Nutrition and Brain Aging: How Can We Move Ahead&Quest;

REVIEW Nutrition and brain aging: how can we move ahead?

P Barberger-Gateau1,2

Epidemiological studies and basic research suggest a protective effect of long-chain omega-3 polyunsaturated fatty acids, antioxidants and B vitamins against brain aging. However, most randomized controlled trial (RCTs) with nutritional supplements have yielded disappointing effects on cognition so far. This paper suggests some original directions for future research to better support a role of nutrition in brain aging. The role of other nutrients such as docosapentaenoic acid and fat-soluble vitamins D and K should be investigated. A more holistic approach of nutrition is necessary, encompassing potential synergies between nutrients as found in a balanced diet. Potential beneﬁciaries of a nutritional supplementation should be better targeted, according to their dietary, cognitive and maybe genetic characteristics. Innovative RCTs should be implemented to assess the impact of nutrition for the prevention or treatment of cognitive decline in older persons, using intermediate biomarkers of disease progression and mechanisms of action of nutrients as outcomes.

European Journal of Clinical Nutrition (2014) 68, 1245–1249; doi:10.1038/ejcn.2014.177; published online 27 August 2014

INTRODUCTION However, previous studies have neglected some fatty acids or In accordance with the results of basic research, epidemiological fat-soluble vitamins that could have an important role in the brain. studies suggest a protective effect of several classes of nutrients against cognitive decline and risk of dementia,1,2 including Docosapentaenoic acid (DPA) principally long-chain omega-3 polyunsaturated fatty acids (n-3 Actually, the term DPA refers to two different fatty acids: one in PUFA),3,4 vitamins C and E,5 carotenoids,6 polyphenols7 and B 8 the omega3 series C22:5n-3, situated between eicosapentaenoic vitamins, although some discordant data exist as well. Many acid (EPA) and docosahexaenoic acid (DHA) in the desaturation underlying mechanisms can be evoked to support biological and elongation chain of alpha-linolenic acid, and another one in plausibility of a protective effect of these nutrients against brain 9 the omega6 series C22:5n-6 resulting from elongation, desatura- aging: role in brain composition and function, hippocampal tion and beta-oxidation of arachidonic acid. As EPA and DHA, n-3 10 neurogenesis, limitation of accumulation of the beta-amyloid DPA is mainly found in fatty fish and could contribute to the 11,12 13 peptide, decreased oxidative stress and inflammation, apparently protective effect of fish consumption against cognitive 8 14 decreased homocysteine concentration and vascular effects. decline. The metabolism and biological functions of DPA are still However, most well-conducted randomized controlled trials poorly understood. Supplementation with pure n-3 DPA induced a (RCTs) with nutritional supplements have yielded disappointing significant rise in the proportions of EPA and DHA in plasma 15 effects on cognition so far (for reviews, see Wald et al., triacylglycerides, suggesting that DPA may act as a reservoir of the 16 17 Mazereeuw et al. and Dangour et al. ). As written by Dangour major long-chain n-3 PUFA in humans.18 In healthy humans under 17 et al. regarding n-3 PUFA but easily transferable to other their spontaneous diet, n-3 DPA is found in non-negligible nutrients, whether discrepancies between epidemiological and amounts in cerebrospinal fluid (CSF) and positively correlated intervention studies ‘reflect a real absence of benefit on cognitive with total plasma n-3 PUFA.19 function from (nutritional) supplementation, or whether they N-6 DPA in erythrocytes was higher in 48 older individuals with reflect intrinsic limitations in the design of published studies mild cognitive impairment (MCI) than in 27 healthy controls in a remains open to question’. The aim of this paper was to suggest cross-sectional analysis carried at baseline of an RCT.20 Higher n-6 new areas of research to better support a role of nutrition in brain DPA also correlated with poorer mental health and less aging. Two aspects are developed: nutritional exposure, concerning satisfaction with life, while lower n-3 DPA was associated with a the investigation of new nutrients and a more holistic approach of higher frequency of self-reported body pain. Data from this small the diet, and innovative RCTs with nutritional supplements, study with multiple statistical testing should be reproduced in regarding their inclusion criteria and outcomes in relation with larger, longitudinal studies before drawing firm conclusions. In the cognition. Three-City cohort study, plasma n-3 DPA was not associated with risk of incident dementia, and n-6 DPA was not available.21

INVESTIGATING NEW NUTRIENTS Vitamin D There is convincing evidence that fats are a major class of Beyond its role in bone health, the multiple biological functions of nutrients for brain development, structure and functioning.9 vitamin D are raising increasing interest.22 In humans, vitamin D

1ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, Universite de Bordeaux, Bordeaux, France and 2INSERM, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, Bordeaux, France. Correspondence: Dr P Barberger-Gateau, Université de Bordeaux, ISPED, Centre de Recherche INSERM U897, 146 rue Léo Saignat, CS61292, Bordeaux, Cedex 33076, France. E-mail: [email protected] Received 9 July 2014; accepted 6 August 2014; published online 27 August 2014 Nutrition and brain aging: how can we move ahead? P Barberger-Gateau 1246 comes from both synthesis during exposure to sunlight and food potential interaction between these nutrients and the absorption sources, mainly fatty fish as for EPA and DHA. Thus it is difficult to or bioavailability of n-3 PUFA. However, an another RCT, ancillary disentangle their respective effects in observational studies. The study of the SU.FOL.OM3 trial providing B vitamins (including prevalence of vitamin D deficiency is very high in older adults.22 560 μg/d folate), EPA (400 mg/d) and DHA (200 mg/d) in Meta-analyses of case–control studies showed that patients individuals with a history of cardiovascular disease did not with Alzheimer’s disease (AD) had lower serum vitamin D evidence any improvement of cognitive function after 4 years, concentrations than controls,23 with borderline significance after except maybe in some specific subgroups.35 adjusting for age.24 Longitudinal studies are scarce. Participants in fi the InCHIANTI cohort study who were severely vitamin D de cient Healthy diets according to their serum 25-hydroxy-vitamin D levels (o25 nmol/l) In observational studies, several models of healthy diets combin- had a significantly increased risk of cognitive decline over 6 ing multiple classes of nutrients have been found to be associated years.25 However, this association was not reproduced in another with lower cognitive decline and risk of dementia, the most widely longitudinal study.26 Several RCTs assessing the impact of vitamin studied being the Mediterranean diet.2,31 A recent meta-analysis D on cognition, either as primary or a secondary outcome, are in evidenced that higher adherence to a Mediterranean-type diet is progress (clinicaltrials.gov). In the Women’s Health Initiative, associated with a reduced risk of developing MCI and AD.36 supplementation with 400 IU/day of vitamin D, along with However, the construct of ‘Mediterranean diet’ may actually calcium, did not result in decreased risk of dementia or cognitive encompass very different food and nutrient intakes, depending on decline, compared with the placebo group over a mean follow-up the population and geographical area, as most scoring instru- of 8 years.27 If ongoing RCTs yield more positive results with ments developed to assess adherence to this dietary model are higher doses of vitamin D, improvement of cognitive function based on sample-specific medians. would be a beneficial side-effect of systematic vitamin D Very few RCTs have assessed the impact of shifting to a global supplementation in deficient individuals. healthier diet on cognition. In the PREDIMED-NAVARRA study, participants at high vascular risk randomized to receive intensive Vitamin K advice to adopt a Mediterranean diet enriched with virgin olive oil A growing body of evidence supports a role for vitamin K in brain or nuts scored significantly better than the low-fat control group and cognition.28 Several vitamin K-dependent proteins contribute on the Mini Mental Status Examination (MMSE), a global test of to brain function, notably Gas6 which is expressed in the cognitive performance, and the Clock Drawing Test, assessing a hippocampus of adult rat and contributes to survival of neurons wide range of high-level cognitive abilities including executive and microglia. Moreover, vitamin K is involved in sphingolipid functions, after 6½-year follow-up.37 However, cognition was not metabolism.28 Dietary vitamin K is provided by vegetables, whose measured at baseline, and the impact of the diets on cognitive consumption is inversely associated with cognitive decline and decline could thus not be assessed. The Exercise and Nutritional risk of dementia.29 Data on the relationship between vitamin K Interventions for Cardiovascular Health RCT was designed to status and cognition in humans are lacking. A single cross- examine the effects of the Dietary Approach to Stop Hypertension, sectional epidemiological study showed a specific relationship alone or in combination with weight management through between high serum vitamin K (phylloquinone) concentrations physical exercise and calorie restriction, on blood pressure in and better performances in verbal episodic memory in 320 overweight adults with high blood pressure. The Dietary Approach healthy older adults.30 These data need to be confirmed in to Stop Hypertension diet was associated with a significantly longitudinal studies using serum phylloquinone as a biomarker of improved psychomotor speed relative to controls.38 vitamin K status. Supplements with multiple nutrients FROM A SINGLE-NUTRIENT APPROACH TO DIETARY PATTERNS RCTs with supplements containing various combinations of nutrients trying to reproduce healthy diets can be used to provide Most previous epidemiological studies and RCTs have focused on a proof of concept of their global impact on cognition. single nutrients, ignoring their potential synergistic effects when A systematic review of 10 RCTs with multivitamins provided weak they are provided in optimal quantities and proportions as in a evidence of improvement of some cognitive abilities, especially balanced diet. Considering dietary patterns may lead to a more immediate free recall.39 However, the few available studies were holistic approach of the diet.31 Diets rich in fruits, vegetables, very heterogeneous regarding inclusion criteria, multivitamin vegetable oils, legumes, cereals and fish provide folate, vitamins C constituents and cognitive outcomes. More convincingly, the and E, carotenoids, polyphenols and long-chain n-3 PUFA along Souvenir-II placebo-controlled RCT showed that a 24-week with a low glycemic index that contribute to lower inflammation, supplementation with Souvenaid was able to improve memory oxidative stress and homocysteine concentration, improve in drug-naive patients with mild AD, that is, an MMSE score ⩾ 20.40 vascular status and insulin sensitivity and maintain brain structure Souvenaid provides EPA, DHA, B vitamins, antioxidants (vitamins C and functioning.32 Moreover, some combinations of nutrients may and E, selenium), choline and uridine monophosphate, a specific have synergistic effects that will reinforce their individual proper- combination intended to improve synaptic dysfunction in AD. ties. For example, antioxidant nutrients can protect long-chain n-3 These trials need to be replicated in populations with various PUFA from peroxidation to which they are particularly susceptible degrees of cognitive impairment to identify the most responsive because of their multiple double bonds. individuals in whom a supplementation could be recommended. Folate and n-3 PUFA In the Three-City cohort study, we observed that regular fish BETTER TARGETING POTENTIAL BENEFICIARIES OF consumption was not protective against risk of dementia if not NUTRITIONAL INTERVENTIONS accompanied by regular intake of fruits and vegetables.33 RCTs with nutritional supplements have been carried for the Accordingly, a placebo-controlled RCT showed that response to primary or secondary prevention of dementia or for treatment of n-3 PUFA supplementation (2 g EPA and 1 g DHA per day) for patients with mild-to-moderate AD (MMSE range 10–26). Some 6 weeks was enhanced in individuals who reported being high may have failed to show any significant impact on cognition, consumers of dark-green vegetables.34 These vegetables are good either because they have included healthy participants who did dietary sources of folate and lutein, a carotenoid, suggesting a not decline during the few months of the trial41 or, conversely,

European Journal of Clinical Nutrition (2014) 1245 – 1249 © 2014 Macmillan Publishers Limited Nutrition and brain aging: how can we move ahead? P Barberger-Gateau 1247 individuals with AD whose disease was probably too severe to genotype would be unethical, but it will probably emerge in the expect a significant effect from nutrition.42–44 Few studies have future with the perspective of a ‘personalized nutrition’. specifically targeted the MCI stage.45,46 Identifying individuals who are the most susceptible to benefit from a nutritional supplementation is therefore of upmost importance.47 DESIGNING INNOVATIVE INTERVENTION STUDIES Inability of most RCTs with nutritional supplements to show any Cognitive criteria and biomarkers of disease progression effect on cognitive performance may in part lie in lack of sensitivity of the selected outcomes to change over a relatively In its strict definition, primary prevention takes place before the short period. Beside traditional criteria based on cognitive and development of the disease, that is, before any sign of functional decline, biomarkers could contribute to provide neurodegeneration in the case of AD. Healthy diets in early life 48 evidence of an impact of nutrients and shed new light into their could contribute to develop brain reserve. However, the impact mechanisms of action. of interventions targeting this population on late life cognitive performance is obviously impossible to evidence. Thus primary and secondary prevention of dementia cannot be disentangled. Biomarkers of disease progression However, cognitive decline is a relatively late event in the course Few RCTs with nutritional supplements have used brain or CSF of the disease, and it has been estimated that beta-amyloid, the biomarkers of neurodegeneration as outcomes. These biomarkers hallmark of AD, accumulates sharply for about 15 years in the could be more sensitive and capture early changes in the course brain before reaching a plateau when the first clinical signs of the disease that do not translate yet into improved cognitive emerge.49 This 15-year interval would represent a large window performances. In the VITACOG RCT, the rate of brain atrophy over for secondary prevention, especially with nutritional interventions. 24 months measured by magnetic resonance imaging as primary In the absence of specific impairment on most neuropsychological outcome was significantly reduced by 30% by supplementation tests at this stage, biomarkers of disease progression could help to with B vitamins compared with placebo in 168 elderly subjects 45 identify the best window of opportunity for RCTs with nutritional with MCI. Conversely, there was no effect of DHA supplementa- supplements. These biomarkers include brain atrophy as mea- tion on brain volume change over 18 months in the subsample of sured by magnetic resonance imaging, impaired brain glucose 102 participants with AD who had repeated magnetic resonance metabolism and imaging of beta-amyloid accumulation with imaging examination in the Alzheimer’s Disease Cooperative 53 positron emission tomography and measurements of beta- Study RCT. However, that subsample size was probably too small amyloid and phosphorylated tau in CSF.50 However, in our present to achieve sufficient power. state of knowledge these should be considered only as research Forty-nine older adults (20 healthy and 29 with amnestic MCI criteria and not used for screening individuals at high risk of (aMCI)) were randomized to follow a HIGH or LOW diet for 4 46 dementia. weeks. The HIGH diet was high in fat, especially saturated fat, and with a high glycemic index. Conversely, the LOW diet was low in fat, especially saturated fat, and had a low glycemic index. In Nutritional criteria aMCI patients, the LOW diet increased beta42-amyloid concentra- Contrarily to RCTs with drugs, participants in nutritional interventions in CSF but had the opposite effect in healthy adults, tions do not have a null basal level of the nutrient to be evaluated suggesting different mechanisms of action on the accumulation or before any supplementation. There is a large day-to-day (intra- clearance of beta-amyloid depending on the stage of the disease. individual) variability, especially for nutrients brought by foods The apolipoprotein E concentration in CSF was increased by the that are not consumed on a daily basis such as fish, the main LOW diet and decreased by the HIGH diet. These changes in dietary provider of EPA and DHA. In addition, there is a large inter- disease biomarkers were accompanied by improvement in individual variability, depending on dietary habits. Both sources of delayed visual recall assessed by the Brief Visuospatial Memory variability decrease the power of the study by inflating confidence Test with the LOW diet. intervals and may hamper its external validity. Providing individuals who already meet their dietary requirements with Biomarkers of mechanism of action additional quantities of nutrients is probably useless and may even be harmful when upper tolerable intake levels are Many biomarkers of putative mechanisms of action of nutrients surpassed.51 can also be proposed, preferably as secondary outcomes, in RCTs. These include principally measures of inflammation,60 oxidative Inclusion criteria should consider nutritional criteria such as low 44,46 61 52–54 stress assessed by isoprostanes in CSF, homocysteine and intake of EPA or DHA or low blood levels of long-chain n-3 46 4 markers of insulin resistance. PUFA. Global malnutrition assessed on generic tools such as 46 the Mini-Nutritional Assessment could also help targeting In the LOW/HIGH RCT cited above, the CSF insulin concentra- older individuals who could benefit from a nutritional tion increased with the LOW diet in aMCI patients, whereas the supplementation.55 HIGH diet lowered the CSF insulin concentration for healthy adults. As an interpretation of these findings, the authors suggest that restoration of normal insulin concentration and activity in Genetic characteristics central nervous system may have beneficial effects, such as Gene × diet interactions on cognition are still poorly understood. protection against synaptotoxicity of beta-amyloid oligomers. The The epsilon 4 allele of the Apolipoprotein E (APOE4) gene, the peripheral metabolic profile of participants was also changed as main genetic risk factor for AD, is associated with poorer blood the HIGH diet increased and the LOW diet decreased plasma lipids response to supplementation with n-3 PUFA56 or fish intake.57 and insulin concentration in both groups, indicating improved Moreover, some epidemiological studies and RCTs have evidenced insulin sensitivity with the LOW diet. The LOW diet also had a that APOE4 carriers had no benefit of n-3 PUFA supplementation favourable impact on oxidative stress with reduced F2-isoprostane or fish consumption on cognition.58 Other genetic risk factors of concentrations in CSF.46 AD involved in lipid metabolism could also interact with dietary However, some inconsistent results may arise from cognitive n-3 PUFA.59 Further research is needed to better identify these and biomarker outcomes. For instance, most RCTs with B vitamins interactions before considering genetic characteristics as inclusion have shown a non-significant impact on cognition15 despite a criteria in RCTs with nutritional supplements. In the present state strong homocysteine-lowering effect. Paradoxically, supplementa- of knowledge, population screening of individuals based on their tion with a cocktail of antioxidant nutrients was able to decrease

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