Μάθημα 7 Παράδειγμα Μεταανάλυσης

Mediterranean diet and stroke, cognitive impairment, depression: a
meta-analysis
Theodora Psaltopoulou PhD1 , Theodoros N. Sergentanis MD1, Demosthenes B.
Panagiotakos PhD2, Ioannis N. Sergentanis MD1,3, Rena Kosti PhD1, Nikolaos
Scarmeas MD MSc PhD4,5
Affiliations
1
Department of Hygiene, Epidemiology and Medical Statistics, University of Athens
School of Medicine, Athens, Greece

2
Department of Nutrition and Dietetics, Harokopio University, Athens, Greece
3
Hôpital de Psychiatrie, Hôpitaux Universitaires de Genève, Geneva, Switzerland
4
Department of Neurology, University of Athens Medical School, Athens, Greece
5
Department of Neurology, Columbia University, New York, USA
Running head: Mediterranean diet, stroke, cognition & depression
Word count (excluding abstract, references, tables): 3,471
Corresponding author:
Psaltopoulou Theodora, Internist, Assistant Professor,
Department of Hygiene, Epidemiology and Medical Statistics
School of Medicine, University of Athens
75 M. Asias str, Goudi 11527, Athens, Greece
Phone: +30-210-7462061, e-mail: tpsaltop@med.uoa.gr,
Fax: +30-210-7462079
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as an
‘Accepted Article’, doi: 10.1002/ana.23944
2
Abstract
OBJECTIVE: This meta-analysis aims to quantitatively synthesize all studies that
examine the association between adherence to a Mediterranean diet and risk of stroke,
depression, cognitive impairment and Parkinson’s disease.
METHODS: Potentially eligible publications were those providing effect estimates of
relative risk (RR) for the association between Mediterranean diet and the
aforementioned outcomes. Studies were sought in PubMed up to October 31, 2012.
Maximally adjusted effect estimates were extracted; separate analyses were
performed for high and moderate adherence.
RESULTS: 22 eligible studies were included (11 for stroke, nine for depression and
eight for cognitive impairment; only one pertained to Parkinson’s disease). High
adherence to Mediterranean diet was consistently associated with reduced risk for
stroke (RR=0.71, 95%CI: 0.57-0.89), depression (RR=0.68, 95%CI: 0.54-0.86) and
cognitive impairment (RR=0.60, 95%CI: 0.43-0.83). Moderate adherence was
similarly associated with reduced risk for depression and cognitive impairment,
whereas the protective trend concerning stroke was only marginal. Subgroup analyses
highlighted the protective actions of high adherence in terms of reduced risk for
ischemic stroke, mild cognitive impairment, dementia and particularly Alzheimer’s
disease. Meta-regression analysis indicated that the protective effects of
Mediterranean diet in stroke prevention seemed more sizeable among males.
Concerning depression, the protective effects of high adherence seemed independent
of age, whereas the favorable actions of moderate adherence seemed to fade away
along with older age.

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INTERPRETATION: Adherence to a Mediterranean diet may contribute to the
prevention of a series of brain diseases; this may be of special value given the aging
of Western societies.
4
Introduction
“Active” aging and “healthy” aging are among Western societies’ public
health priorities, with primary prevention playing a critical role. Maintaining
cognitive health in the elderly, as well as avoiding brain vascular diseases and
affective disorders, is a vital part of their well-being; otherwise, a heavy personal,
familial, public health, financial and societal burden emerges.
Prospective studies have provided evidence for a favorable relation of
Mediterranean-type diet with slower cognitive decline, reduced risk of progression
from mild cognitive impairment (MCI) to Alzheimer’s disease (AD), lower risk of
AD and reduced crude mortality in AD patients.1-3 In addition, adherence to a
Mediterranean diet, as well as to Dietary Approaches to Stop Hypertension (DASH)
and other prudent dietary patterns seems to protect from stroke, as food groups such
as fish intake, fruits and vegetables, and moderate alcohol intake characterize this
dietary pattern, too.4 The prevalence of affective disorders, like depression, is
increasing in order age groups and omega-3 intake is a promising factor for non-
pharmacological treatment.5
Mediterranean diet has heterogeneous characteristics among countries residing
in the Mediterranean basin.6 Precise definition including appropriate characterization
of the food items or food groups and reference to its macronutrient composition, as
well as quantitative measurement of its adherence varies between studies,7 but, in
general, it is characterized by high intake of vegetables, fruits, cereals, pulses, nuts
and seed; moderate consumption of dairy products, fish, poultry and eggs, unsaturated
fats, such as olive oil as the primary source of mono-unsaturated fat for cooking and
5
dressing, a low to moderate intake of wine during meals and low intake of red,
processed meats and saturated fats.7,8 Mediterranean diet is characterized as a healthy
dietary pattern among others, characterized by the United Nations as an intangible
cultural heritage of humanity,9 and related to a better overall survival, as well as
cardiovascular and cancer prevention8,10 leading to a reduction of premature mortality
among middle-aged adults.11
The protective role of the Mediterranean diet in the ageing process could be
multidimensional, encompassing antiinflammatory functions,12 protection from
oxidative stress13 and atherothrombosis14 potentially by modulating the expression of
pro-atherogenic genes.15 Favorable results in cardiovascular risk factors have also
been observed, such as reduction in total and LDL cholesterol as well as increase in
HDL cholesterol levels,16 lower blood pressure,17 protective association with
metabolic syndrome,18 possibly with diabetes mellitus19 and obesity.20 Among a
multitude of suggested mechanisms, alterations in biochemical mediators’ levels such
as homocysteine,21 adiponectin22 and improvement in endothelial function and
regenerative capacity23 have been named.
Data have accumulated from prospective, case-control and cross-sectional
studies, concerning the relation between adherence to Mediterranean diet and risk of
stroke, cognitive impairment, depression and Parkinson’s disease in the adult
population. Several years after the last quantitative synthesis,10 where only four
papers were available in the field, the current number exceeds 20 published studies.
The scope of the present meta-analysis is to quantitatively synthesize relevant
literature, taking into account that different Mediterranean diet indices have been used
and that these studies have been undertaken in countries where Mediterranean diet is
the traditional food pattern, as well as in countries away from the Mediterranean Sea.
6
The number of the studies available will enable more sub-analyses, in an effort to
answer critical questions, such as if the results are generalizable in non-Mediterranean
countries, or, irrespective of the Mediterranean diet scale used, and what is the extent
of the outcomes if a moderate or a high adherence to Mediterranean diet is followed.
Materials and Methods
Search strategy and eligibility of studies
This meta-analysis was performed in accordance with the Meta-analysis Of
Observational Studies in Epidemiology (MOOSE) guidelines.24 Eligible studies were
sought in PubMed without any restriction of publication language; end-of-search date
was October 31, 2012. The details about search algorithm, eligibility criteria and data
extraction are provided in the online-only Supplemental Methods.
Statistical analyses, study quality, risk of bias and meta-regression analyses
Given that adherence to Mediterranean diet was quantified by means of a
variety of scores, a conceptual framework had to be constructed regarding the
definitions of the terms “low”, “medium” and “high” adherence. To this direction, the
framework was principally based on the seminal work by Trichopoulou et al.,
according to whom a scale 0-9 represents the whole continuum of adherence, with
“low”, “medium” and “high” adherence levels corresponding to values between 0-3,
4-5 and 6-9.8 In light of this, the various scores were proportionally converted to the
0-9 range and the midpoint of each exposure category was qualified as “low” when it
fell within the 0-3 region, “medium” within the 4-5 range (i.e., 3.5 to 5.4 prior to
numerical rounding) and “high” the “6-9” region (i.e., 5.5 to 9 prior to numerical
rounding), respectively. For instance, the fairly frequent “0-29”, “30-33” and “34-55”
7
categories of the 0-55 score by Panagiotakos et al.25 represented low, medium and
high adherence, as their midpoints were equal to 2.37, 5.15 and 7.28 at the 0-9 scale,
respectively. The conversion was deemed necessary, so as to maximize the statistical
power of the quantitative synthesis; nevertheless, subanalyses by the type of score
were always performed, so that the reproducibility of the findings among the various
questionnaires could be examined.
Statistical analyses included pooling of studies at two separate levels (high vs.
low adherence; moderate vs. low adherence). Random-effects (DerSimonian-Laird)
models were appropriately used to calculate pooled effect estimates. Between-study
heterogeneity was assessed through Cochran Q statistic and by estimating I2.26 Details
about subgroup analyses, assessment of study quality, evaluation of publication bias,
alternative analyses and meta-regression analysis are provided in the online-only
Supplemental Methods. Statistical analysis was performed using STATA version 11.1
(Stata Corp, College Station, TX, USA).
Results
Description of eligible studies
Supplemental Figure 1 presents the flow chart describing the subsequent steps
of the selection of eligible studies. The details regarding the selection of studies are
presented in the online-only Supplemental Results. 22 eligible studies were finally
included in this meta-analysis1,27-47; 11 of them pertained to stroke (nine cohorts
including 162,092 subjects among whom 3,176 cases of stroke were noted; two case-
control studies with 297 cases and 296 controls)30,31,36-38,40,41,43,44,46,47, nine examined
depression (eight cohorts including 16,719 subjects among whom 2,092 cases of
depression were noted; one case-control study with 111 cases and 345
8
controls),28,29,32,34,38,39,42,45,46 and eight evaluated cognitive impairment (seven cohorts
including 8,291 subjects among whom 1,278 cases of cognitive impairment were
nnote; one case-control study with 194 cases and 1790 controls).1,27,28,30,33-35,44 The
characteristics of the included studies are presented in Supplemental Table 1. Contact
with the authors of the individual studies was particularly valuable, as seven authors
provided us with additional data on depression28,29,34,38,39,42,45, two on cognitive
impairment28,34 and one on stroke.40 The evaluation of the quality of included studies
is presented in Supplemental Tables 2 and 3.
Meta-analysis: high adherence to Mediterranean diet
Table 1 illustrates the results of the meta-analysis regarding high adherence to
Mediterranean diet. At the overall analysis, high adherence was consistently
associated with reduced risk for stroke (pooled effect estimate= 0.71, 95%CI: 0.57-
0.89, Figure 1), depression (pooled effect estimate= 0.68, 95%CI: 0.54-0.86, Figure 2)
and cognitive impairment (pooled effect estimate= 0.60, 95%CI: 0.43-0.83, Figure 3).
Regarding stroke, the protective effect was reproducible among case-control and
longitudinal cohort studies; a similar pattern was noted regarding cognitive
impairment. The protective effect of high adherence in terms of depression risk was
replicated upon the subsets of case-control, longitudinal cohort and cross-sectional
studies, as well as by region of origin and published/unpublished status. Supplemental
Figures 2-10 present the forest plots underlying the associations summarized in Table
1; specifically, Supplemental Figures 2-4 display the results on stroke, Supplemental
Figures 5-7 and 8-10 pertain to depression and cognitive impairment, respectively.
No significant publication bias was detected at any analysis on high adherence;
(p=0.112 regarding stroke, p=0.434 for depression and p=0.229 for cognitive
9
impairment). Finally, the alternative analysis adopting the earlier “wave 1” (instead of
“wave 2”) of the study by Luciano et al.45 for depression did not result in substantial
modification of results (pooled effect estimate=0.68, 95%CI: 0.54-0.86 i.e., exactly
equal to the main analysis).
Meta-analysis: moderate adherence to Mediterranean diet
Table 2 presents the results about moderate adherence to Mediterranean diet.
Similarly to the associations on high adherence, the protective effects regarding
depression (pooled effect estimate= 0.77, 95%CI: 0.62-0.95) and cognitive
impairment (pooled effect estimate= 0.79, 95%CI: 0.67-0.94) emerged again. On the
other hand, the protective trend concerning stroke was only marginal (pooled effect
estimate= 0.90, 95%CI: 0.81-1.00). Regarding depression as well as cognitive
impairment, the protective effects were reproducible in the subanalyses containing the
larger number of studies, as analyses on smaller subgroups tended to be hampered by
lower power.
Supplemental Figures 2-13 present the forest plots underlying the associations
summarized in Table 2; specifically, Supplemental Figures 2-4 and 11 portray the
results on stroke, Supplemental Figures 5-7, 12 and 8-10, 13 the results on depression,
and cognitive impairment, respectively.
Significant publication bias was noted regarding stroke (p=0.024); on the other
hand, no significant publication bias was detected with respect to depression
(p=0.576), and cognitive impairment (p=0.957). The alternative analysis adopting the
earlier “wave 1” (instead of “wave 2”) of the study by Luciano et al.45 was not
necessitated, as the study provided exclusively data pertaining to high adherence.

10
Subcategories of outcomes
The analyses regarding subcategories of stroke (ischemic; hemorrhagic; fatal;
non-fatal) and cognitive impairment (mild and advanced) are presented in
Supplemental Results (Supplemental Tables 4-6 and Supplemental Figures 14-28).
Meta-regression analysis
Table 3 presents the results of meta-regression analyses. The protective effects
mediated by high adherence to Mediterranean diet in terms of risk for stroke seemed
more pronounced among males (exponentiated coefficient=0.84, 95%CI: 0.74-0.94,
Supplemental Figure 29a). Similarly, the potentially protective effects mediated by
moderate adherence in terms of stroke risk (exponentiated coefficient=0.94, 95%CI:
0.88-0.99, Supplemental Figure 29b) seemed to follow the same pattern.
The protective association between moderate adherence and depression seemed
to fade away along with older age (exponentiated coefficient=1.13, 95%CI: 1.01-1.26,
Supplemental Figure 30); such a modifying effect was not observed regarding the
effects mediated by high adherence.
Supplemental Table 7 presents the results of the post hoc meta-regression
analysis examining effect modification by study quality measures and study
characteristics; no major effects were revealed, except for two cases. First, regarding
high adherence to Mediterranean diet and cognitive impairment, multivariate
adjustment was associated with attenuation of the protective association. Second,
regarding moderate adherence and depression, longitudinal cohort studies seemed to
yield more pronounced protective effects.
Discussion
11
This meta-analysis shows that high adherence to a healthy dietary pattern, such
as Mediterranean diet, seems beneficial along many central nervous system-related
axes, as it was inversely associated with stroke, cognitive impairment and depression.
At a lesser extent, moderate adherence to Mediterranean diet seemed also to confer
protection in terms of depression, as well as cognitive impairment risk, whereas its
protective effects regarding stroke remained only marginal; indeed, the pattern of
results may be indicative of a dose-response relationship. Interestingly, the protective
effects of Mediterranean diet in stroke prevention seemed more sizeable among
males, whereas the favorable actions of moderate adherence concerning depression
seemed to fade away along with older age.
In an effort to describe in detail all relevant information for cognitive
impairment, the distinction between MCI and advanced cognitive impairment (AD,
cognitive impairment ascertained through lower scores in MMSE,48 as well as
dementia clinically diagnosed) was made. Mediterranean diet was found protective
for both subgroups (mild and advanced) and the finding was reproduced upon AD,
which was the predominant condition among studies addressing advanced cognitive
decline. Throughout studies, cognitive assessment was heterogeneous, done either by
neurologists though pre-defined batteries and clinical examination, or through MMSE
questionnaire, although there are inherent limitations regarding the latter, such as
association with age and educational level.49
Adherence to Mediterranean diet was found protective for depression, in any
type of studies (longitudinal cohort, case-control and cross-sectional ones) both in
Mediterranean and non-Mediterranean countries. Depression was assessed with GDS
(geriatric depression score) or with other relevant questionnaires (such as CES-D),
interrelated to an extent. According to meta-regression analysis, it was shown that

12
gender was not a modifier in the relations, whereas age was. Specifically, it seems
that the protective effects of high adherence to Mediterranean diet were independent
of age, whereas moderate adherence might lose its protective properties in older age.
Interestingly, depression is a risk factor for AD;50 thus, the protective role mediated
by Mediterranean diet in terms of both depression and AD, seems to point to the
internal consistency of results.
Concerning stroke, the protective association of high adherence to
Mediterranean diet has been replicated in both longitudinal cohort and case-control
studies, and in non-Mediterranean countries, the latter accounting for the majority of
the sample. According to a recent review, 70% of the stroke could be avoided by
healthy food choices that are consistent with the traditional Mediterranean diet.51
Gender emerged as a modifier in the relation of Mediterranean diet with stroke; our
meta-regression analysis showed that the protective effects seemed more sizeable
among males, regarding both high and moderate adherence. It would be tempting to
hypothesize that males may particularly profit from the antioxidant, anti-
inflammatory, anti-thrombotic and anti-atherogenic properties of Mediterranean diet
against stroke, probably due to smoking and other lifestyle habits. Ischemic stroke had
a statistically significant inverse association with Mediterranean diet; the
accumulation of further studies seems however mandatory for the achievement of
statistical significance in subanalyses pertaining to the type of score used and
Mediterranean region to guarantee the external generalizability of results.
Interestingly, the results of the present meta-analysis seem in accordance with the
recently published, randomized multicenter PREDIMED Study, which showed that
allocation of high cardiovascular risk participants to Mediterranean diet was

13
associated with protection from major cardiovascular events (myocardial infarction,
stroke, or death from cardiovascular causes).52
Regarding the underlying mechanisms, studies demonstrating protective relation
between Mediterranean diet and white matter hyperintensity53 as well as infarcts
detected in brain MRIs40 are suggestive of a vascular protective component of this
diet. On the other hand, it has been highlighted that, regarding AD, other mechanisms,
such as inflammation and oxidation could play a role, with vascular comorbidity
having secondary or no role.54
Recent bibliography has shown that adherents to Mediterranean diet may be
more health conscious,55 more physical active, smoke less or have more favorable
social and lifestyle determinants.56 Notably, in many eligible studies, these
confounders have been taken into account, whereas meta-regression analysis in our
study did not reveal any sizeable modifying effects mediated by them; although this
may be considered an asset of this meta-analysis, residual confounding can still exist.
The analysis through diet scores can capture the extremes of the nutritional exposures
and incorporate possible dietary confounding in the score.57 Two main indices, one
with nine components with the use of sex-specific median as cut-offs and a range
from 0 (minimum adherence) to 9 (maximum one) and another with positive and
negative scoring of the components have been used in most of the articles synthesized
herein. Moreover, all studies used food frequency questionnaires, but the latter
differed across studies, adding to the complexity of analyses; nevertheless, apart from
reviewing single food groups or macro-, micro-nutrients, it is equally important to
systematically review nutritional patterns’ impact, since dietary components are not
eaten in isolation and could exhibit synergistic and antagonistic interactions.58

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The exclusion of studies which have not sent their data is a potential limitation
of this study, despite the rigorous contact with authors, as appropriate.59 Cherbuin et
al.60 and Vercambre et al.46 concluded that Mediterranean diet was not related to
cognitive decline, whereas Tangney and colleagues47 showed that higher
Mediterranean diet scores were associated with slower rates of cognitive decline after
correcting for age, sex, race, education, participation in cognitive activities, and
energy. In addition, Gao and colleagues found that an alternate Mediterranean diet
score was inversely related with the development of Parkinson disease, in a non-
significant way.61 On the other hand, the inclusion of results obtained after the
rigorous contact with authors59 seems to have increased the statistical power
especially regarding depression. Indeed, regarding the latter, seven out of nine study
arms pertaining to high adherence and six out of nine arms pertaining to moderate
adherence were obtained after contact with authors; this may represent an asset of this
meta-analysis, especially given the fact that the effect estimates of the aforementioned
arms did not seem to differ from those published, as attested by the respective
subgroup analyses. On the contrary, concerning stroke and cognitive impairment, the
majority of study arms stemmed from published studies.
Moreover, limitations of the included studies were reflected upon their quality
ratings. In longitudinal cohort studies, median follow-up was often shorter than five
years,30,32,33,35 whereas ascertainment of exposure was sometimes based on self-
report31,32,35,36 rather than structured interview. Cross-sectional studies mainly
suffered from the lack of independent, blind, record linkage-based assessment of the
outcome. The lack of independent validation pertaining to case definition, the lack of
blinding in interviews as well as the suboptimal reporting of non-response rate
differences between cases and controls compromised the quality of the included case-
15
control studies. Of note however, the majority of studies had ensured the
comparability of groups through matching or adjusting for various factors, with
occasional exceptions pertaining to cross-sectional studies which provided only
unadjusted, descriptive data on frequencies. Future studies should thus ideally
encompass a longitudinal cohort design with long enough follow-up periods and
meticulous ascertainment of exposure and outcomes. Moreover, forthcoming studies
might also seem interesting regarding the interaction of Mediterranean diet with
endogenous or exogenous factors, as well as aiming to disentangle underlying
mechanisms of action. Modern brain imaging and cerebrospinal fluid biomarkers can
potentially enlighten us on the association between Mediterranean diet and cerebral
amyloid, tau, α-synuclein, infarcts, connectivity and metabolites; subsequently,
findings from observational epidemiological studies may well be validated by
carefully designed clinical trials adopting both detailed neurological assessments and
biomarker endpoints as main outcomes.
Apart from the limitations of the individual studies, a core limitation regarding
the synthesis of Mediterranean diet scores pertains to the fact that scores do not use
absolute cutoffs but relative cutoffs to identify adherence, so someone could be
differentially classified among studies. Nevertheless, subgroup analyses by type of
score did not point to sizeable differences, underlining the consistency of effect
estimates. Moreover, given the fact that individual studies did not present detailed
dietary behavior characteristics and Mediterranean diet score components, neither a
reclassification based on dietary behavior differences nor detailed analyses by score
components were feasible. Another limitation pertains to the considerable
heterogeneity, especially regarding the analyses on high adherence to Mediterranean
diet. Heterogeneity might be due to differences in study design, variability in scores

16
used, geographical reasons and other factors; in an attempt to trace its origins, detailed
subgroup analyses have been presented for each outcome. The explanation underlying
the fact that heterogeneity seemed more pronounced among high adherence arms
remains elusive, but may at a certain extent be associated with the mere fact that high
adherence originally covers a broader numerical range (six to nine i.e., three units)
than moderate adherence (four to five i.e., two units), in the 0-9 continuum of
adherence, integrating a wider spectrum of dietary behaviors, as per the seminal work
by Trichopoulou et al.8
Strengths of the meta-analysis are the inclusion of all available data in the field,
the exhaustive set of subanalyses and the lack of significant publication bias, as a rule.
Critically comparing our meta-analysis with the approach by Sofi et al.,10 that
synthesized data from four studies regarding collectively neurodegenerative diseases,
a variety of notions may seem worth commenting. First, our meta-analysis made the
distinction between moderate and high adherence to Mediterranean diet, whereas Sofi
et al. adopted the assumption of a uniform trend, presenting the effects of a 2-point
increase in the Mediterranean diet score; as a result, our approach could distinguish
the effects mediated by the two different adherence levels. Second, a variety of
meaningful subgroup analyses and meta-regression analyses have been conducted in
our approach. Moreover, the clear and straightforward description of our statistical
method seems to represent a valuable asset of our approach, allowing the
reproducibility and testing of our algorithm by other research teams. Although
randomized controlled trials are the gold standard, most of them span very short
periods of time,62 and are thus difficult to conduct for longer periods of time. Finally,
taking into account that the association between Mediterranean diet and the brain is a
field on which knowledge is rapidly accumulating, the demonstration of dose-

17
response effects and the achievement of statistical significance by the present
synthesis of studies may represent a reference dipole for future studies.
In conclusion, given the limited availability of pharmaceutical agents to treat
cognitive impairment, cognitive decline and stroke, one could argue for the
importance of preventive measures, such as of a healthy, dietary regime, to diminish
the risk of mild and advanced cognitive decline, AD, depression, as well as stroke.
18
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Health 2009;21:864-880.
30. Feart C, Samieri C, Rondeau V, et al. Adherence to a Mediterranean diet,
cognitive decline, and risk of dementia. JAMA 2009;302:638-648.
31. Fung TT, Rexrode KM, Mantzoros CS, et al. Mediterranean diet and incidence
of and mortality from coronary heart disease and stroke in women. Circulation
2009;119:1093-1100.
32. Sanchez-Villegas A, Delgado-Rodriguez M, Alonso A, et al. Association of
the Mediterranean dietary pattern with the incidence of depression: the Seguimiento
Universidad de Navarra/University of Navarra follow-up (SUN) cohort. Arch Gen
Psychiatry 2009;66:1090-1098.
22
33. Scarmeas N, Stern Y, Mayeux R, et al. Mediterranean diet and mild cognitive
impairment. Arch Neurol 2009;66:216-225.
34. Chrysohoou C, Tsitsinakis G, Siassos G, et al. Fish Consumption Moderates
Depressive Symptomatology in Elderly Men and Women from the IKARIA Study.
Cardiol Res Pract 2010;2011:219578.
35. Roberts RO, Geda YE, Cerhan JR, et al. Vegetables, unsaturated fats,
moderate alcohol intake, and mild cognitive impairment. Dement Geriatr Cogn Disord
2010;29:413-423.
36. Agnoli C, Krogh V, Grioni S, et al. A priori-defined dietary patterns are
associated with reduced risk of stroke in a large Italian cohort. J Nutr 2011;141:1552-
1558.
37. Gardener H, Wright CB, Gu Y, et al. Mediterranean-style diet and risk of
ischemic stroke, myocardial infarction, and vascular death: the Northern Manhattan
Study. Am J Clin Nutr 2011;94:1458-1464.
38. Kastorini CM, Milionis HJ, Ioannidi A, et al. Adherence to the Mediterranean
diet in relation to acute coronary syndrome or stroke nonfatal events: a comparative
analysis of a case/case-control study. Am Heart J 2011;162:717-724.
39. Milaneschi Y, Bandinelli S, Penninx BW, et al. Depressive symptoms and
inflammation increase in a prospective study of older adults: a protective effect of a
healthy (Mediterranean-style) diet. Mol Psychiatry 2011;16:589-590.
40. Scarmeas N, Luchsinger JA, Stern Y, et al. Mediterranean diet and magnetic
resonance imaging-assessed cerebrovascular disease. Ann Neurol 2011;69:257-268.
41. Yau WY, Hankey GJ. Which dietary and lifestyle behaviours may be
important in the aetiology (and prevention) of stroke? J Clin Neurosci 2011;18:76-80.

23
42. Antonogeorgos G, Panagiotakos DB, Pitsavos C, et al. Understanding the role
of depression and anxiety on cardiovascular disease risk, using structural equation
modeling; the mediating effect of the Mediterranean diet and physical activity: the
ATTICA study. Ann Epidemiol 2012;22:630-637.
43. Hoevenaar-Blom MP, Nooyens AC, Kromhout D, et al. Mediterranean style
diet and 12-year incidence of cardiovascular diseases: the EPIC-NL cohort study.
PLoS One 2012;7:e45458.
44. Gardener S, Gu Y, Rainey-Smith SR, et al. Adherence to a Mediterranean diet
and Alzheimer's disease risk in an Australian population. Transl Psychiatry
2012;2:e164.
45. Luciano M, Mottus R, Starr JM, et al. Depressive symptoms and diet: their
effects on prospective inflammation levels in the elderly. Brain Behav Immun
2012;26:717-720.
46. Vercambre MN, Grodstein F, Berr C, et al. Mediterranean diet and cognitive
decline in women with cardiovascular disease or risk factors. J Acad Nutr Diet
2012;112:816-823.
47. Tangney CC, Kwasny MJ, Li H, et al. Adherence to a Mediterranean-type
dietary pattern and cognitive decline in a community population. Am J Clin Nutr
2011;93:601-607.
48. Christa Maree Stephan B, Minett T, Pagett E, et al. Diagnosing Mild
Cognitive Impairment (MCI) in clinical trials: a systematic review. BMJ Open
2013;3.
49. Tombaugh TN, McIntyre NJ. The mini-mental state examination: a
comprehensive review. J Am Geriatr Soc 1992;40:922-935.

24
50. Ownby RL, Crocco E, Acevedo A, et al. Depression and risk for Alzheimer
disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen
Psychiatry 2006;63:530-538.
51. Willett WC. The Mediterranean diet: science and practice. Public Health Nutr
2006;9:105-110.
52. Estruch R, Ros E, Salas-Salvado J, et al. Primary prevention of cardiovascular
disease with a Mediterranean diet. N Engl J Med 2013;368:1279-1290.
53. Gardener H, Scarmeas N, Gu Y, et al. Mediterranean diet and white matter
hyperintensity volume in the Northern Manhattan Study. Arch Neurol 2012;69:251-
256.
54. Gu Y, Scarmeas N. Dietary patterns in Alzheimer's disease and cognitive
aging. Curr Alzheimer Res 2011;8:510-519.
55. Knopman DS. Mediterranean diet and late-life cognitive impairment: a taste of
benefit. JAMA 2009;302:686-687.
56. Chrysohoou C, Panagiotakos DB, Pitsavos C, et al. Adherence to the
Mediterranean diet attenuates inflammation and coagulation process in healthy adults:
The ATTICA Study. J Am Coll Cardiol 2004;44:152-158.
57. Trichopoulou A, Orfanos P, Norat T, et al. Modified Mediterranean diet and
survival: EPIC-elderly prospective cohort study. BMJ 2005;330:991.
58. Sofi F, Cesari F, Abbate R, et al. Adherence to Mediterranean diet and health
status: meta-analysis. BMJ 2008;337:a1344.
59. Mullan RJ, Flynn DN, Carlberg B, et al. Systematic reviewers commonly
contact study authors but do so with limited rigor. J Clin Epidemiol 2009;62:138-142.
25
60. Cherbuin N, Anstey KJ. The Mediterranean diet is not related to cognitive
change in a large prospective investigation: the PATH Through Life study. Am J
Geriatr Psychiatry 2012;20:635-639.
61. Gao X, Chen H, Fung TT, et al. Prospective study of dietary pattern and risk
of Parkinson disease. Am J Clin Nutr 2007;86:1486-1494.
62. McMillan L, Owen L, Kras M, et al. Behavioural effects of a 10-day
Mediterranean diet. Results from a pilot study evaluating mood and cognitive
performance. Appetite 2011;56:143-147.

26
Figure Legends
Figure 1. Forest plot describing the association between high adherence to
Mediterranean diet and risk for stroke. Apart from the overall analysis, the
subanalyses on case-control (upper panels), longitudinal cohort (middle panels) and
cross-sectional studies (lower panels) are presented.
Mediterranean diet and risk for depression. Apart from the overall analysis, the
subanalyses on case-control (upper panels), longitudinal cohort (middle panels) and
Mediterranean diet and risk for cognitive impairment. Apart from the overall analysis,
the subanalyses on case-control (upper panels), longitudinal cohort (middle panels)
and cross-sectional studies (lower panels) are presented.

Page 27 of 93 Annals of Neurology
Forest plot describing the association between high adherence to MdD and risk for stroke. Apart from the
overall analysis, the subanalyses on case-control (upper panels), longitudinal cohort (middle panels) and
185x146mm (72 x 72 DPI)
John Wiley & Sons

Annals of Neurology Page 28 of 93
Figure 2. Forest plot describing the association between high adherence to MdD and risk for depression.
Apart from the overall analysis, the subanalyses on case-control (upper panels), longitudinal cohort (middle
panels) and cross-sectional studies (lower panels) are presented.
198x145mm (72 x 72 DPI)
John Wiley & Sons

Figure 3. Forest plot describing the association between high adherence to MdD and risk for cognitive
impairment. Apart from the overall analysis, the subanalyses on case-control (upper panels), longitudinal
cohort (middle panels) and cross-sectional studies (lower panels) are presented.
195x145mm (72 x 72 DPI)
John Wiley & Sons

1
Table 1. Results of the meta-analyses examining the association between the examined outcomes and high adherence to Mediterranean diet.
Bold cells denote statistically significant associations.
Stroke Depression Cognitive impairment
Effect estimate Heterogeneity Effect estimate Heterogeneity Effect estimate Heterogeneity

n§ n§ n§
(95%CI) I2, p (95%CI) I2, p (95%CI) I2, p
Overall analysis 12 0.71 (0.57-0.89) 69.1%, <0.001 9 0.68 (0.54-0.86) 53.4%, 0.028 9 0.60 (0.43-0.83) 76.4%, <0.001
Case-control studies 2 0.20 (0.10-0.41) 26.5%, 0.243 1 0.21 (0.09-0.48) NC 1 0.31 (0.16-0.59) NC
Longitudinal Cohort 5 0.84 (0.74-0.95) 0.0%, 0.768 1 0.58 (0.44-0.77) NC 4 0.72 (0.58-0.88) 0.0%, 0.407
studies
Cross-sectional studies 5 0.83 (0.66-1.06) 13.2%, 0.330 7 0.80 (0.69-0.93) 0.0%, 0.625 4 0.52 (0.22-1.22) 87.9%, <0.001
Score according to 8 0.85 (0.72-1.00) 0.0%, 0.663 4 0.71 (0.59-0.85) 31.3%, 0.225 8 0.59 (0.42-0.83) 79.3%, <0.001
Trichopoulou et al
Score according to 2 0.43 (0.15-1.18) 91.1%, 0.001 4 0.64 (0.25-1.63) 74.9%, 0.008 1 1.00 (0.11-9.29) NC
Panagiotakos et al
Other scores 2 0.34 (0.05-2.57) 90.0%, 0.002 1 0.46 (0.17-1.24) NC 0 NC NC
Mediterranean 3 0.51 (0.21-1.21) 85.2%, 0.001 7 0.68 (0.50-0.93) 63.3%, 0.012 3 1.01 (0.80-1.28) 0.0%, 0.945
countries
2
Non-Mediterranean 9 0.80 (0.66-0.97) 50.1%, 0.042 2 0.69 (0.51-0.92) 0.0%, 0.402 6 0.49 (0.34-0.70) 70.7%, 0.004
countries
Data drawn from 11 0.69 (0.55-0.88) 71.8%, <0.001 2 0.64 (0.52-0.78) 0.0%, 0.328 7 0.54 (0.38-0.77) 72.5%, 0.001
manuscripts†
Data from re-analyses 1 0.87 (0.47-1.60) NC 7 0.68 (0.48-0.98) 56.8%, 0.031 2 1.00 (0.77-1.28) 0.0%, 0.997
provided after contact
with corresponding
authors
§
number of study arms; †includes also effect estimates calculated by means of published 2x2 tables.; NC: not calculable
3
Table 2. Results of the meta-analyses examining the association between the examined outcomes and moderate adherence to Mediterranean diet.
Bold cells denote statistically significant associations.

n§ n§ n§
2 2
(95%CI) I,p (95%CI) I,p (95%CI) I2, p
Overall analysis 12 0.90 (0.81-1.00) 17.4%, 0.273 9 0.77 (0.62-0.95) 54.4%, 0.025 9 0.79 (0.67-0.94) 28.3%, 0.193
Case-control studies 1 0.50 (0.31-0.79) NC 1 0.71 (0.40-1.26) NC 1 0.48 (0.29-0.79) NC
Longitudinal Cohort 6 0.96 (0.87-1.05) 0.0%, 0.836 2 0.57 (0.43-0.77) 50.1%, 0.157 4 0.90 (0.75-1.08) 0.0%, 0.690
studies
Cross-sectional studies 5 0.89 (0.74-1.09) 0.0%, 0.273 6 0.92 (0.78-1.09) 0.0%, 0.587 4 0.73 (0.56-0.97) 16.1%, 0.311
Score according to 8 0.87 (0.74-1.02) 0.0%, 0.824 5 0.73 (0.56-0.94) 70.6%, 0.009 8 0.79 (0.66-0.94) 34.3%, 0.155
Trichopoulou et al
Score according to 2 0.71 (0.37-1.38) 82.9%, 0.016 4 0.90 (0.64-1.27) 0.0%, 0.405 1 1.89 (0.18-19.82) NC
Panagiotakos et al
Other scores 2 0.98 (0.87-1.09) 4.6%, 0.306 0 NC NC 0 NC NC
Mediterranean 3 0.66 (0.42-1.06) 55.3%, 0.107 8 0.71 (0.58-0.88) 36.0%, 0.142 3 1.02 (0.73-1.43) 0.0%, 0.803
4
countries
Non-Mediterranean 9 0.95 (0.87-1.04) 0.0%, 0.775 1 1.00 (0.78-1.28) NC 6 0.74 (0.60-0.91) 39.4%, 0.143
countries
Data drawn from 11 0.91 (0.82-1.01) 16.8%, 0.284 3 0.69 (0.46-1.04) 84.9%, 0.001 7 0.77 (0.63-0.93) 39.2%, 0.130
manuscripts†
Data from re-analyses 1 0.67 (0.38-1.17) NC 6 0.83 (0.67-1.03) 0.0%, 0.666 2 0.98 (0.64-1.49) 0.0%, 0.576
provided after contact
with corresponding
authors
§
number of study arms; †includes also effect estimates calculated by means of published 2x2 tables; NC: not calculable
5
Table 3. Results of the meta-regression analyses examining whether gender and age modified the association between adherence to
Mediterranean diet and the evaluated conditions. Bold cells denote statistically significant modification effects.
Exponentiated Exponentiated Exponentiated

§ § §
n coefficient p n coefficient p n coefficient p
(95%CI) (95%CI) (95%CI)
High adherence
Age (increments of 10 years) 11 0.94 (0.67-1.33) 0.714 8 0.98 (0.71-1.36) 0.899 9 1.09 (0.31-3.83) 0.879
Percentage of males (increments of 10%) 12 0.84 (0.74-0.94) 0.008 8 0.91 (0.72-1.16) 0.388 9 1.00 (0.52-1.93) 0.997
Moderate adherence
Age (increments of 10 years) 10 0.96 (0.81-1.14) 0.576 8 1.13 (1.01-1.26) 0.038 9 1.06 (0.56-1.98) 0.841
Percentage of males (increments of 10%) 12 0.94 (0.89-0.99) 0.043 8 0.92 (0.80-1.07) 0.232 9 0.95 (0.69-1.31) 0.723
§
number of study arms -the numbers are smaller than those in Tables 2 and 3, as some studies did not report the exact mean age and/or percentage of males; NC: not
calculable due to small number of study arms

1
Supplemental Methods
Search algorithm and eligibility of studies
Eligible studies were sought in PubMed; end-of-search date was October 31, 2012.
The following search algorithm was used: (dementia OR Alzheimer OR
"Alzheimer's" OR cognitive OR cognition OR mood OR psychology OR
psychological OR psychiatry OR psychiatric OR mental OR brain OR
cerebrovascular OR stroke OR ischemic OR hemorrhagic OR Parkinson OR
"Parkinson's" OR depression OR neurodegenerative OR neurodegeneration) AND
(Mediterranean AND (diet OR dietary OR nutrition OR nutritional OR food OR
foods)), without any restriction of publication language.
Eligible articles included case-control, cohort and cross-sectional studies
providing directly or indirectly effect estimates for relative risk regarding the
association between adherence to a Mediterranean diet (expressed by means of a
variety of scores) and incidence of the following outcomes: i. stroke, ii. depression,
iii. cognitive impairment (mild or advanced), iv. Parkinson’s disease. The term “cross-
sectional” referred to studies assessing the dietary pattern at a contemporaneous time
point to the outcome in a cohort of subjects, whereas the term “longitudinal” referred
to a prospective study examining the effect of a Mediterranean diet measure which
preceded the occurrence of the outcome. Case-only studies examining the mortality of
the aforementioned conditions were excluded. Moreover, studies on childhood
populations were also excluded. In case of overlapping study populations, only the
larger study was included. Reference lists of reviews and eligible articles were
systematically searched for relevant articles in a “snowball” procedure.
Data extraction and effect estimates

2
The extraction of data comprised first author’s name, study year, journal, study
design (case-control; longitudinal cohort; cross-sectional), follow-up period, study
region, age of participants (range, mean), percentage of males, outcome examined
[stroke (ischemic, hemorrhagic, fatal, non-fatal); depression; cognitive impairment
(mild or advanced); Parkinson’s disease] definitions of adherence to a Mediterranean
diet (score; range of score; components-food groups included), sources of information
for cases and controls (for case-control studies), number of cases and controls (for
case-control studies; diseased and not diseased for cross-sectional studies), matching
factors (for case-control studies), cohort size and incident cases (for cohort studies),
and factors adjusted for in multivariate analyses. If the required data for the meta-
analysis were not readily available in the published article, the corresponding authors
were contacted twice (a reminder e-mail was sent seven days after the first e-mail).
Data were independently extracted and analyzed by two reviewers (TP and TNS) and
final decision was reached by consensus.
The maximally adjusted effect estimates i.e., Odds Ratios (ORs) for case-
control studies or Relative Risks (RRs) / Hazard Ratios (HRs) for cohort studies, with
their Confidence Intervals (CIs) were extracted from each study along the various
categories of adherence. In case the aforementioned information was not available,
crude effect estimates and 95% CIs were calculated by means of 2x2 tables presented
in the articles.
Subgroup analyses
Apart from the subanalyses by type of score that are explained in the main
manuscript, separate analyses were performed on case-control, cohort and cross-
sectional studies, as well as by study region (Mediterranean and non-Mediterranean

3
countries, with the former including Cyprus, France, Greece, Italy and Spain in the
dataset). Moreover, subanalyses on published data and unpublished data provided
after contact with the corresponding authors were performed. Especially regarding
the outcome cognitive impairment, subanalyses on mild and advanced cognitive
impairment were performed. Further subanalyses within the group of advanced
cognitive impairment were conducted, making the distinction between AD, advanced
cognitive impairment detected exclusively by means of the Mini-Mental State
Examination (MMSE) test (MMSE score<24)1 and clinically diagnosed dementia was
performed, so as to explore any heterogeneity due to the definitions of the outcome.
Assessment of study quality and publication bias
Regarding the risk of bias, the quality of the included studies was evaluated
using the Newcastle-Ottawa Quality scale.2 With respect to longitudinal cohort
studies, the item assessing whether the follow-up period was enough for outcomes to
occur, the cut-off value was a priori set at 5 years. Two reviewers (TP and TNS)
working independently rated the studies and final decision was reached by consensus.
Concerning publication bias, the overall analyses (on high as well as moderate
adherence to Mediterranean diet) were chosen to maximize the power of underlying
tests, as appropriate.3 Egger’s statistical test4 was implemented to evaluate the
evidence of publication bias. For the interpretation of Egger’s test, statistical
significance was defined as p<0.1.
Alternative analyses
One study presented alternative analyses, namely Luciano et al.5 presented two
cross-sectional waves, an earlier “wave 1” and a later “wave 2”. For the main
4
analysis, the latest “wave 2” was retained in the main analysis, because it represented
a longer time frame during which Mediterranean diet may have functioned;
longitudinal data were not sought by our team regarding this study, as we aimed to
stay as close to the original publication and study design as possible. Nevertheless, an
alternative analysis was conducted, including the arms that were not pooled in the
main analysis at the place of the main ones, so as to ensure the comprehensiveness of
the analysis. The results of the alternative analysis are additionally and briefly
presented in the relevant section.
Meta-regression analysis
Meta-regression analysis aimed to assess whether gender (expressed as percentage of
males in the individual studies) and age (expressed as the mean age in the individual
studies) modified the association between adherence to Mediterranean diet and the
examined conditions. The meta-regression approach was confined to the overall
analyses, so as to maximize the number eligible study arms.3 Moreover, a post hoc
meta-regression analysis examining effect modification by study quality measures and
study characteristics was also conducted. The exponentiated slope-coefficient exp(b)
is presented throughout the manuscript, so as to provide a more straightforward
interpretation, denoting the multiplicative effects upon the effect estimates.6

5
Supplemental Results
Description of eligible studies
Supplemental Figure 1 presents the flow chart describing the subsequent steps
of the selection of eligible studies. A total of 621 abstracts were identified and
screened; among them 589 were deemed irrelevant. Five articles had to be excluded
due to mutual overlap with other eligible articles; specifically, two articles7,8
overlapped with the eligible article by the Scarmeas et al.9 on AD spanning shorter
follow-up periods than the latter, two articles by Kastorini et al.10,11 overlapped with
the eligible study by the same author12 and one report13 represented the summary of
the published study by Feart et al.14 Despite our efforts to contact the corresponding
authors, reporting reasons were not resolved for two articles15,16 (the articles did not
provide the necessary data for inclusion in this meta-analysis) and had thus to be
excluded. In addition, regarding the study by Tangney et al.,17 only data pertaining to
stroke were included, as reporting reasons pertaining to cognitive impairment and
depression could not be resolved; similarly reporting reasons did not allow the
inclusion of the results by Vercambre et al.18 pertaining to cognitive decline, as once
again effect estimates of relative risk were not available. Two more articles had to be
excluded for various other reasons; in particular, a study by Scarmeas et al.19
presented the association between mortality of diagnosed AD and adherence to
Mediterranean diet, whereas one study20 examined childhood depression.
Of note, only one study21 provided the necessary effect estimates for
Parkinson’s disease; as mentioned above, the authors of another potentially eligible
article15 did not reply to our contact e-mails for the provision of the necessary
6
statistical data. Consequently, the meta-analysis on Parkinson’s disease was not
possible.
As a result, 22 eligible studies were finally included in this meta-analysis5,9,12,14,17,18,22-

37
; 11 of them pertained to stroke12,14,17,18,25,30,31,33,34,36,37, nine5,12,18,23,24,26,28,32,35
examined depression, and eight9,14,22,23,27-29,37 evaluated cognitive impairment.
Subcategories of outcomes
Supplemental Table 4 presents the associations between subcategories of stroke
(ischemic; hemorrhagic; fatal; non-fatal) and adherence to Mediterranean diet.
Despite the rather small number of eligible study arms, the protective effect mediated
by high adherence was replicated upon ischemic stroke (pooled effect estimate= 0.52,
95%CI: 0.28-0.96). Supplemental Figures 14-20 present in detail the forest plots
underlying Supplemental Table 4.
Supplemental Table 5 presents the subanalyses on mild (Supplemental Figure
21) and advanced (Supplemental Figures 22-25) cognitive impairment. High
adherence to Mediterranean diet seemed to confer protection regarding both entities
(pooled effect estimate=0.67, 95%CI: 0.50-0.91 for MCI; pooled effect
estimate=0.57, 95%CI: 0.34-0.98 for advanced disease, respectively). Moderate
adherence was not associated with reduced risk.
Supplemental Table 6 (Supplemental Figures 26-28) presents the further
subanalyses within the subgroup of advanced cognitive impairment. The overall
protective effect mediated by high adherence to Mediterranean diet was reproducible
upon AD, which represented the majority of studies (pooled effect estimate=0.43,
95%CI: 0.25-0.75, Supplemental Figures 26-27).

8
Supplemental references
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Cognitive Impairment (MCI) in clinical trials: a systematic review. BMJ Open
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2. Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS)
for assessing the quality if nonrandomized studies in meta-analyses. Dept of
Epidemiology and Community Medicine, University of Ottawa: Ottawa, Canada.
Available at: (http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm.
Accessed 30.6.2012. . 2011.
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by a simple, graphical test. BMJ 1997;315:629-634.
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metabolic biomarkers, and risk of Alzheimer's disease. J Alzheimers Dis
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9. Scarmeas N, Luchsinger JA, Schupf N, et al. Physical activity, diet, and risk of
Alzheimer disease. JAMA 2009;302:627-637.
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hypercholesterolemic participants: results of a case/case-control study. Angiology
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12. Kastorini CM, Milionis HJ, Ioannidi A, et al. Adherence to the Mediterranean
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14. Feart C, Samieri C, Rondeau V, et al. Adherence to a Mediterranean diet,
cognitive decline, and risk of dementia. JAMA 2009;302:638-648.
15. Gao X, Chen H, Fung TT, et al. Prospective study of dietary pattern and risk
of Parkinson disease. Am J Clin Nutr 2007;86:1486-1494.
16. Cherbuin N, Anstey KJ. The Mediterranean diet is not related to cognitive
change in a large prospective investigation: the PATH Through Life study. Am J
Geriatr Psychiatry 2012;20:635-639.
17. Tangney CC, Kwasny MJ, Li H, et al. Adherence to a Mediterranean-type
dietary pattern and cognitive decline in a community population. Am J Clin Nutr
2011;93:601-607.
9
18. Vercambre MN, Grodstein F, Berr C, et al. Mediterranean diet and cognitive
decline in women with cardiovascular disease or risk factors. J Acad Nutr Diet
2012;112:816-823.
19. Scarmeas N, Luchsinger JA, Mayeux R, et al. Mediterranean diet and
Alzheimer disease mortality. Neurology 2007;69:1084-1093.
20. Gussinyer S, Garcia-Reyna NI, Carrascosa A, et al. [Anthropometric, dietetic
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21. Alcalay RN, Gu Y, Mejia-Santana H, et al. The association between
Mediterranean diet adherence and Parkinson's disease. Mov Disord 2012;27:771-774.
22. Scarmeas N, Stern Y, Mayeux R, et al. Mediterranean diet, Alzheimer disease,
and vascular mediation. Arch Neurol 2006;63:1709-1717.
23. Psaltopoulou T, Kyrozis A, Stathopoulos P, et al. Diet, physical activity and
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24. Bountziouka V, Polychronopoulos E, Zeimbekis A, et al. Long-term fish
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women: the MEDIS (MEDiterranean ISlands Elderly) epidemiological study. J Aging
Health 2009;21:864-880.
25. Fung TT, Rexrode KM, Mantzoros CS, et al. Mediterranean diet and incidence
of and mortality from coronary heart disease and stroke in women. Circulation
2009;119:1093-1100.
26. Sanchez-Villegas A, Delgado-Rodriguez M, Alonso A, et al. Association of
the Mediterranean dietary pattern with the incidence of depression: the Seguimiento
Universidad de Navarra/University of Navarra follow-up (SUN) cohort. Arch Gen
Psychiatry 2009;66:1090-1098.
27. Scarmeas N, Stern Y, Mayeux R, et al. Mediterranean diet and mild cognitive
impairment. Arch Neurol 2009;66:216-225.
28. Chrysohoou C, Tsitsinakis G, Siassos G, et al. Fish Consumption Moderates
Depressive Symptomatology in Elderly Men and Women from the IKARIA Study.
Cardiol Res Pract 2010;2011:219578.
29. Roberts RO, Geda YE, Cerhan JR, et al. Vegetables, unsaturated fats,
moderate alcohol intake, and mild cognitive impairment. Dement Geriatr Cogn Disord
2010;29:413-423.
30. Agnoli C, Krogh V, Grioni S, et al. A priori-defined dietary patterns are
associated with reduced risk of stroke in a large Italian cohort. J Nutr 2011;141:1552-
1558.
31. Gardener H, Wright CB, Gu Y, et al. Mediterranean-style diet and risk of
ischemic stroke, myocardial infarction, and vascular death: the Northern Manhattan
Study. Am J Clin Nutr 2011;94:1458-1464.
32. Milaneschi Y, Bandinelli S, Penninx BW, et al. Depressive symptoms and
inflammation increase in a prospective study of older adults: a protective effect of a
healthy (Mediterranean-style) diet. Mol Psychiatry 2011;16:589-590.
33. Scarmeas N, Luchsinger JA, Stern Y, et al. Mediterranean diet and magnetic
resonance imaging-assessed cerebrovascular disease. Ann Neurol 2011;69:257-268.
34. Yau WY, Hankey GJ. Which dietary and lifestyle behaviours may be
important in the aetiology (and prevention) of stroke? J Clin Neurosci 2011;18:76-80.
35. Antonogeorgos G, Panagiotakos DB, Pitsavos C, et al. Understanding the role
of depression and anxiety on cardiovascular disease risk, using structural equation
10
modeling; the mediating effect of the Mediterranean diet and physical activity: the
ATTICA study. Ann Epidemiol 2012;22:630-637.
36. Hoevenaar-Blom MP, Nooyens AC, Kromhout D, et al. Mediterranean style
diet and 12-year incidence of cardiovascular diseases: the EPIC-NL cohort study.
PLoS One 2012;7:e45458.
37. Gardener S, Gu Y, Rainey-Smith SR, et al. Adherence to a Mediterranean diet
and Alzheimer's disease risk in an Australian population. Transl Psychiatry
2012;2:e164.
10
Supplemental Table 1. Characteristics of the eligible studies.
Number of cases; Follow-

number of up Percentage of Mean age
Study (year) Outcome Design controls Cohort size Cases in cohort (years) Study period Region males (%) (years) Age range (years)
Scarmeas et al. (2006)22 CI (Alzheimer) case-control 194; 1790 NA NA NA 1992-NR Northern Manhattan, New 31.8 76.3 NR
York, USA
Psaltopoulou et al. CI (MMSE); Depression cross-sectional NA 732 Dementia: 173; NA 1993-2006 Attica, Greece 35.1 67.9 60-86
(2008)23 evaluation of a cohort Depression: 270
Bountziouka et al. Depression cross-sectional NA 1190 (data for 407 NA 2005-2007 Cyprus; Mitilini, 33.4 75.1 65+
(2009)24 evaluation of a cohort 595) Samothraki, Cephalonia,
Crete, Corfu, Limnos and
Zakynthos islands, Greece
Feart et al. (2009)14 Cross-sectional: Stroke; cross-sectional & NA 1410 Alzheimer:66 4.1 1999-2007 Bordeaux, Dijon, 37.4 75.9 65+
Longitudinal: CI(Alzheimer, longitudinal cohort (full data on 50); Montpellier, France
Dementia) Dementia: 99
(full data on 74);
Stroke: 24
Fung et al. (2009)25 Stroke cohort NA 74886 1763 20 1984-2004 11 US States 0.0 NR 30-55 (at entry)
Sanchez-Villegas et al. Depression cohort NA 10094 480 4.4 1999-NR Spain 41.6 37.2 NR
(2009)26
Scarmeas et al. MCI cohort NA 1393 275 4.5 1992-NR New York, USA 32.1 76.7 65-103
(2009a)27
Scarmeas et al. (2009b)9 CI (Alzheimer) cohort NA 1880 282 5.4 1992-2006 New York, USA 31.2 77.2 65-103
Chrysohoou et al. (2010) CI (MMSE); Depression cross-sectional NA 673 (data for 269) Dementia: 39; ΝΑ June 2009 - Ikaria island, Greece 49.0 75.4 65+
28
Depression: 106 October 2009
Roberts et al. (2010)29 Cross-sectional: MCI; cross-sectional & NA Cross- Cross- 2.2 2004-2006 Olmsted County, Cross-sectional: 80.0 70-89
Longitudinal: CI (MCI and/or longitudinal cohort sectional:1233; sectional:163; Minnesota, USA 52.0;
dementia) Longitudinal: Longitudinal:116 Longitudinal:
1141 52.8
Agnoli et al. (2011)30 Stroke cohort NA 40681 178 7.89 1993-2004 Varese, Turin, Florence, 30.9 49.7 35-74
Ragusa, Naples in Italy
31
Gardener et al. (2011) Stroke cohort NA 2568 171 9 NR Northern Manhattan, New 36.0 68.6 40+
York City, US
Kastorini et al. (2011)12 Stroke, Depression case-control Stroke: 250; 250 NA NA NA 2009-2010 Greece 55.6 75.0 NR
Depression:
111;345
Milaneschi et al. Depression cross-sectional NA 793 167 NA 1998-2004 Tuscany, Italy NR NR 65+
(2011)32 evaluation of a cohort
Scarmeas et al. (2011)33 Stroke cross-sectional NA 575 182 MRI infarct; NA 1992-2004 New York, USA 34.0 80.3 65+
evaluation of a cohort 81 clinical stroke
Tangney et al. (2011)17 Stroke cross-sectional NA 3790 276 NA 1993-NR Chicago, USA 38.3 75.4 65+
evaluation of a cohort
Yau et al. (2011)34 Stroke case-control 47; 46 NA NA NA March 2008 - Perth, Western Australia 72.0 66.5 23-92
September
2008
Antonogeorgos et al. Depression cross-sectional NA 853 245 NA 2001-2002 Athens, Greece 53.1 44.5 18-89
(2012)35
Gardener et al. (2012)37 CI (Alzheimer, MCI); Stroke cross-sectional NA 970 Alzheimer:149; NA NR Australia 42.0 71.7 60+
evaluation of a cohort MCI:98;
Stroke:29
Hoevenaar-Blom et al. Stroke cohort NA 34708 448 11.4 1993-2008 Amsterdam, Maastricht, 25.3 49.4 20-70
(2012)36 Doetinchem, Utrecht in the
Netherlands
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Luciano et al. (2012)5 Depression cross-sectional NA 879 49 (wave 1) ; 41 3 2004-2010 Scotland, UK 50.0 69.5 67.6-71.3
evaluation of a cohort (wave 2)
in two waves
Vercambre et al. (2012) Depression; Stroke cross-sectional NA 2504 Stroke; 206 NA 1995-1996 USA 0.0 72.3 66.1-91.2
18
evaluation of a cohort Depression: 376
CI: cognitive impairment; MCI: Mild cognitive impairment; MMSE: Mini-Mental State Examination; NA: not applicable; NR: not reported
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Supplemental Table 1 -continued. Characteristics of eligible studies.
Definitions of
categories in
Study Subcategories Mediterranean Reference Components of Range
(year) Parameters pertaining to case-control studies Parameters pertaining to cohort and cross-sectional studies of outcome Diet Score category score of score Adjusting factors
Definition of Matching Definition/features of the outcome in
Definition/features of Cases Controls factors Cohort Characteristics cohort
Scarmeas et Diagnosis made at a conference of Participants of 2 None NA NA NR Low: 0-3; Low (0-3) fruits; vegetables; 0-9 cohort, age, sex, ethnicity,
al. (2006)22 neurologists and neuropsychologists related cohorts Middle: 4-5; legumes; cereals; education, apolipoprotein
based on DSM criteria (Third Revision (WHICAP 1992, High: 6-9 fish; ratio of E genotype, caloric intake,
Revised); Alzheimer diagnosis based WHICAP 1999), monounsaturated to smoking, comorbidity
on criteria of the National Institute of which were saturated fat; index, BMI, history of
Neurological and Communicative identified from a alcohol; red and stroke, diabetes mellitus,
Disorders and Stroke-Alzheimer probability sample processed meat; hypertension, heart
Disease and Related Disorders of Medicare dairy products disease, plasma levels of
Association; Prevalent cases, beneficiaries total cholesterol, HDL,
excluding: 1) subjects who were non- residing in an area triglycerides and LDL
demented at baseline and developed of 3 contiguous
dementia at follow-up (incident cases), census tracts
2) subjects who were deemed within a
nondemented but had a CDR higher geographically
than 0, 3) subjects who were deemed defined area of
demented but had either a non-AD Northern
diagnosis or a CDR higher than 1 Manhattan
Psaltopoulou NA NA NA Residence in the Attica region, age of Cognitive impairment: evaluated using NR 0-3; 4-5; 6-9 Low: 0-3 vegetables; legumes; 0-9 sex, age education,
et al. enrolment 60+ years (out of the EPIC- MMSE; Depression: Geriatric Depression fruit and nuts; physical activity
(2008)23 Greece cohort) Scale>=5 cereals; fish; meat
and meat products;
dairy products;
ethanol;
MUFA:SFA ratio
Bountziouka NA NA NA The Mediterranean Islands Elderly Symptoms of depression during the past NR First: 0-29; 0-29 nonrefined cereals; 0-55 age, sex, education status,
et al. (MEDIS) Epidemiological Study; month were measured using a shortened Second: 30-33; fruits; vegetables; living alone, physical
(2009)24 random, population-based, multistage version of the self report Geriatric Third: 34-55 legumes; olive oil; activity status, financial
sampling method for the selection of Depression Scale; also asked a close fish; potatoes; meat status
participants; individuals residing in friend, companion or sibling to answer the and meat products;
assisted living centers as well as those same questions to increase precision; poultry; full fat
with a clinical history of CVD or participants with significant discordance dairy products;
cancer were not included in the survey (i.e., >3%) from their counterparts were alcohol
excluded from the psychological analyses.
Depression was defined as GDS score
>=5.
Feart et al. NA NA NA Three-City (3C) Study; sample of Dementia: diagnosis based on a 2-step NR 0-3, 4-5, 6-9 0-3 fruits; vegetables; 0-9 Analysis on Dementia and
(2009)14 community dwellers, 65 years or older procedure following administration of the MeDi legumes; cereals; Alzheimer: sex, education,
from electoral rolls of three French battery of neuropsychological tests [Mini fish; ratio of marital status, total energy
cities, participants with dementia were Mental State Examination (MMSE), The monounsaturated to intake, practice of physical
excluded at baseline Isaacs Set Test (IST), Benton Visual saturated fat; exercise, taking 5
Retention Test (BVRT), Free and Cued alcohol; meat; dairy medications/d or more,
Selective Reminding Test (FCSRT)]. products Center for
Participants suspected of having dementia Epidemiological Studies-
were examined by neurologist, and Depression Scale, score,
independent committee of neurologists and apolipoprotein E
reviewed all potential cases of dementia genotype, body mass
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and analyzed their history to obtain a index, hypertension,

consensus based on DSM Fourth Edition. hypercholesterolemia,
Cases of dementia and probable or diabetes, tobacco use,
possible cases of Alzheimer disease were stroke; Analysis on
identified; Stroke: NR Stroke: None
Fung et al. NA NA NA Nurses Health Study; female nurses Stroke confirmed by medical record ischemic 54%, Q1: 1.8 (0-2.5); Q1 Alternate 0-9 age, smoking, BMI,
(2009)25 living at the time of inception (1976); review using National Survey of Stroke hemorrhagic Q2: 3.1 (2.5- Mediterranean Diet menopausal status and
at baseline, those with a history of criteria which require a constellation of 19%, not 3.4); Q3: 4.0 Score (aMed): postmenopausal hormone
coronary heart disease, stroke, or neurological deficits, sudden or rapid in clearly (3.5-4.4); Q4: vegetables use, energy intake,
diabetes were excluded onset with a duration of at least 24 hours classified 27%; 4.9 (4.5-5.4); (excluding multivitamin intake,
or until death. Strokes were classified as nonfatal 84%, Q5: 6.3 (5.5-9.0) potatoes), fruits, alcohol intake, family
ischemic (embolic or thrombotic), fatal 16% nuts, whole grains, history, physical activity,
hemorrhagic (subarachnoid or legumes, fish, ratio aspirin use
intracerebral), or undetermined according of monounsaturated
to medical record evidence and computed to saturated fat, red
tomography, magnetic resonance imaging, and processed
or autopsy findings. Deaths were identified meats, alcohol
from state vital statistics records and the
National Death Index or reported by the
families and the postal system
Sanchez- NA NA NA Seguimiento Universidad de Navarra / Free of depression and antidepressant NR 5 groups: 0-2, 3, 0-2 Mediterranean Diet 0-9 sex, age, smoking status
Villegas et University of Navarra Follow-up medication at baseline, reporting a 4, 5, 6-9 Pattern (never, current, past
al. (2009)26 (SUN) Project, composed of former physician-made diagnosis of clinical (Trichopoulou smoker), BMI and its
students of the University of Navarra, depression and/or antidepressant score): ratio of quadratic term, physical
registered professionals from some medication during follow-up MUFAs to saturated activity during leisure time
Spanish provinces and other university fatty acids; alcohol (metabolic equivalent
graduates; participants lost to follow- intake; intake of hours per week), energy
up, those who reported extremely low legumes; cereals intake (kcal per day),
or high values for total energy intake, (such as bread); fruit employment status
patients with cancer or cardiovascular and nuts;
disease at baseline, users of vegetables; meat
antidepressant medication, or patients and meat products;
who reported physician-diagnosed milk and dairy
depression at baseline were excluded products; fish
Scarmeas et NA NA NA Two cohorts recruited through the Diagnosis retrospectively applied: MCI with Low: 0-3, Low fruits; vegetables; 0-9 cohort, age, sex, ethnicity,
al. (2009a)27 Washington Heights-Inwood Columbia subjective memory complaint; objective objective Middle: 4-5, legumes; cereals; education, APOE
Aging Project (WHICAP), identified impairment in at least one cognitive memory High: 6-9 fish; ratio of genotype, caloric intake,
from a probability sample of Medicare domain; essentially preserved activities of impairment, monounsaturated to BMI, time between first
beneficiaries from 3 contiguous census daily living; no diagnosis of dementia at MCI without saturated fat; dietary assessment and
tracts in northern Manhattan the consensus conference objective alcohol; red and first cognitive assessment
memory processed meat;
impairment dairy products
Scarmeas et NA NA NA Two cohorts recruited through the diagnosis made at a diagnostic conference NR Low: 0-3; Low (0-3) fruits; vegetables; 0-9 cohort, age, sex, ethnicity,
al. (2009b) 9 Washington Heights-Inwood Columbia of neurologists and neuropsychologists Middle: 4-5; legumes; cereals; education, apolipoprotein
Aging Project (WHICAP), identified based on DSM criteria (Third Edition High: 6-9 fish; ratio of E ε4 allele, caloric intake,
from a probability sample of Medicare Revised); the diagnosis of probable or monounsaturated to BMI, smoking,
beneficiaries from 3 contiguous census possible AD was based on the criteria of saturated fat; depression, leisure
tracts in northern Manhattan the National Institute of Neurological alcohol; red and activities, comorbidity
Disorders and Stroke and the Alzheimer’s processed meat; index, baseline Clinical
Disease and Related Disorders Association dairy products Dementia Rating score,
time between first dietary
and first physical activity
assessment
Chrysohoou NA NA NA IKARIA study; permanent inhabitants Depression: Geriatric Depression NR First: 0-29; 0-29 nonrefined cereals; 0-55 age, sex
et al. of Ikaria Island Scale>=5; Dementia: Mini Mental State Second: 30-33; fruits; vegetables;
(2010)28 Examination <24 Third: 34-55 legumes; olive oil;
fish; potatoes; meat
and meat products;
poultry; full fat
dairy products;
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alcohol
Roberts et NA NA NA Mayo Clinical Study of Aging; Mild cognitive impairment (MCI): amnestic MCI, Three groups: 0- 0-3 MeDi Trichopoulou 0-9 age, years of education,
al. (2010)29 randomly selected residents from cognitive concern by participant, nonamnestic 3, 4-5, 6-9 score: vegetables; total energy, sex, stroke,
Olsted County aged 70-89 years on physician, nurse or informant; impairment MCI legumes; fruits; ApoE ε4, stroke, coronary
October 1, 2004; subjects who died in 1 or more of the 4 cognitive domains cereals; fish; meat; disease, depressive
before they could be contacted, (including nonmemory domains) from the dairy products; symptoms
subjects who were terminally ill and in cognitive testing battery; essentially MUFA to SFA;
hospice, subjects with previously normal functional activities from the alcohol
diagnosed confirmed dementia, and Clinical Dementia Rating (CDR) and
subjects who could not be contacted Functional Activities Questionnaire;
were excluded absence of dementia. Dementia: according
to the DSM-IV criteria
Agnoli et al. NA NA NA Volunteers recruited to the Italian Record linkage between the study database ischemic tertile 1: 0-4; tertile 1 vegetables; legumes, 0-9 sex, smoking status,
(2011)30 section of the European Prospective and regional mortality and hospital stroke, tertile 2: 5; tertile (0-4) fruit and nuts; dairy education, nonalcoholic
Investigation into Cancer and Nutrition discharge databases was performed. hemorrhagic 3: 6-9 products; cereals; energy intake, BMI;
(EPIC) from 5 centers; prospectively Deaths were identified in mortality files stroke meat and meat stratified for center and
examined for the causes of when ICD-10 codes I60-I69 were reported products; fish; age
cardiovascular diseases (EPICOR); as an underlying cause of death or E10- alcohol;
participants with stroke or myocardial E14, I10-I15, I46, I49 and I70 were monounsaturated:sat
infarction at recruitment, those who reported in association with I60-I69; fatal urated fat
did not complete the dietary or lifestyle CBVD was assigned after verification
questionnaires, those in whom the ratio against hospital discharge and clinical
of total energy records. Suspected CBVD was identified
intake to basal metabolic rate was at on hospital discharge forms by ICD9-CM
either extreme of the distribution codes 342, 430-434, 436-438 or by
(cutoffs first and last-half percentiles), procedure codes for carotid
those in treatment for hyperlipidemia revascularization. Ischemic thrombotic
or diabetes, those following a special stroke or hemorrhagic stroke were
diet for hypertension, dyslipidemia, or diagnosed when brain infarction was
diabetes were excluded mentioned in the diagnosis and/or
confirmed on the basis of imaging exams
(computed tomography or MRI).
Gardener et NA NA NA Northern Manhattan Study (NOMAS); Incident ischemic stroke; medical records 100% ischemic 0-2, 3, 4-5, 6-9 0-2 fruits; vegetables; 0-9 age at baseline, sex, race-
al. (2011)31 study designed to determine stroke of all hospitalizations were reviewed to stroke legumes; cereals; ethnicity, completion of
incidence, risk factors, and prognosis verify the details of suspected events; two fish; ratio of high school education,
in a multi-ethnic urban population. neurologists classified the strokes monounsaturated to moderate-to-heavy
Eligible subjects were those who 1) independently after review of the data, and saturated fat; physical activity,
had never been diagnosed with one of the principal investigators alcohol; red and kilocalories, cigarette
ischemic stroke, 2) were >40 y old, adjudicated disagreements. processed meat; smoking, hypertension,
and 3) resided in Northern Manhattan dairy products diabetes,
for >3 months in a household with a hypercholesterolemia, and
telephone. Subjects were identified by history of cardiac disease
random-digit dialing.; participants with
a myocardial infarction before baseline
were excluded.
Kastorini et Stroke: ischemic strokes defined selected age (+/-3 NA NA NR First: 0-29; 0-29 nonrefined cereals; 0-55 None
al. (2011)12 through symptoms of neurologic concurrently with years), Second: 30-33; fruits; vegetables;
dysfunction of acute onset of any the patients on a sex Third: 34-55 legumes; olive oil;
severity, consistent with focal brain volunteer, fish; potatoes; meat
ischemia and imaging / laboratory population basis, and meat products;
confirmation of an acute vascular and from the same poultry; full fat
ischemic pathology; Depression: Zung region of the dairy products;
scale score >=50. Patients entered in patients; without alcohol
the cardiology and pathology clinics or clinical symptoms
the emergency units of 3 major general or suspicions of
hospitals in Greece; subjects with CVD in their
chronic neoplasmatic disease or medical history
chronic inflammatory disease, as well
as individuals with recent changes in
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their dietary habits, were excluded
Milaneschi NA NA NA InCHIANTI, prospective population- Depression: symptoms assessed with the NR Low: 0-3; 0-3 fruits; vegetables; 0-9 age, sex, physical activity,
et al. based study of older persons in Center for Epidemiologic Studies- Medium: 4-5; legumes; cereals; lower extremity function,
(2011)32 Tuscany Depression scale (CES-D>=20) High: 6-9 fish; ratio of number of medications,
monounsaturated to use of antidepressants and
saturated fat; NSAIDs
alcohol; red and
processed meat;
dairy products
Scarmeas et NA NA NA Washington Heights/Hamilton Heights MRI infarct: Presence of brain infarction MRI infarcts; Low : 0-3, low fruits; vegetables; 0-9 For MRI infarct: age, sex,
al. (2011)33 Columbia Aging Project (WHICAP) on MRI (at least one infarct); derived from MRI infarcts middle:4-5, high: legumes; cereals; ethnicity, education,
participants; large-scale community- the WHICAP cohort; the presence or without 6-9 fish; ratio of APOE genotype, caloric
based project of aging and dementia absence of brain infarction on MRI was dementia; MRI monounsaturated to intake, body mass index,
based in upper Manhattan. The source determined using all available images, infarcts saturated fat; duration between diet
cohort include was identified (via including T1-weighted images, FLAIR- without alcohol; red and evaluation and MRI,
ethnicity and age stratification weighted images, and proton density– clinical stroke processed meat; smoking, diabetes,
processes) from a probability sample weighted and T2-weighted double-echo dairy products hypertension, and heart
of Medicare beneficiaries. images; only lesions 3mm or larger disease, plasma TC, HDL,
qualified for consideration as brain TG, LDL; For clinical
infarcts; other necessary imaging stroke: age, sex, ethnicity,
characteristics included cerebrospinal fluid education, APOE
(CSF) density on the T1-weighted image genotype, caloric intake,
and, if the stroke was in the basal ganglia body mass index and
area, distinct separation from the circle of duration between diet
Willis vessels and perivascular spaces; evaluation and MRI
Stroke: clinical stroke
Tangney et NA NA NA Chicago Health and Aging Project History defined by self report NR Lowest tertile: 12-25 nonrefined cereals; 0-55 None
al. (2011)17 (CHAP); older residents residing on 12-25; Middle potatoes; fruit;
the south side of Chicago tertile: 26-29; vegetables; legumes,
Highest tertile: nuts and beans; fish;
30-45 olive oil; red meat
and meat products;
poultry; full-fat
cheese and other
dairy; alcohol
Yau et al. Patients that met the World Health Community based: age (5 NA NA first-ever 94%; score >= median <median whole grain breads, 0-20 waist-to-hip ratio,
(2011)34 Organization diagnostic criteria for random selection years ischaemic score of the rice and pasta; dairy periodontal disease, acute
stroke, and also underwent a brain CT of individuals older or 85%, controls products; poultry; febrile illness within the
scan or MRI within one week of listed on the younger) haemorrhagic eggs; fish and past four weeks
presentation to exclude non-vascular electoral registry and sex 15% seafood; legumes,
causes of stroke; excluded if unable to of the same area nuts and seeds;
communicate, presented with a stroke code; hospital potatoes; fruit juice
secondary to non-cerebral endovascular based: not stroke and drinks; fruits;
procedure or surgery or concurrent or TIA related vegetables; olive oil;
hospitalisation for acute coronary patients, attendants as wall as refined
syndrome or myocardial infarction or relatives of grain breads, rice
(non-stroke) and pasta; red meat;
patients; excluded organ meat; pickled
if unable to food; deep fried
communicate, had food; salty snacks;
a previous stroke dessert and sweet
or concurrent snacks; carbonated
hospitalisation for beverages; pizza
acute MI
Antonogeorg NA NA NA ATTICA study; a health and nutrition Participants underwent a detailed NR First: 0-29; 0-29 nonrefined cereals; 0-55 age, gender, years of
os et al. cross-sectional study carried out in the psychological evaluation by a group of Second: 30-33; fruits; vegetables; education, physical
(2012)35 province of Attica (including 78% specialists; depressive symptomatology Third: 34-55 legumes; olive oil; activity level and financial
urban was assessed using a translated and fish; potatoes; meat status
and 22% rural areas); only one validated version of the Zung Self-Rating and meat products;
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participant per household was enrolled; Depression Scale (ZDRS); ZDRS score >= poultry; full fat
sampling was random, multistage, and 50 denoted depression dairy products;
based on the age (5 strata), gender (2 alcohol
strata), and distribution of the Attica
region (27 strata) according to the
2001 census; people with history of
CVD or living in institutions or having
chronic viral infections were excluded.
Gardener et NA NA NA Australian Imaging, Biomarkers and Consensus AD diagnosis assigned during NR Low: 0-3; low tertile fruits; vegetables; 0-9 None
al. (2012)37 Lifestyle Study of Ageing (AIBL) clinical review panels, including Middle: 4-5; legumes; cereals;
cohort; excluded if they had a history consideration of diagnostic criteria (DSM- High: 6-9 fish; ratio of
of non-AD dementia, schizophrenia, IV, ICD-10); MCI diagnosis made monounsaturated to
bipolar disorder, significant current according to the protocol based upon saturated fat;
depression, Parkinson's disease, cancer Winblad et al. criteria: either personally or alcohol; red and
(other than basal cell skin carcinoma) through an informant reported memory processed meat;
within the last two years, symptomatic difficulties; Stroke: defined by self-report dairy products
stroke, insulin-dependent diabetes,
uncontrolled diabetes mellitus or
current regular alcohol use exceeding
two standard drinks per day (women)
or four (men)
Hoevenaar- NA NA NA The Dutch contribution to the Morbidity data were provided by the NR 0-2, 3-4, 5-6, 7-9 0-2 fruits; vegetables; 0-9 age, sex, cohort, smoking,
Blom et al. European Prospective Investigation National Medical Registry (NMR) using legumes; cereals; physical activity, energy
(2012)36 into Cancer and Nutrition (EPIC-NL the Dutch Hospital Discharge data. Stroke fish; ratio of intake and educational
cohort). EPIC-NL consists of the was coded as ICD-9 codes 430–434, and monounsaturated to level
Monitoring Project on Risk Factors for 436; causes of death after 1996 were coded saturated fat;
Chronic Diseases (MORGEN) and the according to the corresponding ICD10 alcohol; red and
PROSPECT cohort. The MORGEN codes. Vital status was obtained through processed meat;
cohort consists of 22,654 men and linkage with municipal population dairy products
women who were recruited through registries; subsequently, primary
random population sampling in three (underlying) and secondary causes of
Dutch towns; the PROSPECT cohort death were obtained through linkage with
included 17,357 women who data from "Statistics Netherlands".
participated in a breast cancer
screening program. The researchers
excluded participants with prevalent
CVD or type 2 diabetes based on self-
report and hospital admission data,
women who were pregnant at baseline,
those with extremely low or high
reported energy intakes (i.e., those in
the lowest and highest 0.5% of the
ratio of energy intake over basal
metabolic rate), those with no
information on dietary intake or any of
the covariates, as well as those with no
information on vital status or
cardiovascular events.
Luciano et NA NA NA Lothian Birth Cohort of 1936, Depressive symptoms measured by the NR First: -1.76 to - First: - vegetables; fish; -1.76 to None
al. (2012)5 participants aged about 70 years, living Hospital Anxiety and Depression Scale, a 0.47; Second: - 1.76 to - poultry; pasta; rice; +6.99
independently in the community, free self-report inventory assessing the recent 0.46 to +0.22; 0.47 water; tomato-based
from serious current illness or frequency of depressive symptoms in Third: +0.23 to sauces; oil and
dementia seven questions. People were categorized +6.99 vinegar dressing;
as having depression if their HADS score beans (standardized
was >=8. score, data extracted
from the Scottish
Collaborative Group
168-item Food
Frequency
Questionnaire)
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Vercambre NA NA NA Women participants in the Women’s Depression history: NR; Stroke: NR; NR MeDi tertiles low vegetables, legumes, 0-9 None
et al. Antioxidant Cardiovascular Study Global cognitive score is a composite (low : 0-3, fruits, cereals, fish,
(2012)18 (WACS), a cohort of female health score of the z-scores of the Telephone middle:4-5, high meat, dairy
professionals Interview of Cognitive Status, immediate : 6-9) products, ratio of
and delayed recalls of the East Boston monounsaturated to
Memory Test, category fluency, and saturated fat, alcohol
delayed recall of the Telephone Interview
of Cognitive Status 10-word list
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Supplemental Table 2. Evaluation of quality based on the Newcastle-Ottawa scale for all included cohort (longitudinal as well as cross-
sectional) studies.
Selection Comparability Outcome Total

Study Representativeness Selection of Ascertainment Outcome not On gender On other Assessment of Long enough follow- Adequacy
non-exposed of exposure present at start risk factors outcome up (median ≥5 years) (completeness)
of follow-up
Longitudinal
cohorts Max: 9
Feart (2009) 1 1 1 1 1 1 1 0 1 8
Fung (2009) 1 1 0 1 1 1 1 1 1 8
Sanchez-Villegas (2009) 0 1 0 1 1 1 0 0 1 5
Scarmeas (2009a) 1 1 1 1 1 1 1 0 1 8
Scarmeas (2009b) 1 1 1 1 1 1 1 1 1 9
Roberts (2010) 1 1 0 1 1 1 1 0 1 7
Agnoli (2011) 1 1 0 1 1 1 1 1 1 8
Gardener (2011) 1 1 1 1 1 1 1 1 1 9
Hoevenaar-Blom (2012) 1 1 0 1 1 1 1 1 1 8
Cross-sectional
evaluations of
cohorts Max: 6
Psaltopoulou (2008) 1 1 1 NA 1 1 0 NA NA 5
Bountziouka (2009) 1 1 1 NA 1 1 0 NA NA 5
Chrysohoou (2010) 1 1 1 NA 1 1 0 NA NA 5
Milaneschi (2011) 1 1 1 NA 1 1 0 NA NA 5
Scarmeas (2011) 1 1 1 NA 1 1 0 NA NA 5
Tangney (2011) 1 1 0 NA 0 0 0 NA NA 2
Antonogeorgos (2012) 1 1 0 NA 1 1 0 NA NA 4
3:CI;
Gardener (2012) 1 1 0 NA 0 0 1: CI; 0: stroke NA NA 2:stroke
Luciano (2012) 1 1 0 NA 0 0 0 NA NA 2
Vercambre (2012) 0 1 0 NA 0 0 0 NA NA 1
CI: cognitive impairment; NA: not applicable items to cross-sectional studies; 0 and 1 represent no allocation and allocation of a “star” according to the Newcastle-Ottawa coding manual, respectively
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Supplemental Table 3. Evaluation of quality based on the Newcastle-Ottawa scale for the case-control studies.
Selection Comparability Exposure Total

Study Case definition Representativeness Selection of Definition of On gender On other Assessment of Same method of Non-response
of the cases controls controls risk factors exposure ascertainment for rate
cases and controls Max: 9
Scarmeas (2006) 1 1 1 1 1 1 0 1 0 7
Kastorini (2011) 0 1 1 1 1 1 0 1 0 6
Yau (2011) 1 1 1 1 1 1 0 1 1 8
0 and 1 represent no allocation and allocation of a “star” according to the Newcastle-Ottawa coding manual, respectively
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Supplemental Table 4. Results of the meta-analyses examining the association between the subtypes of stroke and adherence to Mediterranean
diet. Bold cells denote statistically significant associations. No subanalyses regarding data drawn from manuscripts / data from re-analyses
provided after contact with the corresponding authors was performed, as the examination of stroke subcategories was confined to data drawn
from manuscripts.
Ischemic Stroke Hemorrhagic stroke Non-Fatal stroke Fatal stroke
Effect estimate Heterogeneity Effect estimate Heterogeneity Effect estimate Heterogeneity Effect estimate Heterogeneity
n§ n§ n§ n§
(95%CI) I2, p (95%CI) I2, p (95%CI) I2, p (95%CI) I2, p
High adherence
86.8%,
Overall analysis 5 0.52 (0.28-0.96) <0.001 2 0.97 (0.57-1.67) 50.0%, 0.157 2 0.48 (0.14-1.71) 95.2%, <0.001 1 0.69 (0.44-1.08) NC
Case-control studies 2 0.19 (0.08-0.46) 36.8%, 0.209 0 NC NC 1 0.25 (0.15-0.42) NC 0 NC NC
Longitudinal Cohort
studies 3 0.88 (0.70-1.12) 16.2%, 0.303 2 0.97 (0.57-1.67) 50.0%, 0.157 1 0.90 (0.75-1.08) NC 1 0.69 (0.44-1.08) NC
Cross-sectional studies 0 NC NC 0 NC NC 0 NC NC 0 NC NC
Score according to
Trichopoulou et al 2 0.80 (0.49-1.31) 45.6%, 0.175 1 1.40 (0.70-2.80) NC 0 NC NC 0 NC NC
Score according to
Panagiotakos et al 1 0.25 (0.15-0.42) NC 0 NC NC 1 0.25 (0.15-0.42) NC 0 NC NC
Other scores 2 0.33 (0.03-3.23) 89.1%, 0.002 1 0.79 (0.54-1.16) NC 1 0.90 (0.75-1.08) NC 1 0.69 (0.44-1.08) NC
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Mediterranean
countries 2 0.39 (0.16-0.96) 83.1%, 0.015 1 1.40 (0.70-2.80) NC 1 0.25 (0.15-0.42) NC 0 NC NC
Non-Mediterranean
countries 3 0.67 (0.33-1.39) 78.9%, 0.009 1 0.79 (0.54-1.16) NC 1 0.90 (0.75-1.08) NC 1 0.69 (0.44-1.08) NC
Moderate adherence
Overall analysis 6 0.91 (0.74-1.13) 50.6%, 0.072 3 0.91 (0.72-1.16) 0.0%, 0.477 3 0.84 (0.64-1.09) 74.4%, 0.020 2 1.12 (0.86-1.46) 0.0% 0.742
Case-control studies 1 0.50 (0.31-0.79) NC 0 NC NC 1 0.50 (0.31-0.79) NC 0 NC NC
Longitudinal Cohort
studies 5 1.03 (0.89-1.18) 0.0%, 0.835 3 0.91 (0.72-1.16) 0.0%, 0.477 2 0.95 (0.84-1.08) 0.0%, 0.399 2 1.12 (0.86-1.46) 0.0% 0.742
Cross-sectional studies 0 NC NC 0 NC NC 0 NC NC 0 NC NC
Score according to
Trichopoulou et al 3 0.92 (0.68-1.25) 0.0%, 0.984 1 1.14 (0.53-2.45) NC 0 NC NC 0 NC NC
Score according to
Panagiotakos et al 1 0.50 (0.31-0.79) NC 0 NC NC 1 0.50 (0.31-0.79) NC 0 NC NC
Other scores 2 1.05 (0.90-1.23) 0.0%, 0.366 2 0.89 (0.68-1.16) 11.1%, 0.289 2 0.95 (0.84-1.08) 0.0%, 0.399 2 1.12 (0.86-1.46) 0.0% 0.742
Mediterranean
countries 2 0.66 (0.37-1.19) 65.8%, 0.087 1 1.14 (0.53-2.45) NC 1 0.50 (0.31-0.79) NC 0 NC NC
Non-Mediterranean
countries 4 1.04 (0.90-1.20) 0.0%, 0.760 2 0.89 (0.68-1.16) 11.1%, 0.289 2 0.95 (0.84-1.08) 0.0%, 0.399 2 1.12 (0.86-1.46) 0.0% 0.742
§
number of study arms; NC: not calculable
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Supplemental Table 5. Results of the subgroup analyses examining the association between adherence to Mediterranean diet and mild cognitive
impairment (left columns) as well as advanced cognitive impairment (dementia, right columns). Bold cells denote statistically significant
associations.
Mild Cognitive impairment Advanced Cognitive Impairment
Heterogeneity Heterogeneity
n§ Effect estimate (95%CI) n§ Effect estimate (95%CI)
I2, p I2, p
High adherence
Overall analysis 3 0.67 (0.50-0.91) 30.4%, 0.238 6 0.57 (0.34-0.98) 84.1%, <0.001
Case-control studies 0 NC NC 1 0.31 (0.16-0.59) NC
Longitudinal Cohort studies 1 0.72 (0.52-1.00) NC 2 0.78 (0.43-1.42) 64.9%, 0.091
Cross-sectional studies 2 0.61 (0.33-1.11) 62.6%, 0.102 3 0.56 (0.17-1.90) 90.7%, <0.001
Score according to Trichopoulou et al 3 0.67 (0.50-0.91) 30.4%, 0.238 5 0.56 (0.32-0.98) 87.2, <0.001
Score according to Panagiotakos et al 0 NC NC 1 1.00 (0.11-9.29) NC
Other scores 0 NC NC 0 NC NC
Mediterranean countries 0 NC NC 3 1.01 (0.80-1.28) 0.0%, 0.945

Non-Mediterranean countries 3 0.67 (0.50-0.91) 30.4%, 0.238 3 0.36 (0.20-0.68) 77.1%, 0.013
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Data drawn from manuscripts† 3 0.67 (0.50-0.91) 30.4%, 0.238 4 0.47 (0.25-0.88) 81.9%, 0.001
Data from re-analyses provided after contact
with corresponding authors 0 NC NC 2 1.00 (0.77-1.28) 0.0%, 0.997
Moderate adherence
Overall analysis 3 0.84 (0.68-1.04) 0.0%, 0.644 6 0.79 (0.59-1.06) 54.1%, 0.054
Case-control studies 0 NC NC 1 0.48 (0.29-0.79) NC
Longitudinal Cohort studies 1 0.83 (0.62-1.12) NC 2 1.01 (0.77-1.32) 0.0%, 0.703
Cross-sectional studies 2 0.85 (0.63-1.15) 0.0%, 0.352 3 0.76 (0.49-1.19) 43.9%, 0.168
Score according to Trichopoulou et al 3 0.84 (0.68-1.04) 0.0%, 0.644 5 0.78 (0.58-1.06) 61.5%, 0.035
Score according to Panagiotakos et al 0 NC NC 1 1.89 (0.18-19.82) NC
Other scores 0 NC NC 0 NC NC
Mediterranean countries 0 NC NC 3 1.02 (0.73-1.43) 0.0%, 0.803

Non-Mediterranean countries 3 0.84 (0.68-1.04) 0.0%, 0.644 3 0.67 (0.43-1.04) 73.8%, 0.022
Data drawn from manuscripts† 3 0.84 (0.68-1.04) 0.0%, 0.644 4 0.74 (0.51-1.08) 68.6%, 0.023
with corresponding authors 0 NC NC 2 0.98 (0.64-1.49) 0.0%, 0.576
§
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Supplemental Table 6. Further subanalyses within the group of advanced cognitive impairment. Bold cells denote statistically significant
associations.
Cognitive impairment, as detected only by

Alzheimer Disease Dementia, clinically diagnosed
means of MMSE

n§ n§ n§
(95%CI) I2, p (95%CI) I2, p (95%CI) I2, p
High adherence
Overall analysis 4 0.43 (0.25-0.75) 74.0%, 0.009 2 1.00 (0.77-1.28) 0.0%, 0.997 1 1.12 (0.60-2.10) NC
Case-control studies 1 0.31 (0.16-0.59) NC 0 NC NC 0 NC NC
Longitudinal Cohort studies 2 0.64 (0.46-0.89) 0.0%, 0.416 0 NC NC 1 1.12 (0.60-2.10) NC
Cross-sectional studies 1 0.23 (0.13-0.41) NC 2 1.00 (0.77-1.28) 0.0%, 0.997 0 NC NC
Score according to Trichopoulou et al 4 0.43 (0.25-0.75) 74.0%, 0.009 1 1.00 (0.77-1.29) NC 1 1.12 (0.60-2.10) NC
Score according to Panagiotakos et al 0 NC NC 1 1.00 (0.11-9.29) NC 0 NC NC
Other scores 0 NC NC 0 NC NC 0 NC NC
Mediterranean countries 1 0.86 (0.39-1.89) NC 2 1.00 (0.77-1.28) 0.0%, 0.997 1 1.12 (0.60-2.10) NC
Non-Mediterranean countries 3 0.36 (0.20-0.68) 77.1%, 0.013 0 NC NC 0 NC NC
Data drawn from manuscripts† 4 0.43 (0.25-0.75) 74.0%, 0.009 0 NC NC 1 1.12 (0.60-2.10) NC
with corresponding authors 0 NC NC 2 1.00 (0.77-1.28) 0.0%, 0.997 0 NC NC
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Moderate adherence
Overall analysis 4 0.72 (0.50-1.04) 64.3%, 0.039 2 0.98 (0.64-1.49) 0.0%, 0.576 1 1.11 (0.63-1.95) NC
Case-control studies 1 0.48 (0.29-0.79) NC 0 NC NC 0 NC NC
Longitudinal Cohort studies 2 0.98 (0.74-1.30) 0.0%, 0.978 0 NC NC 1 1.11 (0.63-1.95) NC
Cross-sectional studies 1 0.58 (0.39-0.85) NC 2 0.98 (0.64-1.49) 0.0%, 0.576 0 NC NC
Score according to Trichopoulou et al 4 0.72 (0.50-1.04) 64.3%, 0.039 1 0.96 (0.62-1.47) NC 1 1.11 (0.63-1.95) NC
Score according to Panagiotakos et al 0 NC NC 1 1.89 (0.18-19.82) NC 0 NC NC
Other scores 0 NC NC 0 NC NC 0 NC NC
Mediterranean countries 1 0.99 (0.51-1.93) NC 2 0.98 (0.64-1.49) 0.0%, 0.576 1 1.11 (0.63-1.95) NC
Non-Mediterranean countries 3 0.67 (0.43-1.04) 73.8%, 0.022 0 NC NC 0 NC NC
Data drawn from manuscripts† 4 0.72 (0.50-1.04) 64.3%, 0.039 0 NC NC 1 1.11 (0.63-1.95) NC
with corresponding authors 0 NC NC 2 0.98 (0.64-1.49) 0.0%, 0.576 0 NC NC
§
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Supplemental Table 7. Results of the post hoc meta-regression analyses examining whether study characteristics and quality measures modified
the association between adherence to Mediterranean diet and the evaluated conditions. Bold cells denote statistically significant modification
effects.
Exponentiated Exponentiated Exponentiated

n§ coefficient p n§ coefficient p n§ coefficient p
(95%CI) (95%CI) (95%CI)
High adherence
Prospective data collection (vs. cross-sectional or
case-control) 12 1.43 (0.74-2.76) 0.258 9 0.84 (0.33-2.11) 0.660 9 1.63 (0.71-3.76) 0.210
Multivariate adjustment (vs. unadjusted) 12 1.22 (0.59-2.49) † 0.554 9 1.57 (0.78-3.15) 0.173 9 2.30 (1.04-5.05)‡ 0.041
Adjustment for any of:smoking, BMI, WHR, total
energy intake, physical activity (vs. unadjusted) 12 1.22 (0.59-2.49) † 0.554 8 1.59 (0.75-3.37) 0.180 8 2.28 (0.95-5.49) 0.061
Score by Trichopoulou et al. (vs. any other score) 12 1.66 (0.88-3.16) 0.107 9 1.12 (0.52-2.40) 0.733 9 0.59 (0.03-11.79) 0.688
Moderate adherence
Prospective data collection (vs. cross-sectional or
case-control) 12 1.17 (0.91-1.50) 0.189 9 0.64 (0.46-0.89) 0.016 9 1.33 (0.94-1.89) 0.091
Multivariate adjustment (vs. unadjusted) 12 1.13 (0.86-1.48) † 0.344 9 0.79 (0.46-1.34) 0.321 9 1.36 (0.88-2.11) 0.142
Adjustment for any of:smoking, BMI, WHR, total
energy intake, physical activity (vs. unadjusted) 12 1.13 (0.86-1.48) † 0.344 8 0.79 (0.44-1.43) 0.368 8 1.35 (0.84-2.18) 0.171
Score by Trichopoulou et al. (vs. any other score) 12 0.92 (0.72-1.18) 0.478 9 0.79 (0.44-1.45) 0.392 9 0.42 (0.02-8.17) 0.510
§
number of study arms ; † the pairs of meta-regression estimates are identical, as all multivariate effect estimates also adjusted for any of: smoking, BMI, WHR, total energy intake, physical activity; ‡ the pooled effect
estimate was 0.31 (95% CI: 0.17-0.57) for unadjusted studies and 0.72 (95%CI: 0.55-0.96) for studies adopting multivariate adjustment; BMI: body mass index; WHR: waist-to-hip ratio
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Supplemental Figure 1. Flow chart presenting the successive steps in the selection of eligible studies.
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Supplemental Figure 2. Forest plot describing the association between risk for stroke and adherence to Mediterranean diet. The
subanalyses on studies adopting the score by Trichopoulou et al. (upper panels), Panagiotakos et al. (middle panels) and other
scores (lower panels) are presented.
(a): High adherence
Study %
ID OR/RR (95% CI) Weight
1
Feart cross-sectional stroke MeDi 6-9 (2009) 0.68 (0.24, 1.88) 3.64
Agnoli stroke MeDi 6-9 (2011) 0.82 (0.57, 1.18) 10.45
Gardener stroke MeDi 6-9 (2011) 1.03 (0.61, 1.73) 8.16
Scarmeas stroke MeDi 6-9 (2011) 0.87 (0.47, 1.60) 7.03
Hoevenaar-Blom stroke MeDi 5-6 (2012) 0.77 (0.55, 1.07) 11.01
Vercambre stroke MeDi 6-9 (2012) 1.13 (0.78, 1.64) 10.42
Subtotal (I-squared = 0.0%, p = 0.663) 0.85 (0.72, 1.00) 64.42
.
2
Kastorini stroke MDS 34-55 (2011) 0.25 (0.15, 0.42) 8.16
Tangney stroke MDS 30-45 (2011) 0.70 (0.52, 0.96) 11.41
.
3
Fung total stroke aMed 6.3 [Q5] (2009) 0.87 (0.74, 1.03) 13.42
Yau stroke MD 14-20 (2011) 0.11 (0.03, 0.39) 2.59
.
Overall (I-squared = 69.1%, p = 0.000) 0.71 (0.57, 0.89) 100.00
NOTE: Weights are from random effects analysis
.0309 1 32.4
(b): Moderate adherence
Study %
ID OR /RR (95% CI)Weight
1
Agnoli stroke MeDi 5 (2011) 0.93 (0.63, 1.37) 6.41
Gardener stroke MeD i 4 (2011) 0.91 (0.53, 1.56) 3.51
Gardener stroke MeD i 4-5 (2012) 0.61 (0.27, 1.40) 1.52
.
2
.
3
.
.213 1 4.7
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subanalyses on studies conducted in Mediterranean countries (upper panels) and non-Mediterranean countries (lower panels) are
presented.
(a): High adherence
Study %
Fung total strok e aMed 6.3 [Q5] (2009) 0.87 (0.74, 1.03) 13.42

Yau stroke MD 14-20 (2011) 0.11 (0.03, 0.39) 2.59
.0309 1 32.4
Study %
1
.
2
Gardener stroke MeDi 4 (2011) 0.91 (0.53, 1.56) 3.51
.
.213 1 4.7
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subanalyses on data drawn from the manuscripts (upper panels), and data from re-analyses provided after contact with
corresponding authors (lower panels) are presented.
(a): High adherence
Study %
Fung total strok e aMed 6.3 [Q5] (2009) 0.87 (0.74, 1.03) 13.42
Yau stroke MD 14-20 (2011) 0.11 (0.03, 0.39) 2.59

Subtotal (I-squared = .%, p = .) 0.87 (0.47, 1.60) 7.03
.0309 1 32.4
Study %
ID OR/RR (95% C I) Weight
1
.
2
.
.213 1 4.7
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Supplemental Figure 5. Forest plot describing the association between risk for depression and adherence to Mediterranean diet.
The subanalyses on studies adopting the score by Trichopoulou et al. (upper panels), Panagiotakos et al. (middle panels) and
other scores (lower panels) are presented.
(a): High adherence
Study %
Psaltopoulou depression MeDi 6-9 ( 2008) 0.84 (0.68, 1.03) 21.79
Sanchez- Villegas depression MeDi 6-9 (2009) 0.58 (0.44, 0.77) 19.20
Milaneschi depression MeDi 6-9 (2011) 0.66 (0.39, 1.11) 11.40
Vercambre depression MeDi 6-9 (2012) 0.71 (0.53, 0.97) 18.27
Bountziouka depression MDS 34-55 (2009) 1.04 (0.67, 1.60) 13.90
Chrysohoou depression MDS 34- 55 (2010) 0.68 (0.15, 2.98) 2.29
Kastorini depression MDS 34- 55 (2011) 0.21 (0.09, 0.48) 6.31
Antonogeorgos depression MDS 34-55 (2012) 1.37 (0.31, 6.04) 2.28
Luciano depression StMeDi +0.23 to +6.99 wave 2 (2012) 0.46 (0.17, 1.24) 4.57
.0949 1 10.5
Study %
Psaltopoulou depression MeDi 4-5 (2008) 0.80 (0.56, 1.14) 14.24
Sanchez-Villegas depression MeDi 4 (2009) 0.66 (0.50, 0.87) 17.09
Chrysohoou depression MDS 30-33 (2010) 0.76 (0.17, 3.51) 1.77
Kastorini depression MDS 30-33 (2011) 0.71 (0.40, 1.26) 8.72
.107 1 9.37
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The subanalyses on studies conducted in Mediterranean countries (upper panels) and non-Mediterranean countries (lower panels)
are presented.
(a): High adherence
Study %
ID OR/ RR (95% CI) Weight
Ps altopoulou depression MeDi 6-9 (2008) 0.84 (0.68, 1.03) 21.79
Sanchez-Villegas depression MeDi 6-9 (2009) 0.58 (0.44, 0.77) 19.20
Subtot al (I-squared = 63.3%, p = 0.012) 0.68 (0.50, 0.93) 77.16
Luciano depression StMeDi +0. 23 to +6.99 wave 2 (2012) 0.46 (0.17, 1.24) 4.57
Subtot al (I-squared = 0.0% , p = 0.402) 0.69 (0.51, 0.92) 22.84
Ov erall (I -squared = 53.4%, p = 0.028) 0.68 (0.54, 0.86) 100. 00
.0949 1 10.5
Study %
.107 1 9.37
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The subanalyses on data drawn from the manuscripts (upper panels), and data from re-analyses provided after contact with
corresponding authors (lower panels) are presented.
(a): High adherence
Study %
ID OR/ RR (95% CI) Weight
Sanchez-Villegas depression MeDi 6-9 (2009) 0.58 (0.44, 0.77) 19.20
Subtot al (I-squared = 0.0% , p = 0.328) 0.64 (0.52, 0.78) 37.47
Ps altopoulou depression MeDi 6-9 (2008) 0.84 (0.68, 1.03) 21.79
Luciano depression StMeDi +0. 23 to +6.99 wave 2 (2012) 0.46 (0.17, 1.24) 4.57
Subtot al (I-squared = 56.8%, p = 0.031) 0.68 (0.48, 0.98) 62.53
Ov erall (I -squared = 53.4%, p = 0.028) 0.68 (0.54, 0.86) 100. 00
.0949 1 10.5
Study %
.107 1 9.37
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Supplemental Figure 8. Forest plot describing the association between risk for cognitive impairment and adherence to
Mediterranean diet. The subanalyses on studies adopting the score by Trichopoulou et al. (upper panels) and Panagiotakos et al.
(lower panels) are presented.
(a): High adherence
Study %
Scarmeas Alzheimer MeDi 6-9 (2006) 0.31 (0.16, 0.59) 10.20
Psaltopoulou MMSE<24 MeDi 6-9 (2008) 1.00 (0.77, 1.29) 15.07
Feart longitudinal dementia MeDi 6-9 (2009) 1.12 (0.60, 2.10) 10.42
Scarmeas MCI MeDi 6-9 (2009a) 0.72 (0.52, 1.00) 14.25
Scarmeas Alzheimer MeDi 6-9 (2009b) 0.60 (0.42, 0.86) 13.79
Roberts MCI-dementia longitudinal MeDi 6-9 (2010) 0.75 (0.46, 1.22) 12.24
Gardener MCI MeDi 6-9 (2012) 0.43 (0.24, 0.78) 10.77
Gardener Alzheimer MeDi 5-9 (2012) 0.24 (0.13, 0.41) 11.31
Chrysohoou MMSE<24 MDS 34- 55 (2010) 1.00 (0.11, 9.29) 1.96
Overall (I-square d = 76.4%, p = 0.000) 0.60 (0.43, 0.83) 100.00
.108 1 9.29
Study %
Feart longitudinal dementia MeDi 4 -5 (2009) 1.11 (0.63, 1.95) 7.63
Gar dener MCI MeDi 4-5 (2012) 0.72 (0.44, 1.15) 9.92
Gar dener Alzheimer MeDi 4-5 (2012) 0.58 (0.39, 0.85) 13.35
Chrysohoou MMSE<24 MDS 30-33 (2010) 1.89 (0.18, 19.82) 0.53
.0504 1 19.8
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Mediterranean diet. The subanalyses on studies conducted in Mediterranean countries (upper panels) and non-Mediterranean
countries (lower panels) are presented.
(a): High adherence
Study %
Chrysohoou MMSE<24 MDS 34- 55 (2010) 1.00 (0.11, 9.29) 1.96
Roberts MCI-dementia longitud inal MeDi 6-9 (201 0) 0.75 (0.46, 1.22) 12.24
Gardener MCI MeDi 6-9 (2 012) 0.43 (0.24, 0.78) 10.77
NOTE: Weights ar e from random effects analysis
.108 1 9.29
Study %
Chrysohoou MMSE<24 MDS 30-33 (2010) 1.89 (0.18, 19 .82) 0.53
Subtotal (I-squar ed = 0.0%, p = 0.803) 1.02 (0.73, 1.43) 19.75
NOTE: Weights are from ran dom effects analysis
.0504 1 19.8
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10
Mediterranean diet. The subanalyses on data drawn from the manuscripts (upper panels), and data from re-analyses provided
after contact with corresponding authors (lower panels) are presented.
(a): High adherence
Study %
Scarmeas Alzheimer MeDi 6-9 (2006) 0.31 (0.16, 0 .59) 10.20
Feart longitudinal dementia MeDi 6-9 (2009) 1.12 (0.60, 2 .10) 10.42
Scarmeas MCI MeDi 6-9 (2009a) 0.72 (0.52, 1 .00) 14.25
Scarmeas Alzheimer MeDi 6-9 (2009b) 0.60 (0.42, 0 .86) 13.79
Roberts MCI-dementia longitudinal MeDi 6-9 (201 0) 0.75 (0.46, 1 .22) 12.24
Gardener MCI MeDi 6-9 (2 012) 0.43 (0.24, 0 .78) 10.77
Gardener Alzheimer MeDi 5-9 (2012) 0.24 (0.13, 0 .41) 11.31
Subtotal (I-squared = 72.5%, p = 0.001) 0.54 (0.38, 0 .77) 82.97
Psaltopoulou MMSE<24 MeDi 6-9 (2008) 1.00 (0.77, 1 .29) 15.07
Chrysohoou MMSE<24 MDS 34- 55 (2010) 1.00 (0.11, 9 .29) 1.96
Subtotal (I-squared = 0.0%, p = 0.997) 1.00 (0.77, 1 .28) 17.03
Overall (I-sq uare d = 76.4%, p = 0.000) 0.60 (0.43, 0 .83) 100.00
NOTE: Weights ar e from random effects analysis
.108 1 9.29
Study %
Chrysohoou MMSE<24 MDS 30-33 (2010) 1.89 (0.18, 19 .82) 0.53
NOTE: Weights are from ran dom effects analysis
.0504 1 19.8
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Supplemental Figure 11. Forest plot describing the association between risk for stroke and moderate adherence to
Mediterranean diet. Apart from the overall analysis, the subanalyses on case-control (upper panels), longitudinal cohort (middle
panels) and cross-sectional studies (lower panels) are presented. The respective forest plot for high adherence is presented in
Figure 1 (main manuscript).
Study %
ID OR /RR (95% CI)Weight
1
.
2
.
3
Feart cross-sectional stroke MeD i 4-5 (2009) 0.54 (0.21, 1.39) 1.20
Gardener stroke MeD i 4-5 (2012) 0.61 (0.27, 1.40) 1.52
.
.213 1 4.7
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Supplemental Figure 12. Forest plot describing the association between risk for depression and moderate adherence to
panels) and cross-sectional studies (lower panels) are presented. The respective forest plot for high adherence is presented in
Figure 2 (main manuscript).
Study %
1
Kastorini depression MDS 30-33 (2011) 0.71 (0. 40, 1.26) 8. 72
Subtotal (I-squared = .%, p = .) 0.71 (0. 40, 1.26) 8. 72
.
2
Sanchez-Villegas depression MeDi 4 (2009) 0.66 (0. 50, 0.87) 17.09
Sanchez-Villegas depression MeDi 5 (2009) 0.49 (0. 36, 0.67) 15.70
Subtotal (I-squared = 50.1%, p = 0.157) 0.57 (0. 43, 0.77) 32.79
.
3
Psaltopoulou depression MeDi 4-5 (2008) 0.80 (0. 56, 1.14) 14.24
Bountziouka depression MDS 30-33 (2009) 0.94 (0. 58, 1.52) 10.69
Chrysohoou depression MDS 30-33 (2010) 0.76 (0. 17, 3.51) 1. 77
Milaneschi depression MeDi 4-5 (2011) 0.78 (0. 50, 1.22) 11.54
Antonogeorgos depression MDS 30-33 (2012) 2.47 (0. 65, 9.37) 2. 27
Vercambre depression MeDi 4-5 (2012) 1.00 (0. 78, 1.28) 17.99
Subtotal (I-squared = 0.0%, p = 0.587) 0.92 (0. 78, 1.09) 58.49
.
Overall (I-squared = 54.4%, p = 0.025) 0.77 (0. 62, 0.95) 100.00
NOTE: Weights are from random ef fects analysis
.107 1 9.37
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13
Supplemental Figure 13. Forest plot describing the association between risk for cognitive impairment and moderate adherence
to Mediterranean diet. Apart from the overall analysis, the subanalyses on case-control (upper panels), longitudinal cohort
(middle panels) and cross-sectional studies (lower panels) are presented. The respective forest plot for high adherence is
presented in Figure 3 (main manuscript).
Study %
1

.
2


.
3


.0504 1 19.8
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14
Supplemental Figure 14. Forest plot describing the association between risk for ischemic stroke and adherence to
Mediterranean diet. Apart from the overall analysis, the subanalyses on case-control (upper panels) and longitudinal cohort
(lower panels) are presented.
(a): High adherence
Study %
Kastorini ischemic stroke MDS 34-55 (2011) 0.25 (0.15, 0.42) 21.66
Yau ischemic stroke MD 14-20 (2011) 0.09 (0.02, 0.40) 10.34
Fung ischemic stroke aMed 6.3 [Q5] (2009) 0.94 (0.74, 1.19) 24.63
Agnoli ischemic stroke MeDi 6-9 (2011) 0.62 (0.37, 1.04) 21.72
Gardener ischemic stroke MeDi 6-9 (2011) 1.03 (0.61, 1.73) 21.66
.0201 1 49.7
Study %
Agnoli ischemic stroke MeDi 5 (2011) 0.90 (0.55, 1.48) 12.11
Gardener ischemic stroke MeDi 4 (2011) 0.91 (0.53, 1.56) 10.95
.314 1 3.18
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15
Mediterranean diet. The subanalyses on studies adopting the score by Trichopoulou et al. (upper panels), Panagiotakos et al.
(middle panels) and other scores (lower panels) are presented.
(a): High adherence
Study %

.
2

.
3

.
.0201 1 49.7
Study %
1
.
2
.
3
.
.314 1 3.18
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(a): High adherence
Study %
.0201 1 49.7
Study %
.314 1 3.18
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17
Supplemental Figure 17. Forest plot describing the association between risk for hemorrhagic stroke and adherence to
Mediterranean diet. The subanalyses on studies adopting the score by Trichopoulou et al. (upper panels) and other scores (lower
panels) are presented.
(a): High adherence
Study %
Agnoli hemorrhagic stroke MeDi 6-9 (2011) 1.40 (0.70, 2.80) 36.61
Fung hemorrhagic stroke aMed 6.3 [Q5] (2009) 0.79 (0.54, 1.16) 63.39
.357 1 2.8
Study %
Agnoli hemorrhagic stroke MeDi 5 (2011) 1.14 (0.53, 2.45) 9.63
.408 1 2.45
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Supplemental Figure 18. Forest plot describing the association between risk for non-fatal stroke and adherence to
Mediterranean diet. Apart from the overall analysis, the subanalyses on case-control (upper panels) and longitudinal cohort
(lower panels) are presented. The same pattern of subanalyses also pertains to a) the score adopted, as the case-control study was
based on the score by Panagiotakos et al., whereas the longitudinal cohort was based on the alternative aMed score; b)
Mediterranean and non-Mediterranean countries, as the study by Kastorini et al. was performed in a Mediterranean country
(Greece), whereas the study by Fung et al. was performed in a non-Mediterranean country (USA).
(a): High adherence
Study %
Kastorini nonfatal stroke MDS 34-55 (201 1) 0.25 (0.15, 0.42) 48 .12
Subtotal (I-squar ed = .%, p = .) 0.25 (0.15, 0.42) 48 .12
Fung nonfatal stroke aMed 6.3 [Q5] (2009) 0.90 (0.75, 1.08) 51 .88
Subtotal (I-squar ed = .%, p = .) 0.90 (0.75, 1.08) 51 .88
Overall (I-sq uared = 95.2%, p = 0.000) 0.48 (0.14, 1.71) 10 0.00
NOTE: W eights are fr om random effects anal ysis
.138 1 7.2 6
Study %
ID O R/RR (95% CI) Weight
Kastorini nonfa tal stroke MDS 30-33 (2011) 0.50 (0.31, 0.79) 19 .66
Subtotal (I-squared = .%, p = .) 0.50 (0.31, 0.79) 19 .66
Subtotal (I-squared = 0.0%, p = 0.399) 0.95 (0.84, 1.08) 80 .34
Overall (I-square d = 74.4% , p = 0.020) 0.84 (0.64, 1.09) 10 0.00
NO TE: Weights are from r andom effects analysis
.314 1 3.1 8
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Supplemental Figure 19. Forest plot describing the association between risk for hemorrhagic stroke and adherence to
(a): High adherence
Study %
Agnoli hemorrhagic stroke MeDi 6-9 (2011) 1.40 (0.70, 2.80) 36.61
.357 1 2.8
Study %
ID OR/RR (95% CI) W eight
Agnoli hemorrhagic strok e MeDi 5 (2011) 1.14 (0.53, 2.45) 9.63
Fung hemorrhagic strok e aMed 4.0 [Q3] (2009) 1.01 (0.72, 1.42) 48.91
Fung hemorrhagic strok e aMed 4.9 [Q4] (2009) 0.77 (0.53, 1.11) 41.47
Overall (I-s quared = 0.0%, p = 0.477) 0.91 (0.72, 1.16) 100.00
NOTE: Weights are from random effects analys is
.408 1 2.45
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Supplemental Figure 20. Forest plot describing the association between risk for fatal stroke and moderate adherence to
Mediterranean diet.
Study %
Fung fatal strok e aMed 4.9 [Q4] (2009) 1.07 (0.73, 1.57) 47.16
Fung fatal strok e aMed 4.0 [Q3] (2009) 1.17 (0.81, 1.68) 52.84
Overall (I -squared = 0.0%, p = 0.742) 1.12 (0.86, 1.46) 100.00
NOTE: W eights are from random effects analysis
.593 1 1.68
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21
Supplemental Figure 21. Forest plot describing the association between risk for mild cognitive impairment and adherence to
Mediterranean diet. Apart from the overall analysis, the subanalyses on longitudinal cohort (upper panels) and cross-sectional
studies (lower panels) are presented.
(a): High adherence
Study %
Roberts MCI cross-sectional MeDi 6-9 (2010) 0.80 (0.52, 1.24) 32.56
.237 1 4.22
Study %
Roberts MCI cross-sectional MeDi 4-5 (2010) 0.96 (0.65, 1.42) 28.87
.445 1 2.25
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22
Supplemental Figure 22. Forest plot describing the association between risk for advanced cognitive impairment and adherence
to Mediterranean diet. Apart from the overall analysis, the subanalyses on case-control (upper panels), longitudinal cohort
(middle panels) and cross-sectional studies (lower panels) are presented.
(a): High adherence
Study %
.108 1 9.29
Study %
ID OR/RR (95% CI) W eight
Overall (I-s quared = 54.1%, p = 0.054) 0.79 (0.59, 1.06) 100.00
NOTE: W eights are from random effects analys is
.0504 1 19.8
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23
to Mediterranean diet. The subanalyses on studies adopting the score by Trichopoulou et al. (upper panels) and Panagiotakos et
al. (lower panels) are presented.
(a): High adherence
Study %
.108 1 9.29
Study %
.0504 1 19.8
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24
to Mediterranean diet. The subanalyses on studies conducted in Mediterranean countries (upper panels) and non-Mediterranean
(a): High adherence
Study %
.108 1 9.29
Study %
.0504 1 19.8
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25
to Mediterranean diet. The subanalyses on data drawn from the manuscripts (upper panels), and data from re-analyses provided
after contact with corresponding authors (lower panels) are presented.
(a): High adherence
Study %
.108 1 9.29
Study %
.0504 1 19.8
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26
Supplemental Figure 26. Forest plot describing the association between risk for Alzheimer disease and adherence to
panels) and cross-sectional studies (lower panels) are presented.
(a): High adherence
Study %
Feart longitudinal Alzheimer MeDi 6-9 (2009) 0.86 (0.39, 1.89) 20.42
.135 1 7.42
Study %
.291 1 3.44
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Supplemental Figure 27. Forest plot describing the association between risk for Alzheimer disease and adherence to
(a): High adherence
Study %
.135 1 7.42
Study %
.291 1 3.44
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28
Supplemental Figure 28. Forest plot describing the association between risk for cognitive impairment (as detected only by
means of MMSE) and adherence to Mediterranean diet. The subanalyses on studies adopting the score by Trichopoulou et al.
(upper panels) and Panagiotakos et al. (lower panels) are presented.
(a): High adherence
Study %
.108 1 9.29
Study %
.0504 1 19.8
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29
Supplemental Figure 29. Plot depicting the modifying effect mediated by the percentage of males upon the association between
stroke and adherence to Mediterranean diet. The circle sizes represent the inverse of each within-study variance.
(a): High adherence
0 -.5
log(effect estimate)
-1.5 -1
-2
0 20 40 60 80
percentage of males (%)

.2
0
-.4 -.2
-.6
-.8
0 20 40 60
percentage of m ales (%)
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Supplemental Figure 30. Plot depicting the modifying effect mediated by the mean age of the study sample upon the association
between depression and moderate adherence to Mediterranean diet. The circle sizes represent the inverse of each within-study
variance.
1 .5
0 -.5
-1
40 50 60 70 80
mean age (years)
John Wiley & Sons

MOOSE Checklist
Criteria Brief description of how the criteria were handled in

the meta-analysis
Reporting of background should
include
√ Problem definition Adherence to Mediterranean diet has been associated with
better overall survival, as well as cardiovascular and
cancer prevention Nevertheless, the protective role of
Mediterranean diet in terms of stroke, depression,
cognitive impairment and Parkinson’s disease remains to
be summarized quantitatively.
√ Hypothesis statement Mediterranean diet may have a multidimensional
protective role regarding stroke, depression, cognitive
impairment and Parkinson’s disease
√ Description of study outcomes Stroke; depression; cognitive impairment (mild or
advanced); Parkinson’s disease
√ Type of exposure or Adherence to Mediterranean diet
intervention used
√ Type of study designs used Case-control; cross-sectional; cohort
√ Study population Adult population
Reporting of search strategy
should include
√ Qualifications of searchers (eg, The credentials of the two investigators TP and TNS are
librarians and investigators) provided in the author list.
√ Search strategy, including time PubMed, up to October 31, 2012
period included in the
synthesis and keywords
√ Effort to include all available If the required data for the meta-analysis were not readily
studies, including contact with available in the published article, the corresponding
authors authors were contacted twice (a reminder e-mail was sent
seven days after the first e-mail).
√ Databases and registries PubMed
searched
√ Search software used, name We did not employ a special search software.
and version, including special
features used (eg, explosion)
√ Use of hand searching (eg, Reference lists of reviews and eligible articles were
reference lists of obtained systematically searched for relevant articles in a
articles) “snowball” procedure.
√ List of citations located and Details of the literature search process and excluded
those excluded, including studies are outlined in the flow chart.
justification
John Wiley & Sons

√ Method of addressing articles We placed no restrictions on language.

published in languages other
than English
√ Method of handling abstracts The search of potentially relevant items in the reference
and unpublished studies lists was not restricted upon full-text articles, but also
conference abstracts and unpublished studies were
evaluated during the “snowball” procedure.
√ Description of any contact with The corresponding authors were contacted twice (a
authors reminder e-mail was sent seven days after the first e-
mail); the provision of data by the authors was also taken
into account during the subgroup analyses.
Reporting of methods should
include
√ Description of relevance or The inclusion criteria are presented in the “Search
appropriateness of studies strategy and eligibility of studies” section.
assembled for assessing the
hypothesis to be tested
√ Rationale for the selection and The list of extracted data from each study pertained to the
coding of data (eg, sound population characteristics, study design, exposure,
clinical principles or outcome, and possible effect modifiers of the association;
convenience) the detailed list is provided in the “Data extraction and
effect estimates” section.
√ Documentation of how data Data were independently extracted and analyzed by two
were classified and coded (eg, reviewers (TP and TNS) and final decision was reached
multiple raters, blinding, and by consensus.
inrerrater reliability)
√ Assessment of confounding (eg Supplemental Table 1 presents the adjustment factors as
comparability of cases and well as matching factors for each study.
controls in studies where
appropriate)
√ Assessment of study quality, Study quality was assessed through the Newcastle-Ottawa
including blinding of quality scale.
assessors; stratification or
regression on possible
predictors of study results
√ Assessment of heterogeneity Heterogeneity of the studies was assessed using Cochrane
Q of heterogeneity and I2 statistic.
√ Description of statistical Description of methods of meta-analyses, subgroup
methods (eg, complete analyses, meta-regression and assessment of publication
description of fixed or random bias are detailed in the “Statistical analyses” section, as
effects models, justification of well as in the Supplemental Methods.
whether the chosen models
account for predictors of study
results, dose-response models,
or cumulative meta-analysis) in
sufficient detail to be
replicated
John Wiley & Sons

√ Provision of appropriate tables Three main tables and six supplemental tables are
and graphics provided. Three forest plots appear in the main text and
30 supplemental graphics are provided in the
Supplemental Figures.
Reporting of results should
include
√ Graph summarizing individual Figures 1-3; Supplemental Figures 2-28
study estimates and overall
estimate
√ Table giving descriptive Supplemental Table 1
information for each study
included
√ Results of sensitivity testing Tables 1 and 2; Supplemental Tables 4-6
(eg, subgroup analysis)
√ Indication of statistical 95% confidence intervals were presented with all

uncertainty of findings summary effect estimates.
Reporting of discussion should
include
√ Quantitative assessment of bias Discussion, last page
(eg, publication bias)
√ Justification for exclusion (eg, The details regarding the exclusion of studies due to
exclusion of non-English- reporting reasons are discussed and their results are
language citations) briefly summarized.
√ Assessment of quality of The shortcomings of the individual studies reflected upon
included studies their quality ratings are discussed in a detailed paragraph.
Reporting of conclusions should
include
√ Consideration of alternative We discussed that adherents to MD may be more health
explanations for observed conscious, more physical active, smoke less or have more
results favorable social and lifestyle determinants. Moreover, the
possibility of residual confounding was acknowledged.
√ Generalization of the We discussed the need for accumulation of further data
conclusions (ie, appropriate for regarding the achievement of statistical significance in
the data presented and within subanalyses pertaining to the type of score used and
the domain of the literature Mediterranean region to guarantee the external
review) generalizability of results.
√ Guidelines for future research Based on the shortcomings of the included studies in
terms of quality, the desirable characteristics of future
studies are stated, in the same paragraph.
√ Disclosure of funding source No separate funding was necessary for the undertaking of
this systematic review and meta-analysis.
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Mediterranean diet and stroke, cognitive impairment, depression: a

Theodora Psaltopoulou PhD1 , Theodoros N. Sergentanis MD1, Demosthenes B.

Panagiotakos PhD2, Ioannis N. Sergentanis MD1,3, Rena Kosti PhD1, Nikolaos

Scarmeas MD MSc PhD4,5

School of Medicine, Athens, Greece

Running head: Mediterranean diet, stroke, cognition & depression

Word count (excluding abstract, references, tables): 3,471

Psaltopoulou Theodora, Internist, Assistant Professor,

Department of Hygiene, Epidemiology and Medical Statistics

School of Medicine, University of Athens

75 M. Asias str, Goudi 11527, Athens, Greece

Phone: +30-210-7462061, e-mail: tpsaltop@med.uoa.gr,

OBJECTIVE: This meta-analysis aims to quantitatively synthesize all studies that

depression, cognitive impairment and Parkinson’s disease.

METHODS: Potentially eligible publications were those providing effect estimates of

aforementioned outcomes. Studies were sought in PubMed up to October 31, 2012.

Maximally adjusted effect estimates were extracted; separate analyses were

performed for high and moderate adherence.

stroke (RR=0.71, 95%CI: 0.57-0.89), depression (RR=0.68, 95%CI: 0.54-0.86) and

cognitive impairment (RR=0.60, 95%CI: 0.43-0.83). Moderate adherence was

ischemic stroke, mild cognitive impairment, dementia and particularly Alzheimer’s

disease. Meta-regression analysis indicated that the protective effects of

Mediterranean diet in stroke prevention seemed more sizeable among males.

Concerning depression, the protective effects of high adherence seemed independent

along with older age.

INTERPRETATION: Adherence to a Mediterranean diet may contribute to the

health priorities, with primary prevention playing a critical role. Maintaining

affective disorders, is a vital part of their well-being; otherwise, a heavy personal,

familial, public health, financial and societal burden emerges.

Prospective studies have provided evidence for a favorable relation of

Mediterranean-type diet with slower cognitive decline, reduced risk of progression

AD and reduced crude mortality in AD patients.1-3 In addition, adherence to a

Mediterranean diet, as well as to Dietary Approaches to Stop Hypertension (DASH)

dietary pattern, too.4 The prevalence of affective disorders, like depression, is

Mediterranean diet has heterogeneous characteristics among countries residing

in the Mediterranean basin.6 Precise definition including appropriate characterization

well as quantitative measurement of its adherence varies between studies,7 but, in

general, it is characterized by high intake of vegetables, fruits, cereals, pulses, nuts

processed meats and saturated fats.7,8 Mediterranean diet is characterized as a healthy

dietary pattern among others, characterized by the United Nations as an intangible

cultural heritage of humanity,9 and related to a better overall survival, as well as

cardiovascular and cancer prevention8,10 leading to a reduction of premature mortality

among middle-aged adults.11

multidimensional, encompassing antiinflammatory functions,12 protection from

oxidative stress13 and atherothrombosis14 potentially by modulating the expression of

pro-atherogenic genes.15 Favorable results in cardiovascular risk factors have also

HDL cholesterol levels,16 lower blood pressure,17 protective association with

metabolic syndrome,18 possibly with diabetes mellitus19 and obesity.20 Among a

multitude of suggested mechanisms, alterations in biochemical mediators’ levels such

as homocysteine,21 adiponectin22 and improvement in endothelial function and

regenerative capacity23 have been named.

Data have accumulated from prospective, case-control and cross-sectional

stroke, cognitive impairment, depression and Parkinson’s disease in the adult

The scope of the present meta-analysis is to quantitatively synthesize relevant

answer critical questions, such as if the results are generalizable in non-Mediterranean

of the outcomes if a moderate or a high adherence to Mediterranean diet is followed.

Materials and Methods

Search strategy and eligibility of studies

This meta-analysis was performed in accordance with the Meta-analysis Of

Observational Studies in Epidemiology (MOOSE) guidelines.24 Eligible studies were

sought in PubMed without any restriction of publication language; end-of-search date

extraction are provided in the online-only Supplemental Methods.

Statistical analyses, study quality, risk of bias and meta-regression analyses

Given that adherence to Mediterranean diet was quantified by means of a