Journal of Alzheimer’s Disease 29 (2012) 1–10
Polyphenol-Rich Foods in the Mediterranean
Diet are Associated with Better Cognitive
Cinta Valls-Pedreta,b, Rosa Maria Lamuela-Ravent´osb,c,d, Alexander Medina-Rem´onb,c,d,
Melibea Quintanaa, Dolores Corellab,e, Xavier Pint´od,f , Miguel ´
Ramon Estruchb,h and Emilio Rosa,b,∗a
Lipid Clinic, Endocrinology and Nutrition Service, Institut d’Investigacions Biom`ediques August Pi i Sunyer(IDIBAPS), Hospital Cl´ınic, Barcelona, Spainb
CIBER Fisiopatolog´ıa de la Obesidad y Nutrici´on (CIBERobn), Instituto de Salud Carlos III (ISCIII), SpainNutrition and Food Science Department, XaRTA, INSA, Pharmacy School, University of Barcelona, Barcelona,RETIC RD06/0045, Instituto de Salud Carlos III (ISCIII), SpainDepartment of Preventive Medicine and Public Health, School of Medicine, University of Valencia, Valencia, SpainUnitat de L´ıpids i Risc Vascular, Servei de Medicina Interna, Hospital Universitari de Bellvitge, Barcelona, SpainDepartment of Preventive Medicine and Public Health, School of Medicine, University of Navarra, Pamplona,Department of Internal Medicine, IDIBAPS, Hospital Cl´ınic, Barcelona, Spain
Handling Associate Editor: Vincenza Frisardi
Abstract. Brain oxidative processes play a major role in age-related cognitive decline, thus consumption of antioxidant-rich
foods might help preserve cognition. Our aim was to assess whether consumption of antioxidant-rich foods in the Mediterranean
diet relates to cognitive function in the elderly. In asymptomatic subjects at high cardiovascular risk (n = 447; 52% women;
age 55–80 y) enrolled in the PREDIMED study, a primary prevention dietary-intervention trial, we assessed food intake and
cardiovascular risk profile, determined apolipoprotein E genotype, and used neuropsychological tests to evaluate cognitive
function. We also measured urinary polyphenols as an objective biomarker of intake. Associations between energy-adjusted food
and cognitive scores were assessed by multiple linear regression models adjusted for potential
confounders. Consumption of some foods was independently related to better cognitive function. The specific associations[regression coefficients (95% confidence intervals)] were: total olive oil with immediate verbal memory [0.755 (0.151–1.358)];virgin olive oil and coffee with delayed verbal memory [0.163 (0.010–0.316) and 0.294 (0.055–0.534), respectively]; walnuts with
working memory [1.191 (0.061–2.322)]; and wine with Mini-Mental State Examination scores [0.252 (0.006–0.496)]. Urinary
polyphenols were associated with better scores in immediate verbal memory [1.208 (0.236–2.180)]. Increased consumption of
∗Correspondence to: Emilio Ros, Lipid Clinic, Endocrinology
and Nutrition Service, Hospital Cl´ınic. Villarroel 170, 08036Barcelona, Spain. Tel.: +34 932279383; Fax: +34 934537829;E-mail:
ISSN 1387-2877/12/$27.50 2012 – IOS Press and the authors. All rights reserved
C. Valls-Pedret et al. / Polyphenol-Rich Foods and Cognition in Aging
antioxidant-rich foods in general and of polyphenols in particular is associated with better cognitive performance in elderly
subjects at high cardiovascular risk. The results reinforce the notion that Mediterranean diet components might counteract
Keywords: Aging, coffee, cognition, Mediterranean diet, nutrition, polyphenols, olive oil, walnuts, wine
INTRODUCTION
adherence to a Mediterranean-type diet is associated
with a reduced incidence of coronary heart disease
Increased lifespan in developed countries has
(CHD) [13–15]. Consistently, epidemiological studies
resulted in a greatly raised frequency of diseases
point to a reduction in the incidence of and mortality
related to aging, such as cardiovascular and neurode-
from cardiovascular diseases [13, 15, 16] and cancer,
generative disorders, including Alzheimer’s disease
which results in increased longevity [16]. Importantly,
(AD), the most common type of dementia [1]. AD
as recently reviewed [17], increasing compliance with
is characterized by cognitive deterioration with a
Mediterranean-type diets has also been associated with
progressive impairment of activities of daily living.
slower cognitive decline [18], a reduction in the inci-
Cognitive changes, however, are not particular to
dence of MCI [19], neurodegenerative disorders such
severe neurodegenerative diseases like AD, as the
as Parkinson’s disease [20] and AD [21, 22], and mor-
aging process naturally entails normal age-associated
cognitive decline. The cognitive functions that are most
Oxidative stress and ensuing inflammation are
frequently affected with aging are memory, especially
believed to play major roles in the pathogenesis of
codification, recall, and working memory, and execu-
age-related diseases, including cognitive impairment
tive functions that imply information processing speed,
and AD. They also are ideal targets for nutritional inter-
divided attention, and planning [2].
vention with antioxidants, for which the Mediterranean
Factors recognized to aid in maintaining cognitive
diet is particularly well suited [25]. Therefore, we eval-
performance include years of schooling, professional
uated in a cross-sectional study whether consumption
achievement, social engagement, and physical activ-
of antioxidant-rich foods from the Mediterranean diet
ity [3]. Such factors are encompassed in the concept
was associated with better cognitive performance in a
of cognitive reserve, described as the brain’s capacity
cohort of elderly persons at high risk for CHD living
to compensate for neuropathological damage in brain
in Spain, a Mediterranean country. In addition, since
aging, making clinical symptoms unobtrusive or even
there is evidence that consumption of flavonoids, a
imperceptible [4]. An appealing link hypothesized in
subclass of polyphenols, positively relates to cogni-
recent years is the association between lifestyle habits,
tive function [26], we complemented dietary data with
particularly food patterns, and cognitive reserve [3,
urinary polyphenol excretion, an objective biomarker
5]. Epidemiological studies suggest that foods such
as fruits, vegetables, fish, and wine and nutrients such
as polyunsaturated fatty acids, E and B-vitamins, and
antioxidants might protect from age-related cognitive
decline, mild cognitive impairment (MCI) and AD
Participants and design of the study
cohort of the PREDIMED (PREvenci´on con DIeta
MEDiterr´anea) study, a clinical trial in asymp-
among food constituents, Uncorrected Author Proof
tomatic persons at high cardiovascular risk testing
health [11, 12]. One such pattern is the traditional
the Mediterranean diet for outcomes on cardio-
Mediterranean diet, a reputed model of healthy eat-
ing that is characterized by a high consumption of
ISRCTN35739639). The design of the PREDIMED
foods and nutrients presumed to be healthy for the
study has been described in detail elsewhere [27]. Can-
brain, such as vegetables, fruits, fish, unsaturated
didates were community-dwelling men aged 55–80
fatty acids, and diverse antioxidants, with moderate
years and women aged 60–80 years, without prior car-
intake of alcoholic beverages, mostly wine [13]. Both
diovascular disease but having a prior diagnosis of
prospective and clinical studies report that greater
diabetes or at least three cardiovascular risk factors,
C. Valls-Pedret et al. / Polyphenol-Rich Foods and Cognition in Aging
namely smoking, hypertension, dyslipidemia, over-
[33], severe cognitive impairment, defined by a score
weight (body mass index (BMI) ≥25 kg/m2), and
<25 in the Mini-Mental State Examination (MMSE)
family history of premature cardiovascular disease
[34], illiteracy, or difficulty in expression or compre-
(≥55 years in men and ≥60 years in women). Other
exclusion criteria were any severe chronic illness, alco-
hol or drug abuse, or BMI ≥40 kg/m2. Participants
fulfilling inclusion criteria and not meeting exclu-
sion criteria provided informed consent to a protocol
An experienced neuropsychologist who was blinded
approved by the local review board and underwent
to the subjects’ diet and cardiovascular risk factors
various tests, including venipuncture to obtain fasting
conducted the cognitive examination. The instruments
blood and collection of a spot urine sample.
used were the MMSE to assess global cognitive
Anthropometric and blood pressure measurements
function [34]; the Rey auditory verbal learning test
were performed by standard methods, as previously
(RAVLT) to rate immediate (sum of words recalled
described [27]. Smoking status was categorized into
on the five learning trials) and delayed episodic ver-
never, current or past smoking according to self-
bal memory [35]; the verbal paired associates test, a
reports. Physical activity was assessed with the
subtest of Wechsler Memory Scale (WMS) [36], to
validated Spanish version of the Minnesota question-
evaluate episodic memory performance; the semantic
naire and expressed in minutes at a given metabolic
verbal fluency test [37]; the digit span test of the Wech-
equivalent (MET-min) per day [28]. Dietary data
sler Adult Intelligence Scale (WAIS) [38] to assess
related to self-selected food intake during the previ-
immediate memory (direct digits) and working mem-
ous year were collected during a face-to-face interview
ory (reverse order digits); and the Color Trail Test (part
with a single trained dietitian using a validated 137-
I and II) [39] to measure executive function, including
item food-frequency questionnaire (FFQ) [29] and
attention, visual-motor speed, and cognitive flexibility.
converted to daily intakes. Energy and nutrient intake
were calculated from Spanish food composition tables.
The apolipoprotein E (APOE) genotype was deter-
mined by using the method of Hixson and Vernier
We fitted multiple linear regression models to assess
[30]. High-sensitivity C-reactive protein (CRP) was
independent associations of demographic, clinical, and
measured using an immunoturbidimetric technique.
dietary variables and urinary polyphenol excretion
Total polyphenols in spot urine samples were deter-
with neuropsychological test scores. In the first model,
mined with the Folin-Ciocalteu assay after solid phase
with cognitive test scores as dependent variables, we
extraction, together with the creatinine concentra-
introduced the energy-adjusted intakes of various food
tion, as described [31]. Total polyphenol excretion
groups (cereals, vegetables, fruits, legumes, nuts, meat
was expressed as mg of gallic acid equivalents
and meat products, seafood, olive oil, alcohol, and cof-
(GAE)/g of creatinine. Urinary total polyphenol excre-
fee) as independent variables. In the second model we
tion expressed by 24-h volume is a better biomarker
adjusted for age, gender, education years, BMI, current
of polyphenol dietary intake than expressed by uri-
smoking, physical activity, APOE genotype, diabetes,
nary creatinine normalization. However, when total
hypertension and hyperlipidemia, and the food groups
volume in 24-h is not available, creatinine-corrected
that were significantly associated with test scores in the
urinary total polyphenol excretion may also be a suit-
first model as potential confounders. Because in addi-
tion to questions on intake of total alcohol, olive oil,
and nuts, the FFQ used in the study contains specific
questions on intake of wine, virgin olive oil (VOO),
and walnuts, we constructed additional models where
recruiting centre located at Hospital Cl´ınic (Barcelona,
alcohol, olive oil, and nut consumption were replaced
Catalonia, Spain) were asked to submit to neuropsy-
by wine and other alcoholic beverages, VOO and
chological testing to assess cognitive function. During
common olive oil, and walnuts and other nuts, respec-
the screening visit, participants were asked about edu-
tively. In a further model, we entered as independent
cation years and information about exclusion criteria
variable urinary polyphenol excretion alone, to avoid
specific for this substudy was sought, namely depres-
collinearity with other antioxidant-rich food groups,
sion, as assessed by the Hamilton Depression Rating
with adjustment for the same variables plus total energy
Scale (participants with a score >13 were excluded)
intake. Finally, the logarithmical transformed values
C. Valls-Pedret et al. / Polyphenol-Rich Foods and Cognition in Aging
of urinary polyphenol excretion and serum CRP were
Socio-demographic and anthropometric characteristics, physical
entered in a partial correlation adjusted by gender, age
activity, cardiovascular risk factors and APOE genotype of the study
and BMI. p values <0.05 were considered significant.
SPSS software, version 16.0 (SPSS Inc., Chicago, IL)
Figure 1 shows the flow of participants. By study
design, there was a high prevalence of cardiovascular
risk factors in the 447 participants available for analysis
As shown in Table 2, the self-selected participant’s
dietary habits reasonably conformed to the traditional
Mediterranean food pattern in several aspects, as they
recorded high intakes of cereals, vegetables, fruits, fish,
Antihypertensive medication, n (%)
and olive oil and moderate intakes of legumes, nuts,
and wine. They deviated from the traditional Mediter-
ranean diet, however, because of high intakes of meat
and dairy products. The extreme ranges underscore the
high between-subject variability of energy and food
*Median. †Sum of E4/3 and E4/4 genotypes (E2/4 excluded).
intake and urinary polyphenol excretion.
GAE/g Cr, gallic acid equivalents (GAE)/g of creatinine. Abbre-
viations: MET-min, minutes at a given metabolic equivalent level(units of energy expenditure in physical activity, 1 MET-min
roughly equivalent to 1 Kcal); CVD, cardiovascular disease; APOE,apolipoprotein E.
Various clinical, demographic and dietary variables
were independently associated with the outcomes of
neuropsychological tests by multiple linear regression
Daily intake of energy and food groups of the study population
analyses after adjustment for various confounders. The
fully adjusted associations are shown in Table 3. Older
age, diabetes, and hypertension were associated with
lower MMSE scores, while higher education years and
higher wine intake were associated with better perfor-
mance. In the immediate recall of RAVLT, older age
and cereal intake were associated with lower scores.
Conversely, higher education years, the female gen-
der, and higher intake of total olive oil were associated
with immediate verbal memory. Intake of coffee and
C. Valls-Pedret et al. / Polyphenol-Rich Foods and Cognition in Aging
Independent associations of cognitive test scores with food intake by multiple linear regression
Cognitive test scores are the dependent variables. The independent variables listed are those showing p < 0.05 after regression analyses. *: Standardized regression coefficient. Abbreviations: MMSE, Mini Mental State Examination; RAVLT, Rey Auditory VerbalLearning Test; MET-min, minutes at a given metabolic equivalent level. Variables allowed into the models were gender, age, education,body mass index, smoking, APOE 4 allele, energy expenditure in physical activity, diabetes, hypertension, and hyperlipidemia.
VOO, higher education years, and the female gen-
urinary polyphenol excretion and CRP (r = −0.102,
der were associated with better performance in the
delayed recall of RAVLT, while older age, hyperten-
sion, and intake of cereals and meat were associated
with lower scores. Total olive oil intake was also
DISCUSSION
independently associated with the delayed recall of
RAVLT (regression coefficient 0.36, p = 0.001), but
In this cross-sectional evaluation of dietary habits
only data on VOO is shown in Table 3 because of
and cognitive function in older persons at high car-
the novelty of the finding. The consumption of wal-
diovascular risk living in a Mediterranean country,
nuts was also associated with better working memory,
higher intakes of both total olive oil and the virgin
as assessed by the reverse digit span test of the WAIS
variety of olive oil, coffee, walnuts, and wine were
associated with better memory function and global
Total urinary polyphenol excretion was significantly
cognition. The magnitude of these associations was
variable and they were present in some but not in all
tests of cognitive function, but were independent of
known cognition-related confounders and consump-
tion of other food groups. The findings on VOO
der and higher education years (directly) and age
and walnuts, two foods with high antioxidant capac-
and diabetes (inversely) also related independently
ity [40, 41], are novel. Another novel finding is the
to RALVT scores. Figure 2 shows that there was a
independent association of total urinary polyphenol
dose-relationship between urinary polyphenols and
excretion, an objective biomarker of polyphenol-rich
enhancement of the RAVLT score. Moreover, after
food intake, with human memory function. Taken
adjusting by gender, age, and BMI, we found a
together, these results suggest that antioxidants in
significant albeit weak inverse correlation between
the usual diet might counteract age-related cognitive
the logarithmically transformed values of total
C. Valls-Pedret et al. / Polyphenol-Rich Foods and Cognition in Aging
Independent associations of cognitive test scores with urinary polyphenols excretion by multiple linear regression analysis
Cognitive test scores are the dependent variables. The independent variables listed are those showing P values close to <0.05 after regressionanalyses. *: Standardized regression coefficient. Abbreviations: RAVLT, Rey Auditory Verbal Learning Test; GAE/g Cr, gallic acid equivalents/gof creatinine. Variables allowed in the models were gender, age, education, body mass index, energy intake (Kcal/day), smoking, APOE 4allele, energy expenditure in physical activity, diabetes, hypertension, and hyperlipidemia.
proportions of bioactive micronutrients, such as phy-
tosterols, vitamin E, and phenolic compounds [40].
Because of a lower cost, common olive oil (a mix-
ture of refined oil with a small proportion of VOO) is
widely used in Spain in the kitchen and at the table,
while VOO, which is obtained by cold pressing of the
ripe fruit and is much richer in minor but bioactive com-
ponents, has a more restricted consumption, as shown
in our study group (Table 2). Greater consumption of
VOO in the Mediterranean diet has been associated
with various health benefits [40]. Few epidemiologi-
cal studies have related consumption of MUFA with
cognitive function. MUFA is contained in other foods,
for example beef, besides olive oil. This heterogene-
ity in the dietary sources of MUFA might explain why
some results are inconsistent [42–46]. Recently, in line
with our results, a weak association of total olive oil
intake with a reduced risk of cognitive impairment was
reported in a large French cohort [47].
We found that increasing consumption of walnuts,
but not of other nuts, was associated with better work-
ing memory scores. Interestingly, walnuts are among
the foods with highest antioxidant capacity, by far
surpassing other nuts [48]. They are also the whole
food richest in ␣-linolenic acid, the vegetable n-3 fatty
acid [41]. Consistent evidence from prospective studies
suggests that frequent nut intake relates to lower CHD
rates [49]. This may be due in part to the beneficial
effects of nuts on blood lipids [50] and other dis-
Fig. 2. RAVLT scores across quintiles of urinary polyphenol excre-
ease biomarkers, including oxidation, inflammation,
and endothelial dysfunction [41]. Furthermore, higher
intake of nuts has been related with better cognitive
Olive oil is a major component of the traditional
function and lesser cognitive decline in a prospective
Mediterranean diet. It contains abundant monoun-
study [51]. Our findings, together with those of a recent
saturated fatty acids (MUFA), mostly oleic acid,
experimental study showing that walnut supplementa-
and, depending on the degree of refinement, variable
tion improves both motor and cognitive function in
C. Valls-Pedret et al. / Polyphenol-Rich Foods and Cognition in Aging
aged rats [52], point to the need for further studies on
intake showed relationships in the expected direction
[3, 5], except for those concerning cereal intake and
There is consistent epidemiological evidence that
physical activity. That cereal intake related inversely
moderate consumption of alcohol relates inversely to
to memory function might be due to the fact that
risk of CHD and total mortality [53]. Among alco-
little amounts of whole grains are consumed in
holic beverages, wine possibly provides additional
Spain. Refined grains have a high glycemic index
cardiovascular benefits because it counteracts oxida-
that is associated with insulin resistance, a covariate
tive stress through its high polyphenolic content [54].
of cognitive dysfunction [5]. The inverse association
In our study participants who consumed alcohol were
between physical activity and verbal memory was
mostly moderate wine drinkers, and the daily dose
unexpected and is difficult to explain. Given the cross-
of wine related to a better overall cognitive function
sectional design of our study, it might be explained
in them. These findings concur with the results of
by reverse causation if participants at higher vas-
other studies showing an association of moderate alco-
cular risk, hence more prone to develop impaired
hol consumption with better cognitive performance
cognition, exercised more following advice of their
and a reduced risk of neurodegenerative diseases [55,
Our study has limitations. First, the sample size
Because coffee, a beverage with high antioxidant
is relatively small. Second, given the cross-sectional
content, is commonly consumed in European Mediter-
design of the study, we cannot exclude the possibility
ranean countries, we assessed its association with
of reverse causation or residual confounding. Third, the
cognitive performance. The observed direct associ-
neuropsychological test battery used does not include
ation with verbal memory is consistent with prior
all cognitive functions, although verbal memory, one
evidence on the protective effect of caffeine against
of the first areas to be affected with aging, was well
assessed with RAVLT and WMS associated pairs.
A common characteristic of the foods directly
Finally, our cohort was at a particularly high vascular
related to cognitive performance in our study is their
risk, thus the results may not be generalized to the aver-
richness in polyphenols, highly bioactive molecules
age elderly population. The study also has strengths,
with beneficial effects that go beyond the modula-
such as the wide between-subject variability of food
tion of oxidative stress to improve brain function, at
consumption, a comprehensive evaluation of cardio-
least in experimental models of aging [58]. Indeed,
vascular risk and dietary intake and, in particular, the
urinary polyphenol excretion was independently asso-
use of urinary polyphenols as an objective biomarker
ciated with memory performance with a continuous,
of intake that is not subject to the possibilities of bias
dose-related effect. These findings, heretofore not
described, support the validity of the observed asso-
In conclusion, in the context of the Mediterranean
ciations among antioxidant-rich foods and cognition.
diet, increasing consumption of antioxidant-rich
Antioxidant-rich foods, but not total polyphenol excre-
foods in general and of polyphenols in particular is
tion, have been related to better cognitive performance
associated with better cognitive performance in an
also in other clinical studies [6, 26, 59–61]. Further-
elderly cohort at high cardiovascular risk. The results
more, animals fed antioxidant foods showed improved
reinforce the notion that Mediterranean diet compo-
cellular signaling and neuronal communication that
nents might counteract age-related cognitive decline
translated into better cognitive and motor perfor-
[19, 21–23]. While causality cannot be inferred
from results of a cross-sectional assessment such as
the present one, antioxidant-rich foods are known
for many beneficial properties with no harm, thus
between urinary polyphenols and Uncorrected Author Proof
they can be recommended to the general public to
in our study is an additional argument in favor of
promote better health, including probably better
antioxidant-rich foods. Our results further support the
cognitive function. The prospective examination
general theory of oxidative stress as a major driv-
of the whole cohort of the 6-year PREDIMED
ing force for age-related neurodegenerative processes
regarding the potential of the Mediterranean diet
Other variables independently associated with cog-
to counteract the effects of aging on cognitive decline
nitive function in our study, such as gender, age,
and reduce the incidence of neurodegenerative
education years, diabetes, hypertension, and meat
C. Valls-Pedret et al. / Polyphenol-Rich Foods and Cognition in AgingACKNOWLEDGMENTS
Gu Y, Nieves JW, Stern Y, Luchsinger JA, Scarmeas N (2010)
Food combination and Alzheimer disease risk. A protective
diet. Arch Neurol 67, 699-706.
We thank the PREDIMED participants for their
Serra-Majem L, Roman B, Estruch R (2006) Scientific
willingness and enthusiasm to collaborate in the
evidence of interventions using the Mediterranean diet: A
study and Emili Corbella for providing expert assis-
systematic review. Nutr Rev 64, S27-S47.
Mente A, de Koning L, Shannon HS, Anand SS (2009) A
tance with statistical analyses. CIBERobn and RETIC
systematic review of the evidence supporting a causal link
RD06/0045 are initiatives of ISCIII, Spain. This
between dietary factors and coronary heart disease. Arch
study was supported by PI07-0954 from ISCIII
Intern Med 169, 659-669.
and GVACOMP2010-181 from Generalitat Valen-
Mart´ınez-Gonz´alez MA, Garc´ıa-L´opez M, Bes-Rastrollo M,
Toledo E, Mart´ınez-Lapiscina EH, Delgado-Rodr´ıguez M,
ciana (Prof Corella); AGL2010-22319-C03-01/02/03
V´azquez Z, Benito S, Beunza JJ (2011) Mediterranean diet
(Drs Lamuela-Ravent´os and Medina-Rem´on); FIS
and the incidence of cardiovascular disease: A Spanish cohort.
PI 07/0473 and AGL2007-66638-C02-01/02 (Dr
Nutr Metab Cardiovasc Dis 21, 237-244.
Estruch); PI070240, PI070312, and PI081943 from
Sofi F, Abbate R, Gensini GF, Casini A (2010) Accruing evi-
dence about benefits of adherence to the Mediterranean diet
ISCIII (Prof Mart´ınez-Gonz´alez).
on health: An updated systematic review and meta-analysis. Am J Clin Nutr 92, 1189-1196.
alz.com/disclosures/view.php?id=1126).
Feart C, Samieri C, Barberger-Gateau P (2010) Mediterranean
diet and cognitive function in older adults. Curr Opin ClinNutr Metab Care 13, 14-18.
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Patterns of STI in HIV affected Dineshkumar D Registrar, Department of Pediatric Dermatology, KK Child's Trust Hospital, Chennai, Tamil Nadu, India Address for correspondence: [email protected] Introduction Sexually Transmitted Diseases (STD), includes diseases that are transmitted by the sexual route. Sexually Transmitted Infections (STI), differs from STD in that, STD includ
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