivitamins on cancer, cardiovascular (CVD), and eye diseases.
Physicians' Health Study II (PHS II) is a randomized, double-blind, placebo-controlled trial enrolling 15,000 willing and eligible physicians aged 55 years and older. PHS II will utilize a 2 x 2 x 2 x 2 factorial design to test alternate day beta-carotene, alternate day vitamin E, daily vitamin C, and a daily multivitamin, in the prevention of total and prostate cancer, CVD, and the age-related eye diseases, cataract and macular degeneration. PRIOR RESULTS: The final results of the recently completed Physicians' Health Study I (PHS I), a randomized, double-blind, placebo-controlled trial in 22,071 healthy US male physicians, indicated that beta-carotene supplementation (50 mg on alternate days) had no significant benefit or harm on cancer or CVD during more than 12 years of treatment and follow-up. In regards to cancer, there were possible benefits on total and prostate cancer in those with low baseline levels assigned to beta-carotene, a finding compatible with the Chinese Cancer Prevention Study for combined treatment with beta-carotene, vitamin E, and selenium in a poorly nourished population. Further, with respect to CVD, there were apparent benefits of beta-carotene supplementation on subsequent vascular events among a small subgroup of 333 men with prior angina or revascularization. The currently available data from randomized trials of primary prevention are sparse and inconsistent for vitamin E and non-existent for vitamin C and multivitamins. For eye diseases, namely cataract and age-related macular degeneration, there are no completed large-scale randomized trials of antioxidant vitamins.
PHS II is unique in several respects. PHS II is the only primary prevention trial in apparently healthy men testing the balance of benefits and risks of vitamin E on cancer and CVD. In addition, PHS II is the only primary prevention trial in apparently healthy men to test the balance of benefits and risks of vitamin C, multivitamins, as well as any single antioxidant vitamin, alone and in combination, on cancer, CVD, and eye diseases. Finally, PHS II is the only trial testing a priori the hypotheses that beta-carotene and vitamin E may reduce the risks of prostate cancer. Thus, PHS II will add unique as well as importantly relevant and complementary information to the totality of evidence from other completed and ongoing large-scale randomized trials on the balance of benefits and risks of beta-carotene, vitamin E, vitamin C, and multivitamins alone and in combination on prevention of cancer, CVD and eye diseases.
To determine whether use of vitamin E and C supplements protects against subsequent development of dementia and poor cognitive functioning.
The Honolulu-Asia Aging Study is a longitudinal study of Japanese-American men living in Hawaii. Data for this study were obtained from a subsample of the cohort interviewed in 1982, and from the entire cohort from a mailed questionnaire in 1988 and the dementia prevalence survey in 1991 to 1993. The subjects included 3,385 men, age 71 to 93 years, whose use of vitamin E and C supplements had been ascertained previously. Cognitive performance was assessed with the Cognitive Abilities Screening Instrument, and subjects were stratified into four groups: low, low normal, mid normal, and high normal. For the dementia analyses, subjects were divided into five mutually exclusive groups: AD (n = 47), vascular dementia (n = 35), mixed/other types of dementia (n = 50), low cognitive test scorers without diagnosed dementia (n = 254), and cognitively intact (n = 2,999; reference).
In a multivariate model controlling for other factors, a significant protective effect was found for vascular dementia in men who had reported taking both vitamin E and C supplements in 1988 (odds ratio [OR], 0.12; 95% CI, 0.02 to 0.88). They were also protected against mixed/other dementia (OR, 0.31; 95% CI, 0.11 to 0.89). No protective effect was found for Alzheimer's dementia (OR, 1.81; 95% CI, 0.91 to 3.62). Among those without dementia, use of either vitamin E or C supplements alone in 1988 was associated significantly with better cognitive test performance at the 1991 to 1993 examination (OR, 1.25; 95% CI, 1.04 to 1.50), and use of both vitamin E and C together had borderline significance (OR, 1.18; 95% CI, 0.995 to 1.39).
These results suggest that vitamin E and C supplements may protect against vascular dementia and may improve cognitive function in late life.
To relate performance on tests of cognitive ability to the subsequent development of probable Alzheimer disease (pAD) and to identify the pattern of earliest changes in cognitive functioning associated with a diagnosis of pAD.
From May 1975 to November 1979, a screening neuropsychological battery was administered to Framingham Study participants. They were followed up prospectively for 22 years and examined at least every 2 years for the development of pAD.
A community-based center for epidemiological research.
Subjects were 1076 participants of the Framingham Study aged 65 to 94 years who were free of dementia and stroke at baseline (initial) neuropsychological testing.
Presence or absence of pAD during a 22-year surveillance period was related to test performance at initial neuropsychological testing.
Lower scores for measures of new learning, recall, retention, and abstract reasoning obtained during a dementia-free period were associated with the development of pAD. Lower scores for measures of abstract reasoning and retention predicted pAD after a dementia-free period of 10 years.
The "preclinical phase" of detectable lowering of cognitive functioning precedes the appearance of pAD by many years. Measures of retention of information and abstract reasoning are among the strongest predictors of pAD when the interval between initial assessment and the development of pAD is long. Arch Neurol. 2000.
Specific patterns of decline over time were evaluated across a spectrum of cognitive measures in presymptomatic Alzheimer disease (AD) within a community sample.
A total of 551 individuals completed a battery of standard cognitive tests 3.5 and 1.5 years before outcome (clinical onset of AD vs continued nondemented status) within a prospective community-based study of AD. Test score changes in 68 cases (who subsequently developed symptomatic AD) and 483 controls (who remained nondemented) on each of 15 cognitive measures were transformed into z scores adjusted for age, sex, and education. A case-control rate ratio of the proportions of individuals who showed "cognitive decline" on each test was calculated, representing the relative magnitude of cognitive decline on each test in presymptomatic AD compared with normal aging.
Declines in Trail-Making Tests A and B and Word List delayed recognition of originals and third immediate learning trial had the highest rate ratios, larger than 3.0 (P<.01). These were followed by Word List delayed recognition of foils and delayed recall, Consortium to Establish a Registry for Alzheimer's Disease Praxis, Clock Drawing, the Boston Naming Test, and Orientation, with rate ratios between 1.7 and 3.0 (P<.05).
Memory and executive dysfunction showed the greatest decline over time in individuals who would clinically manifest AD 1.5 years later. These findings might help us understand the underlying evolution of the early neurodegenerative process. They highlight the importance of executive dysfunction early in the disease process and might facilitate early detection of AD.
Previous studies raise the possibility that antioxidants protect against neurodegenerative diseases.
To examine whether intake of antioxidant nutrients, including vitamin E, vitamin C, and carotene, is associated with reduced cognitive decline with age.
Longitudinal population-based study conducted from September 17, 1993, to November 20, 2000, with an average follow-up of 3.2 years.
The patients were 2889 community residents, aged 65 to 102 years, who completed a food frequency questionnaire, on average 18 months after baseline.
Cognitive change as measured by 4 tests (the East Boston Memory Test, which tests immediate and delayed recall; the Mini-Mental State Examination; and the Symbol Digit Modalities Test) at baseline and 3 years for all participants, and at 6 months for 288 randomly selected participants.
We used random-effects models to estimate nutrient effects on individual change in the average score of the 4 cognitive tests. The cognitive score declined on average by 5.0 x 10(-2) standardized units per year. There was a 36% reduction in the rate of decline among persons in the highest quintile of total vitamin E intake (-4.3 x 10(-2) standardized units per year) compared with those in the lowest quintile (-6.7 x 10(-2) standardized units per year) (P =.05), in a model adjusted for age, race, sex, educational level, current smoking, alcohol consumption, total calorie (energy) intake, and total intakes of vitamin C, carotene, and vitamin A. We also observed a reduced decline with higher vitamin E intake from foods (P =.03 for trend). There was little evidence of association with vitamin C or carotene intake.
Vitamin E intake, from foods or supplements, is associated with less cognitive decline with age.
It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused
by deposition of amyloid ??-peptide (A??) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of A??
in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary
tangles containing tau protein, is proposed to result from an imbalance between A?? production and A?? clearance.
This report reviews the state of the literature and opportunities for research related to "executive control function" (ECF). ECF has recently been separated from the specific cognitive domains (memory, language, and praxis) traditionally used to assess patients. ECF impairment has been associated with lesions to the frontal cortex and its basal ganglia-thalamic connections. No single putative ECF measure can yet serve as a "gold standard." This and other obstacles to assessment of ECF are reviewed. ECF impairment and related frontal system lesions and metabolic disturbances have been detected in many psychiatric and medical disorders and are strongly associated with functional outcomes, disability, and specific problem behaviors. The prevalence and severity of ECF deficits in many disorders remain to be determined, and treatment has been attempted in only a few disorders. Much more research in these areas is necessary.
To examine the relationship of nonsteroidal anti-inflammatory drug (NSAID) use and cognitive decline in young-old women.
The authors prospectively studied 16,128 Nurses' Health Study participants, aged 70 to 81 years at baseline, who provided information on NSAID use and potential confounders in biennial questionnaires from 1976 through 1998. From 1995 through 2001, we administered, by telephone, six tests of cognitive function, including the Telephone Interview of Cognitive Status (TICS). Second interviews were begun 2 years later and completed on 13,255 women to date. The authors used multiple logistic regression to estimate relative risks (RR) of low baseline scores (defined as the bottom 10%) and substantial decline (worst 10%).
Compared to never users, the RR was 0.75 (95% CI 0.59, 0.96) for a low baseline TICS score with current aspirin use of 15+ years duration, and 0.79 (95% CI 0.62, 1.02) for current use of NSAID (primarily ibuprofen) lasting 8+ years. Results for aspirin users were weaker on other tests, but long-term ibuprofen users had a RR of 0.75 (95% CI 0.56, 1.00) for a low baseline global score (combination of all six tests). The RR for substantial global cognitive decline was 0.93 (95% CI 0.68, 1.26) with long-term aspirin use, and 0.77 (95% CI 0.57, 1.05) with long-term ibuprofen use.
In these young-old women, current, long-term NSAID users, especially of nonaspirin agents, showed reduced odds of low cognitive function and possibly lower rates of substantial cognitive decline over 2 years. Continued follow-up will help determine if associations differ at older ages.
In the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, alpha-tocopherol supplementation decreased prostate cancer incidence, whereas beta-carotene increased the risk of lung cancer and total mortality. Postintervention follow-up provides information regarding duration of the intervention effects and may reveal potential late effects of these antioxidants.
To analyze postintervention effects of alpha-tocopherol and beta-carotene on cancer incidence and total and cause-specific mortality.
Postintervention follow-up assessment of cancer incidence and cause-specific mortality (6 years [May 1, 1993-April 30, 1999]) and total mortality (8 years [May 1, 1993-April 30, 2001]) of 25 563 men. In the ATBC Study, 29 133 male smokers aged 50 to 69 years received alpha-tocopherol (50 mg), beta-carotene (20 mg), both agents, or placebo daily for 5 to 8 years. End point information was obtained from the Finnish Cancer Registry and the Register of Causes of Death. Cancer cases were confirmed through medical record review.
Site-specific cancer incidence and total and cause-specific mortality and calendar time-specific risk for lung cancer incidence and total mortality.
Overall posttrial relative risk (RR) for lung cancer incidence (n = 1037) was 1.06 (95% confidence interval [CI], 0.94-1.20) among recipients of beta-carotene compared with nonrecipients. For prostate cancer incidence (n = 672), the RR was 0.88 (95% CI, 0.76-1.03) for participants receiving alpha-tocopherol compared with nonrecipients. No late preventive effects on other cancers were observed for either supplement. There were 7261 individuals who died by April 30, 2001, during the posttrial follow-up period; the RR was 1.01 (95% CI, 0.96-1.05) for alpha-tocopherol recipients vs nonrecipients and 1.07 (95% CI, 1.02-1.12) for beta-carotene recipients vs nonrecipients. Regarding duration of intervention effects and potential late effects, the excess risk for beta-carotene recipients was no longer evident 4 to 6 years after ending the intervention and was primarily due to cardiovascular diseases.
The beneficial and adverse effects of supplemental alpha-tocopherol and beta-carotene disappeared during postintervention follow-up. The preventive effects of alpha-tocopherol on prostate cancer require confirmation in other trials. Smokers should avoid beta-carotene supplementation.
To investigate the relationship between metabolic markers of cobalamin deficiency and cognitive function in normal older adults.
Cross-sectional study.
Queen's University and St. Mary's of the Lake Hospital, Kingston, Ontario, Canada.
Two hundred eighty-one cognitively normal, community-dwelling participants aged 65 and older.
Serum cobalamin, red blood cell folate, methylcitric acid, homocysteine, and methylmalonic acid were determined. Cognitive instruments included the California Verbal Learning Test, Mattis Dementia Rating Scale, and the Stroop Neuropsychological Screening Inventory (Stroop).
Serum levels of methylcitric acid had a significant negative correlation with recall, learning, and discriminability (factor 1) of the California Verbal Learning Test after adjusting for age and sex (beta=-0.138, P=.019). Subjects with elevated methylcitric acid had significantly lower scores (factor 1) than subjects with normal methylcitric acid (P<.01). Bivariate analysis showed significant correlations between levels of homocysteine and the Stroop score and between cobalamin, methylmalonic acid, and homocysteine and some scores of the California Verbal Learning Test, but these relationships did not remain significant after multivariate analysis. Subjects with high homocysteine (tHcy) had lower Stroop scores than subjects with normal tHcy (P<.05). No biochemical parameters were associated with the Mattis Dementia Rating Scale scores.
This study indicates that, in normal elderly subjects, some cognitive scores are related to serum methylcitric acid and possibly homocysteine.
Participants in the Age-Related Eye Disease Study were randomly assigned to receive daily antioxidants (vitamin C, 500 mg; vitamin E, 400 IU; beta carotene, 15 mg), zinc and copper (zinc, 80 mg; cupric oxide, 2 mg), antioxidants plus zinc and copper, or placebo. A cognitive battery was administered to 2,166 elderly persons after a median of 6.9 years of treatment. Treatment groups did not differ on any of the six cognitive tests (p > 0.05 for all). These results do not support a beneficial or harmful effect of antioxidants or zinc and copper on cognition in older adults.
Antioxidants prevent oxidative stress that possibly causes neuronal loss in Alzheimer's disease (AD). We examined whether high plasma levels of the antioxidant vitamins A and E were associated with lower prevalence of AD or cognitive decline (CD). We performed a cross-sectional study within the Rotterdam Study. In an univariate model, higher levels of vitamins A and E were significantly associated with lower prevalence of AD. However, when additional adjustments were made for important confounders, such as age, gender and total cholesterol, the relation substantially weakened -- odds ratios per standard deviation increase were 0.87 (95% CI 0.64-1.19) for vitamin A and 0.94 (95% CI 0.60-1.48) for vitamin E. Antioxidants were not related to CD in non-demented subjects. Our findings suggest no association between plasma levels of vitamin A and E and AD or CD.
Elevated plasma total homocysteine concentration may be a risk factor for cognitive decline and Alzheimer disease, but data from prospective studies are limited. Further, high homocysteine levels are associated with low vitamin status, and it is unknown whether it is homocysteine toxicity or vitamin insufficiency that is responsible for the observed cognitive dysfunction.
We performed cross-sectional and longitudinal analyses of a cohort of 499 high-functioning community-dwelling persons aged 70 to 79 years to determine the effect of homocysteine and related vitamin plasma concentrations on cognitive function and cognitive decline. Nonfasting plasma concentrations of homocysteine, folate, vitamin B(6), and vitamin B(12) were measured at baseline. Summary measures of cognitive function were created from tests of multiple cognitive domains administered at baseline and again after 7 years.
In cross-sectional analyses investigating each variable separately, subjects with elevated homocysteine levels, or low levels of folate or vitamin B(6), demonstrated worse baseline cognitive function. In longitudinal analyses, after adjusting for multiple covariates, including homocysteine, those in the bottom quartile of folate had a 1.6-fold increased risk (95% confidence interval: 1.01 to 2.31; P =0.04) of being in the worst quartile of 7-year cognitive decline. Low folate levels largely accounted for a trend towards greater cognitive decline with elevated homocysteine level.
In high-functioning older adults, low folate levels appear to be a risk factor for cognitive decline. The risk of developing cognitive decline might be reduced through dietary folate intake.
Prior investigations have reported a link between poor status of antioxidants, folate, and cobalamin resulting in elevated total plasma homocysteine (tHcy) and methylmalonic acid (MMA) concentrations with an increased risk for reduced cognitive performance. The aim of the study was to evaluate the effect of a 6-month multivitamin supplementation on the cognitive performance of female seniors and to assess cognitive functioning in relation to vitamin status, tHcy, and MMA values at baseline.
The study was performed as a randomized placebo-controlled double-blind trial. 220 healthy, free-living women (aged 60-91 years) were included. Blood drawings and cognitive tests were performed at the Institute of Food Science of the University of Hanover, Germany. Vitamin and cognitive status have been evaluated prior to and 6 months after supplementation. Plasma ascorbic acid, serum concentrations of alpha-tocopherol, beta-carotene, and coenzyme Q10, serum and erythrocyte folate as well as serum cobalamin, serum MMA, and plasma tHcy concentrations were measured. Activity coefficient of erythrocyte alpha aspartic aminotransferase was used as functional index for vitamin B(6) status. The cognitive performance was assessed by the Symbol Search test, a subtest of the Wechsler Adult Intelligence Scale (WAIS-III) and the pattern-recognition test. Intelligence as assessed by the 'Kurztest für Allgemeine Intelligenz' (KAI) was a further variable.
No significant differences in pattern-recognition and intelligence score were observed between vitamin and placebo group prior to and after multivitamin supplementation. In the Symbol Search test, the vitamin group exhibited better test results than the placebo group at both measure points. One-way ANOVA showed a marginally significant linear trend between the baseline tHcy concentration and the pattern-recognition score (P = 0.051) in the total sample. Multiple backward regression revealed only a significant influence of the school graduation on baseline cognitive function test results. A general linear model showed that the changes in cognitive function scores could not be explained by the type of treatment or blood parameters.
Our data indicate that 6 months supplementation of physiological dosages of antioxidants and B vitamins have no effect on cognitive performance in presumedly healthy and well-nourished female seniors. An intervention period of only 6 months may be too short for improving cognitive performance in well-educated elderly women without dementia.