Dietary Lipids For Healthy Brain Function

Dietary Lipids for
Healthy Brain Function

Dietary Lipids for
Healthy Brain Function
Claude Leray
Originally published in French by Edition Sauramps Medical, Montpellier, France under the title:
Ces Lipides qui stimulent notre cerveau by C. LERAY, 2016.
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Library of Congress Cataloging-in-Publication Data

Names: Leray, Claude, author.
Title: Dietary lipids for healthy brain function / Claude Leray.
Other titles: Ces lipides qui stimulent notre cerveau. English
Description: Boca Raton : Taylor & Francis, 2017. | Includes bibliographical
references and index.
Identifiers: LCCN 2016056527 | ISBN 9781138035256 (hardback : alk. paper)
Subjects: | MESH: Lipids–physiology | Dietary Fats | Brain–growth &
development | Mental Disorders | Nervous System Diseases
Classification: LCC QP752.F35 | NLM QU 85 | DDC 612.3/97–dc23
LC record available at https://lccn.loc.gov/2016056527
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Contents
Foreword ............................................................................................................ ix
Acknowledgment .............................................................................................. xi
Chapter 1 Introduction .................................................................................. 1
Chapter 2 Brain development ...................................................................... 7

2.1 ω-3 Fatty acids.......................................................................................... 7
2.2 Vitamin D ............................................................................................... 19
2.3 Vitamin E ................................................................................................ 21
References.......................................................................................................... 23
Chapter 3 Cognitive development ............................................................ 27

3.1 ω-3 Fatty acids........................................................................................ 27
3.1.1 Epidemiological investigations ............................................. 27
3.1.2 Intervention studies ................................................................ 32
3.2 Fatty acids............................................................................................... 36
3.2.1 Phosphatidylcholine................................................................ 36
3.2.2 Phosphatidylserine.................................................................. 37
3.3 Vitamin D ............................................................................................... 39
References.......................................................................................................... 40
Chapter 4 Cognitive decline and Alzheimer’s disease......................... 45

4.1 Age-related decline................................................................................ 45
4.1.1 ω-3 Fatty acids ......................................................................... 47
4.1.1.1 Epidemiological investigations............................. 48
4.1.2 Vitamin A and carotenoids ................................................... 57
4.1.2.1 Vitamin A ................................................................ 57
4.1.2.2 Carotenoids ............................................................. 58
4.2 Dementia and Alzheimer’s disease .................................................... 59
4.2.1 ω-3 Fatty acids ......................................................................... 62
4.2.1.2 Intervention studies ............................................... 64
v
vi Contents
4.2.2 Vitamin A and carotenoids ................................................... 68

4.2.2.1 Vitamin A ................................................................ 68
4.2.2.2 Carotenoids ............................................................. 70
4.2.3 Vitamin D................................................................................. 70
4.2.4 Vitamin E.................................................................................. 77
4.2.5 Cholesterol................................................................................ 81
References.......................................................................................................... 85
Chapter 5 Other neurological diseases .................................................... 95

5.1 Parkinson’s disease................................................................................ 95
5.1.1 ω-3 Fatty acids ......................................................................... 97
5.1.2 Vitamin D................................................................................. 98
5.1.3 Vitamin E................................................................................ 100
5.1.3.1 Intervention studies ............................................. 100
5.2 Multiple sclerosis ................................................................................. 101
5.2.1 ω-3 Fatty acids ....................................................................... 103
5.2.2 Vitamin D............................................................................... 105
5.3 Epilepsy................................................................................................. 110
5.3.1 ω-3 Fatty acids ....................................................................... 112
5.3.2 Vitamin D............................................................................... 114
References........................................................................................................ 117
Chapter 6 Mental disorders...................................................................... 123

6.1 Major clinical disorders ...................................................................... 124
6.1.1 Depressive disorders ............................................................ 124
6.1.1.1 ω-3 fatty acids ....................................................... 126
6.1.1.2 Vitamin D .............................................................. 135
6.1.1.3 Vitamin E............................................................... 139
6.1.2 Bipolar disorder and ω-3 fatty acids.................................. 140
6.1.2.1 Epidemiological investigations........................... 141
6.1.3 Schizophrenia (psychotic disorders) .................................. 143
6.1.3.1 ω-3 Fatty acids ...................................................... 145
6.1.3.2 Vitamin D .............................................................. 148
Contents vii
6.1.4 Attention-deficit hyperactivity disorder............................ 150

6.1.4.1 ω-3 Fatty acids ...................................................... 152
6.1.4.2 Vitamin D .............................................................. 154
6.1.5 Autism .................................................................................... 156
6.1.5.1 ω-3 Fatty acids ...................................................... 157
6.1.5.2 Vitamin D .............................................................. 159
6.2 Other personality and behavior disorders ...................................... 162
6.2.1 Aggressive behavior ............................................................. 163
6.2.1.1 ω-3 Fatty acids ...................................................... 164
6.2.1.2 Vitamin D .............................................................. 170
6.2.1.3 Cholesterol............................................................. 172
6.2.2 Suicidal behavior................................................................... 174
6.2.2.1 ω-3 Fatty acids ...................................................... 176
6.2.2.2 Vitamin D .............................................................. 180
6.2.2.3 Cholesterol............................................................. 181
References........................................................................................................ 184
Chapter 7 Annexes ..................................................................................... 197

7.1 Essential fatty acids............................................................................. 197
7.2 Dietary allowance of essential fatty acids ....................................... 198
7.2.1 Main DHA and EPA sources as sea products...................... 198
7.2.2 Foods for infants and young children ............................... 201
7.2.3 Food supplements rich in EPA, DHA,
or both ........................................................................202
7.3 Vitamin A and carotenoids................................................................ 203
7.3.1 Vitamin A............................................................................... 203
7.3.2 Carotenoids ............................................................................ 204
7.4 Vitamin D ............................................................................................. 205
7.5 Vitamin E .............................................................................................. 209
7.6 Cholesterol ............................................................................................ 211
7.7 Phospholipids....................................................................................... 212
7.7.1 Phosphatidylcholine.............................................................. 212
7.7.2 Phosphatidylserine................................................................ 213
7.8 Apolipoprotein E ................................................................................. 214
7.9 Evaluation of cognitive performances ............................................. 214
7.9.1 Different types of memory .................................................. 214
7.9.1.1 Working or short-term memory: Baddeley
model...................................................................... 215
7.9.1.2 Long-term memory .............................................. 216
7.9.2 Evaluation of memory capacity by MMSE....................... 217
7.9.3 Test of executive functions .................................................. 219
7.9.4 Global deterioration scale .................................................... 221
7.9.5 Peabody picture vocabulary test ........................................ 222
viii Contents
7.9.6 Wechsler intelligence test..................................................... 222

7.9.7 Bayley motor test .................................................................. 223
7.10 Kaufman children intelligence test ................................................. 223
7.11 Estimation of depression .................................................................. 224
7.12 Evaluation of aggressiveness and violence ................................... 225
Index................................................................................................................. 227
Foreword
Claude Leray, a prolific and recognized scientist in lipids research, presents
here his latest book in which he tackles lipids related to the neurosciences. It
is a vast program! Too vast for those who are not medical doctors? No.
Undoubtedly, his scientific mind, rigorous and methodical, allows him to
address neuroscience holistically, covering both neurology and psychiatry.
These two sides of medicine were separated a little more than 40 years
ago, although so closely intertwined by the substrate on which they work
the nervous system. Neuropsychiatric diseases with an aging population
and the increasing stress accompanying a more urban life style are major
public health concerns. The incidence of multiple sclerosis, Alzheimer’s
disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and depres-
sion is constantly growing. What is the cause? Possibly aging. Also our life-
styles. Surely our environment. Neuropsychiatric medicine and research are
indeed changing, and the neurosciences represent the second investment
field in the development of new treatments.
A main focus of this book is to emphasize, rightly, the importance of
lipids in brain function both structurally and developmentally by high-
lighting the current understanding and data of their key roles. It is also
necessary to review the most emblematic pathologies in the neuropsychia-
tric field, which Claude performs with erudition and remarkable scientific
caution.
You will not find here provocation, miracle recipes, or magic foods.
However, you will have the most relevant data, such as the important
discoveries about the role of vitamin D in the development of the
nervous system, neuronal homeostasis, and neuropsychiatric diseases,
all derived from fundamental and medical research. Claude stresses
the importance of lipids in diseases ranging from multiple sclerosis
and autism to Alzheimer’s. Beyond the methodical and documented
descriptions, he stresses the importance of nutrition from birth to old
age to create the conditions for optimal maintenance of our neuronal
assets. The key issue here is thus aging well. Clearly, lipids are not a
panacea, and Claude balances the nature of his comments, supports his
arguments, and justifies his conclusions.
ix
x Foreword
Knowledge facilitates better insights, answers, and medical treat-

ments; therefore, I am convinced that this work, along with its compre-
hensive bibliography, is important for any researcher or physician
interested in the subject. It will also be a key tool for students by offering
a clear overview of the topic, stimulating their curiosity and their culture,
and providing an essential base to facilitate future research in the
neurosciences.
Prof. William Camu

Montpellier University Hospital
Montpellier, France
Acknowledgment
I sincerely thank my friend Louis Sarliève, INSERM Research Director, for
invaluable assistance in reading of the French and the English manuscripts.
I thank my wife for continuous support and invaluable involvement
in the correction of the final version of the French text.
xi
chapter one
Introduction
Research on the structure and function of the human brain started very
early in the history of medical science. Greek doctors, in the sixth century
BC, recognized the brain as the center of the highest human activities. At
the time of Galen in the second century AD, brain anatomy was already
known in detail, and the brain’s importance was established as the seat
of intelligence, voluntary movements, and sensations. The composition
of the brain generated a significant interest as early as the time of Plato
(428–348 BC), who considered this body part as equal to the bone marrow,
whereas Aristotle (384–322 BC) compared the brain to a fat deposit com-
parable to the spermaceti found in the brain of the sperm whale.
The first observations on the fatty nature of the brain were made in
the seventeenth century by the Danish physician Thomas Bartholin
(1616–1680), discoverer of the lymph system and of the glands present
in women that were given his name (Bartholin glands), and by the Dutch
inventor of the microscope and discoverer of the spermatozoids, Antoni
van Leeuwenhoek (1632–1723). But it was the early work of the French
chemist Michel Eugène Chevreul (1786–1889), the founder of lipid chem-
istry, that led the way for other researchers in the nineteenth century to
provide new knowledge about the composition of brain lipids: Nicolas
Vauquelin, Jean-Pierre Couerbe, Nicolas Gobley (all in France), and
Johann Thudichum (in Britain). All of these researchers described the nat-
ure of brain phospholipids, and Gobley and Thudichum also revealed the
presence of few simple acids (stearic, palmitic, and oleic acids).
In the 1960s, with the advent of more efficient analytical techniques,
many researchers focused on the richness of the brain and retina in doco-
sahexaenoic acid (DHA [22:6 ω-3]), a fatty acid found in 1942 in Japanese
fish (see Section 7.1). This fatty acid, called “marine fatty acid,” likely
appeared during the Cambrian explosion, about 600 million years ago,
when its synthesis became possible because of the rising atmospheric oxy-
gen levels above the Pasteur point responsible for aerobic life. In parallel,
complex cell types also appeared that were characterized by the presence
of a nucleus and several mitochondria, structures known to be common to
all cellular organisms called eukaryotes.
Among the discoverers of the biochemical features characteristic of
all nervous tissues, mention should also be made of John S. O’Brien
(University of California–San Diego). In 1965, he was one of the first to
1
2 Dietary lipids for healthy brain function
describe accurately the fatty acid composition of several lipid fractions

extracted from the white and gray substances of the human brain (O’Brien
and Sampson 1965). Similar observations were made by N. C. Nielsen
(Vision Research Institute, The Ohio State University) on beef retinal cells,
nerve cells specialized in the perception of light (Nielsen 1979). Nielson
found that the DHA content of the photoreceptor lipids was very large
(36%) and higher than that measured in synaptic membranes.
Very quickly and naturally, these biochemical features led investiga-
tors to suggest that high DHA levels in brain cell membranes should cor-
respond to a specific physiological function. One of the first assumptions
was that a dietary deficiency of this fatty acid during the development of
an animal or a human could hinder the formation of the myelin sheath,
known to isolate nerves, thereby inducing instability in the nervous sys-
tem and causing major disorders (Bernsohn and Stephanides 1967).
Subsequently and to this day, this specific affinity of the brain and retina
for DHA has prompted investigations showing the plurality of functional
roles for DHA in humans and animals (rat, monkey). Human clinical studies
have sometimes confirmed the results found in epidemiological studies.
Despite the resistance of the nerve tissue to any change after a dietary
modification, work published in 1971 first revealed that a prolonged diet-
ary deficiency of linolenic acid (18:3 ω-3), the precursor of DHA found in
plants, induced a decrease in the DHA content in rat retina (Anderson
and Maude 1971). Four years later, Wheeler et al. (1975) showed that these
changes were accompanied by a weakening of the electrical functioning of
the retina, thereby affecting the vision of DHA-deficient animals.
Independently of this work on vision, the influence of an essential
fatty acid deficiency on the general functioning of the brain was being
widely explored. It seems that the subject was first described in 1966 by
D. F. Caldwell in Detroit, Michigan. Caldwell and Churchill (1966) clearly
demonstrated that the administration of a diet devoid of fatty acids in
pregnant rats led to a serious reduction in the learning capacity of the
second-generation rats. However, these investigations could not target a
precise group of lipids because the food was totally delipidated.
Several researchers then showed that this lipid deficiency not only
decreased the learning ability of the rats, but also induced a large drop
in the DHA content in specific brain phospholipids (Lamptey and Walker
1976). Similar results were described in monkeys (Fiennes et al. 1973). In
France, Bourre et al. (1989) confirmed that a diet without linolenic acid,
but rich in linoleic acid, induced a significant decrease in learning ability
in rats. All this research finally allowed for the determination that ω-3 fatty
acids, and particularly their precursor linolenic acid, were responsible for
these physiological disorders. Using a fortification of the food given
to pregnant rats with a fish oil rich in DHA and eicosapentaenoic
acid (EPA [20:5 ω-3]), Yonekubo et al. (1994) in Japan demonstrated
Chapter one: Introduction 3
an improvement of learning capacities in young rats born from these

mothers, compared with animals ingesting no fish oil. In addition, this
DHA and EPA intake had no effect when fed during the postpartum per-
iod. From these investigations, it can be considered that surely DHA and
probably its precursor EPA are among the several components involved in
the “noblest” and most vital functions of the brain.
What could be the role of these particular fatty acids of marine origin
in brain function? The problem is very complex, but one of the mechan-
isms underlying the behavioral problems observed after a linolenic acid
deficiency was proposed by Delion et al. (1994) via work done in Tours
University, France. They showed that a linolenic acid deficiency was able
to induce important changes in neurotransmission pathways involving
dopamine- and serotonin-secreting cells in various regions of the rat brain,
changes likely interfering with the animal behavior.
Work on determining the major role of ω-3 fatty acids and especially
long-chain DHA in brain function, as demonstrated by Michael Crawford
of the Brain Chemistry and Human Nutrition Institute in London, pro-
moted with some success the hypothesis of their decisive intervention in
the anatomical and functional development of the human brain during
its development.
Indeed, from the anthropological studies we know that bipedalism,
present in Homo habilis 2 million years ago, was contemporaneous with a
significant increase in brain volume, a phenomenon likely accompanied
by the adoption of a meat-rich diet. These changes were favored by the
migration of this prehistoric early-human ancestor to aquatic areas rich in
land animals where DHA-concentrated prey could be found. Later, about
100,000 years ago, a further increase in brain volume led to modern humans
(Homo sapiens); this brain volume increase was contemporaneous with a
new migration toward East Africa in lakeshore areas or countries close to
marine environments. There, these humans found prey that supplied all of
the long-chain ω-3 fatty acids (EPA, DHA) needed to build the brain. In
addition, this migration was accompanied by a cultural explosion, marked
by the emergence of arts, religions, and unfortunately wars. This develop-
ment may ultimately be characterized more by higher brain functions
than by an increased brain volume (Horrobin 1998). As emphasized by
Horrobin, a prolific and popular English author, the differentiation of
humans and great apes can only be based on lipid metabolism, if one con-
siders the richness of these organic compounds in the brain and the impor-
tance of the neuronal connections.
Just as past trends have been influenced by a steady and increasing
supply of DHA, it is likely that the intellectual evolution of current humans
will depend on the consumption of foods rich in ω-3 fatty acids. The deple-
tion of marine animals suitable for human consumption, as a result of inten-
sive fishing and contamination by pesticides or heavy metals, should
encourage the development of a controlled aquaculture of fish or algae pro-

ducing DHA: this approach may be the only way to ensure good physical
and mental health for future generations.
The role of fatty acids in the functioning of the nervous system of
laboratory animals has been the subject of much research. Although a direct
link has not yet been established, the effects of these fatty acids on behavior
and cognitive abilities of these animals are no longer questionable. This
zoopsychological approach is necessary, but the transposition of the find-
ings from rat or even chimpanzee to the human cognitive domain remains
questionable. Despite the complexity of such research, it is not surprising
that neurophysiologists and psychiatrists were interested in these topics,
with some of them being already investigated in animals. Much epidemio-
logical research was recently undertaken, along with some therapeutic
trials. Thus, various aspects of child development, aging, neurological dis-
orders, or mood (or affective) disorders have been considered for therapeu-
tic or preventive actions. Although the mechanisms involved remain poorly
understood, applications of some of this research are beginning to be
successfully exploited in various situations.
In addition to fatty acids, many observations have indicated that other
lipids such as vitamins (A, D, and E), cholesterol, and some carotenoids
could contribute to maintenance of the noble functions of the brain in aged
people and also prevent serious neurological disorders such as epilepsy or
multiple sclerosis.
Similarly, many mood disorders, as classified in psychopathology,
seem to be under the control of these lipids. Numerous clinical studies
and some experimental interventions now suggest that supplementation
with some of these lipids may improve depressive and bipolar disorders,
schizophrenia, autism, and attention-deficit disorders and also contribute
to reduction in the intensity of aggressive or suicidal impulses.
If new results confirm the initial assumptions of the involvement of ω-3
fatty acids in brain function, and also other related compounds and vita-
mins belonging to the lipid group, it will be important to promote the
consumption of these natural substances, the supply of which should be
sufficient from a diversified diet. As suggested by D. Horrobin in 2003,
the deficiencies observed in a population at risk with an unbalanced diet
should be quickly filled by a supplementation with simple nutrients.
The treatment of mental disorders using a dietary approach is not yet
common among the public or medical doctors. It is significant that a recent
report by the Montaigne Institute in Paris evoked only the possibility of
vitamin D to counteract the environmental effects on mental illness.
Undoubtedly, lipid administration will gain momentum when patients
realize that the current research is usually performed by government teams
receiving no aid from the pharmaceutical industry. This independence
may encourage a pragmatic and sympathetic consideration from the public
Chapter one: Introduction 5
because all of the nervous disorders described in this book could poten-
tially be diminished without risk by a moderate dietary change or by a
simple supply of an appropriate supplementation. Although this cognitive
impairment approach in no way excludes modern medical therapy,
patients should be aware that any alternative or at least complementary
treatment already exists. This topic should be mentioned in the interview
between doctor and patient, especially after taking into account the docu-
ments related to the involved problems.
These encouraging results offer the potential for a new and important
treatment of many mental conditions that are currently a heavy burden on
social budgets. Indeed, the World Health Organization (WHO) found that
more than 450 million people suffer from behavioral or mental disorders
worldwide. In the European Union, a recent analysis has shown that 27%
of individuals aged 18–65 years suffered from psychiatric troubles during
the past year. In France, 1 in 5 people currently suffers from a mental dis-
order (12 million for the whole country), compared with 1 in 10 for cancer.
The Montaigne Institute and the “FondaMental Foundation” in France
estimated that in 2014 the costs associated with mental illness would reach
nearly 110 billion euros per year or 5.8% of the gross domestic product. In
comparison, the cost of cancer for the society was estimated at 60 billion
euros and that of cardiovascular diseases at 30 billion euros. As emphasized
in the Montaigne Institute report, only 2% of the budget of biomedical
research is actually devoted to these problems. It is thus time to make the
fight against mental diseases a public health priority. Taking into account
the steady lengthening of the “total” life expectancy and the incidence of
mental diseases related to old age, the main challenge of medicine in this
twenty-first century is to increase the “healthy” life expectancy. Failure to
achieve this ambitious goal will lead to formidable economic challenges
for all nations in the management of an increasing number of frail or depen-
dent older people.
The purpose of this book is to focus on the most important and recent
work on food lipids and human health, placing the work in a historical
context. Such research has provided some indisputable evidence of the
beneficial effects, even for a moderate intake, of some specific lipids, some-
times absent or introduced at too low amounts in the normal diet. It is
hoped that this information could be propagated widely to more easily
preserve and improve brain development in young people and mental
health of some adults, with only slight dietary modifications. Further-
more, these improvements involve only natural products that are much
cheaper than the current traditional drugs. Despite the lack of support
by pharmaceutical companies, the advances of these “nutritional treat-
ments” as highlighted in this book may be immediately applied by health-
care personnel for the greatest benefit of patients and the global health
budget.
It is regrettable that the basic rules of nutrition and dietetics are not
part of the general culture, a likely consequence of the absence of educa-
tion in these matters at all levels of schooling. Hopefully, the recent rela-
tionships noted between mental or neurological troubles and food lipids
will spur people to take responsibility for their health status. The informa-
tion in this book details how to live to old age in good health and in full
autonomy, particularly by slowing the inevitable decline of the upper
brain functions and by trying to avoid the development of the most
disabling nervous disorders.
References
Anderson, R.E., Maude, M.B. 1971. Lipids of ocular tissues – The effects of essen-
tial fatty acid deficiency on the phospholipids of the photoreceptor mem-
branes of rat retina. Arch. Biochem. Biophys. 151:270–6.
Bernsohn, J., Stephanides, L.M. 1967. Aetiology of multiple sclerosis. Nature
215:821–3.
Bourre, J.M., Francois, M., Youyou, A., et al. 1989. The effects of dietary
alpha-linolenic acid on the composition of nerve membranes, enzymatic
activity, amplitude of electrophysiological parameters, resistance to poi-
sons and performance of learning tasks in rats. J. Nutr. 119:1880–92.
Caldwell, D.F., Churchill, J.A. 1966. Learning impairment in rats administered a
lipid free diet during pregnancy. Psych. Rep. 19:99–102.
Delion, S., Chalon, S., Hérault, J., et al. 1994. Chronic dietary alpha-linolenic acid
deficiency alters dopaminergic and serotoninergic neurotransmission in rats.
J. Nutr. 124:2466–76.
Fiennes, R.N., Sinclair, A.J., Crawford, M.A. 1973. Essential fatty acid studies in
primates linolenic acid requirements of capuchins. J. Med. Primatol. 2:155–69.
Horrobin, D.F. 1998. Schizophrenia: the illness that made us human. Med. Hypoth-
eses 50:269–88.
Lamptey, M.S., Walker, B.L. 1976. A possible essential role for dietary linolenic
acid in the development of the young rat. J. Nutr. 106:86–93.
Nielsen, N.C., Fleischer, S., McConnell, D.G. 1979. Lipid composition of bovine ret-
inal outer segment fragments. Biochim. Biophys. Acta 211:10–19.
O’Brien, J.S., Sampson, E.L. 1965. Fatty acid and fatty aldehyde composition of
the major brain lipids in normal human gray matter, white matter, and myelin.
J. Lipid Res. 6:545–51.
Wheeler, T.G., Benolken, R.M., Anderson, R.E. 1975. Visual membranes: specificity
of fatty acid precursors for the electrical response to illumination. Science
188:1312–14.
Yonekubo, A., Honda, S., Okano, M., et al. 1994. Effects of dietary fish oil during
the fetal and postnatal periods on the learning ability of postnatal rats. Biosci.
Biotech. Biochem. 58:799–801.
chapter two
Brain development
It has long been known that low-weight newborns (less than 2500 g) are
more common in environments with the lowest socioeconomic status.
After examining the dietary habits of mothers, it became clear that mater-
nal nutrition plays a key role. For example, a rigorous study in East
London found that mothers of such children had a dietary energy defi-
ciency, but that deficit could be mostly attributed to lipids, a relationship
implying logically a deficiency in essential fatty acids as well as lipidic
vitamins such as vitamin D and E (Crawford et al. 1986). Although the
hypothesis of essential fatty acid involvement was quickly confirmed by
the analysis of maternal blood, the intervention of vitamins, in particular
vitamin D, has still to be confirmed.
The benefits of breastfeeding in child survival were recognized long
ago in that breast milk had a role in preventing the sometimes fatal effects
of bacterial infections. It is now certain that it guarantees the development
of intelligence, higher performance in school, and even social level in
adults (Victora et al. 2015).
The influence of nutrition on brain development is in short a manifes-
tation of neuronal plasticity as mentioned by neurologists when put at the
service of rehabilitation or functional repair of brain damage. The harmo-
nious development of the brain and cognitive performance in children as in
adults is conditioned by several lipid nutrients. Unfortunately, only three
of these lipids have been the subject of specific research: ω-3 fatty acids,
vitamin D, and vitamin E. The effects of vitamin A are not well known
because experimental research used global supplementation of various
micronutrients, thereby masking the specific effects of that vitamin.
2.1 ω-3 Fatty acids

Among the essential fatty acids (Section 7.1), the links between ω-3 fatty
acids and cerebral function were established early. Since the 1960s, it
is known that docosahexaenoic acid (DHA [22:6 ω-3]) is the brain’s major
ω-3 fatty acid (about 10%–15% of total fatty acids, about 5 g in an adult brain),
with the other ω-3 fatty acids amounting to less than 1% of total fatty acids.
The DHA concentration varies according to the diet and the age of the sub-
ject; it is higher in the young and lower in the elderly. It is synthesized, as
eicosapentaenoic acid (EPA [20:5 ω-3]), by marine phytoplankton and some
7
animals, but not by higher plants. Notably, these two “noble” fatty acids,
DHA and EPA, are absent from vegetable oils and seeds and are found at
very low concentrations in fats of mammalian or poultry meat and in milk
and eggs. The most generous sources are marine fish (or fish oil) and some
other marine animals (molluscs, shellfish) (Section 7.2). Humans may
directly absorb these fatty acids from food, and they also can synthesize
them, albeit slowly, from linolenic acid (18:3 ω-3) that is present in plants
and mainly in some vegetal oils (walnut, soybean, linseed). That biosynth-
esis, the exact efficiency of which is still controversial, is complex and
involves a cascade of enzymes that sequentially elongate, desaturate, and
oxidize the carbon chain (Section 7.1).
EPA and DHA biosynthesis efficiency appears to be higher in
women than in men, but it has been shown that a dietary supplementa-
tion of linolenic acid in pregnant women has no effect on the DHA levels
in maternal blood (de Groot et al. 2004). So, a strict vegan diet (excluding
products and by-products of animal origin) could not be compatible with
normal fetal development, although several observations suggest that an
intake of only linolenic acid would be sufficient to maintain suitable
brain DHA levels. This important issue deserves further epidemiological
research. Importantly, throughout pregnancy, the placenta facilitates the
transfer of DHA from the mother’s body to the fetus, with its supply
being ensured to the newborn through milk (breast or formula). Because
DHA level in milk depends on the maternal diet, it is recommended that
nursing women continue to consume foods rich in marine products.
Indeed, it has been shown that even in Denmark, where fish is frequently
consumed, breast milk provides only one fifth of the recommended vita-
min D intake to the newborn (Streym et al. 2016).
For ethical reasons, experiments using dietary restriction of ω-3 fatty
acids could be performed only in animals. Despite the usual objection
for their transposition in humans, it has been established that an ω-3 fatty
acid deficiency in developing animals produced a DHA depletion in the
brain and that this depletion was associated with lower learning abilities.
Many studies have confirmed that lower DHA levels in nerve cell mem-
branes always induced a slowdown in neurogenesis, the formation of neu-
ronal connections, and cell migration, with these events having negative
consequences for brain growth and function.
It seems now clear that DHA deficiency in humans as in animals is cri-
tical for brain development, but details and importance of the effects are not
fully understood. The impossibility to perform experiments in humans, as
in rats, explains the lag time for our knowledge in this area. Moreover,
in mammals the main fact that emerges is the very different timing of
the brain growth spurt in relation to birth in different species (Figure 2.1).
These features are at the origin of the concept of vulnerability during a
so-called critical period when fast changes in function and structure occur.
Chapter two: Brain development 9
Human
6
Monkey Rat
Weight, %
–30 –20 –10 +10 +20 +30

Age Birth Age
Figure 2.1 Evolution of brain growth in human, monkey, and rat. Weight increase
is expressed in percentage of the brain weight in adults. The time unit has been
adapted for each species: 1 day in rat, 4 days in rhesus monkey, and 1 month in
human. (Modified from Dobbing, J., and Sands, J., Early Hum. Dev., 311, 74–83,
1979. With permission.)
Thus, unlike in monkeys, rats are born very immature, with this feature
being advantageous for the investigator. In contrast, the central nervous sys-
tem of humans grows very rapidly in the perinatal period. Therefore, we
must remain cautious about the conclusions drawn from experiments done
in different animal species focusing on the central nervous system as well as
for other physiological situations that may vary during body development.
The studies of human brain development have suggested that incor-
poration of DHA is essential at the end of the gestation period and imme-
diately after birth (Clandinin et al. 1980). Indeed, it has been found that
nearly 80% of the sum of embryonic arachidonic acid (20:4 ω-6) and
DHA are deposited in the last 3 months of gestation. During these 3 months,
the fetus has accumulated about 67 mg of DHA per day and about 75 mg
during breastfeeding (Makrides and Gibson 2000). The whole amount
should come from the lipid deposit of the mother, with these stocks being
recovered during several months after birth. Considering these data, it is
easier to appreciate the maternal needs of ω-3 and ω-6 fatty acids during
pregnancy and later, especially in the case of a long-lasting breastfeeding.
Through animal studies, it can be assumed that intake of polyunsatu-
rated fatty acids guarantees harmonious development of brain functions
in the early childhood, after 2 years, and toward the final period of brain
maturation.
A confirmation of this hypothesis was reported in 1990 among low-

weight newborns (1000–1500 g) via work done by Dr. R. D. Uauy (Depart-
ment of Pediatrics, Medical School of Dallas, Texas). Indeed, Uauy et al.
(1990) demonstrated that the addition of ω-3 fatty acids from fish oil in
reconstituted milk provided the same results as breast milk in relation
to retinal function. The addition of linoleic acid (LA [18:2 ω-6]) added or
not to linolenic acid (18:3 ω-3) provided the worst results. Subsequent
research, largely carried out by Dr. D. L. O’Connor and colleagues at
The Hospital for Sick Children (SickKids) in Toronto, Canada, has led to
the same conclusions. In addition, there were beneficial effects on both
motor development at 12 months and vocabulary comprehension at
14 months (O’Connor et al. 2001).
Other research in this area is less categorical about the favorable effects
of DHA, and all neonatologists are waiting more coordinated work with
greater numbers of children subjected to comparable experimental proce-
dures and finally tested with unified tools to better assess their psychomo-
tor development (Molloy et al. 2012). Research has identified the essential
role of DHA and sometimes arachidonic acid in the anatomical and func-
tional maturation of the brain. For example, blood DHA levels were
observed to be higher in breastfed children than in those fed with a specia-
lized newborn formula (Sanders and Naismith 1979). In rhesus monkeys
(Connor et al. 1990) as well as in humans (Makrides et al. 1994), brain ana-
lyses have shown that breastfeeding ensured the highest DHA concentra-
tions. In addition, Crawford (1993) promoted the idea that DHA was, as
arachidonic acid, a vital compound in breast milk in ensuring the best
development of a child’s brain. Shortly afterward, a large meta-analysis
consisting of 20 clinical studies conducted in six countries showed that com-
pared with infant formulas, breastfeeding was significantly associated with
better cognitive development (Anderson et al. 1999). Importantly, at that
time infant formulas were not supplemented with DHA or arachidonic
acid, and the ongoing changes in the production of formulas resulted from
this research.
Many studies have been carried out to examine the possible effects of
DHA intake on cognitive and motor development in children. In Denmark,
Lauritzen et al. (2005) could not identify any effect. These negative results
have been explained by the experimental use of too low amounts of
DHA, an usually large consumption of fish in northern populations, or
by balanced diets already rich in essential fatty acids. Moreover, these com-
pounds may induce very early in life psychomotor effects that are unable
to be detected by the current tests (Section 7.9) due to their unsuitability or
low sensitivity.
The large DOMIno study, conducted in five Australian maternity hos-
pitals, based on a supplementation of pregnant women (from the 21st week
to birth) with DHA, did not detect any modification of cognitive and
language development in children aged 18 months or 4 years (Makrides

2016). These negative findings seem to highlight the importance of breast-
feeding because these Australian children were fed only infant formulas.
Several studies have shown that after 4 to 6 months of normal breast-
feeding, a diet enriched with DHA for 1 year had a beneficial effect on the
development of vision in children (Hoffman et al. 2003).
The clinical work published between 2001 and 2008 by Dr. I. B. Helland
(Department of Pediatrics, University of Oslo, Norway) provides the first
serious database enabling the conclusion for improved child mental devel-
opment when the mother has ingested fish oil during 5 months before birth
and during the first 3 months of breastfeeding. These beneficial effects are
clearly observed at 4 years or age (Helland et al. 2003), and some of them
still remain even after 7 years of age (Helland et al. 2008).
How were these conclusions reached? In these studies, selected
mothers were given daily for defined periods 10 mL of cod liver oil (pro-
viding approximately 2.5 g of ω-3 fatty acids). Control subjects received
corn oil (providing about 4.7 g of LA and 92 mg of linolenic acid). At
the age of 4, the children of these mothers were submitted to intelligence
testing according to the Kaufman Assessment Battery for Children. This
classic multi-subtest battery (Section 7.10) aims to evaluate both intelli-
gence and knowledge by using three scales: sequential processing, simul-
taneous processing, and nonverbal abilities. The study of these 4-year-old
children has shown that the children from mothers ingesting fish oil
(48 children) tested 4.1 intelligence quotient (IQ) points higher than those
from mothers ingesting vegetable oil (36 children). The former children
had also a head circumference at birth that was significantly higher than
that of the latter children. At the age of 7 years, the researchers did not
find any IQ difference between the two groups; however, the positioning
on the scale of the sequential processing was still in favor of children born
from mothers who were supplemented with fish oil.
As the authors pointed out with some humor, if new teaching meth-
ods could increase the IQ by 4 points, education authorities would imme-
diately implement the methods. So, why are these intelligence effects in
children via dietary supplementation administered in pregnant women
ignored? In addition, such treatment is without side effects. If there is
any doubt, why not extend these experiences to several groups of women
belonging to different social positions? The interest of such results would
justify the cost of the research work needed to obtain them.
Another study, published by Dr. E. E. Birch (University of Texas–Dallas)
and colleagues, underscores the importance of a diet enriched with DHA
(together with arachidonic acid) for only 17 weeks after birth on visual
acuity and cognitive development (Birch et al. 2007). By comparing the
effects of breastfeeding and infant formula supplemented or not with
DHA plus arachidonic acid, Birch et al. (2007) clearly showed that the
worst results on visual acuity and IQ based on verbal expression are

observed among children receiving no DHA after 4 years. A large European
study (United Kingdom, Belgium, Italy) has revealed that 6-year-old
children who had received a diet enriched with DHA and arachidonic
acid for 4 months after birth were faster at processing information com-
pared with children who received an unsupplemented formula (Willatts
et al. 2013).
A review conducted by Protzko et al. (2013) at the University of
New York focused on a dozen recent studies exploring the effects of a
maternal supplementation with at least 1 g of DHA or an infant supple-
mentation with a reconstituted milk containing up to 0.5 g of DHA and
EPA per 100 g of lipids. All the screened studies have shown that such
a nutritional therapy clearly enabled the measurement of higher IQ sev-
eral years later. After such results, Dr. Protzko did not hesitate to give
as a title for his article, “How to make a young child smarter: evidence
from the database of raising intelligence.”
The scientific community has not entirely adopted the providential
efficiency of ω-3 fatty acids in improving child neurological development.
Those who are the most critical will hide behind the relatively inconclu-
sive conclusions that arose from some meta-analyses, such as the analysis
performed in Australia (Gould et al. 2013). Studies have highlighted many
methodological limitations, but despite reservations, a benefit of the
supplementation with ω-3 fatty acids on cognitive development in 2- to
5-year-old children has been validated. The complexity of this research
is noticeable when one considers the work of Dr. C. L. Jensen and
co-workers (Baylor College of Medicine, Houston, Texas), performed with
5-year-old children whose mothers had received 200 mg of DHA daily for
the first 4 months of breastfeeding (Jensen et al. 2010). The results have
shown that among the battery of 12 neuropsychological tests, only the test
measuring the children’s attention revealed a highly significant positive
effect of the maternal treatment.
In another study, the offspring of an important cohort of 338 women
in Mexico participating in a trial of daily 400-mg DHA supplementation
during the latter half of pregnancy were assessed (Ramakrishnan et al.
2015). At 18 months of age, no overall differences in infant cognitive,
motor, or behavioral development, as measured by the Bayley Scales
of Infant Development (Section 7.9), were found. Nevertheless, the sup-
plementation has attenuated the positive association between home
environment and psychomotor development index observed in controls,
suggesting potential benefits for children living in poor-quality home
environments. The follow-up of the same children up to 5 years of age
showed that DHA supplementation in the second half of pregnancy
had a significant potential to improve sustained attention in preschool
children (Ramakrishnan et al. 2016).
A follow-up of the large DOMInO trial is presently being carried out

to explore the effects of prenatal DHA supplements on child development
beyond the age of 3 years; the results are expected ca. 2018 (Gould et al.
2016).
It is clear that research of the effects of some nutrients on cognitive
development is paved with many difficulties, thereby explaining the wide
dispersion of results and the complexity of the comparisons between inves-
tigations that may seem, at first, similar. The greatest challenges remain the
need to select subjects with well-known fatty acid status; to design well-
defined control groups; and to do experiments for prolonged times, with
the time needed to feed the brain with lipids not being that of the general
body feeding.
The determination of the organizers of the large French EDEN survey
was appreciated in conducting cooperative programs in several epide-
miology laboratories of Institut National de la Santé et de la Recherche
Médicale (INSERM) and in the university hospitals of Poitiers and Nancy
(https://eden.vjf.inserm.fr/). That survey consists of a general study of
many people focusing on what determines child psychomotor develop-
ment and health before and after birth.
Among several topics, nutritional intake of ω-3 and ω-6 fatty acids was
estimated in late pregnancy and was associated with the nursing times,
with evaluations of language at the age of 2 years and psychomotor devel-
opment at the age of 3 years made by parents and assessments made by
psychologists at the age of 3 years.
Taking into account a set of characteristics in children and their
families, the first results showed that the longer the breastfeeding, the
better the children’s cognitive performances at the ages of 2 and 3 years
(Bernard et al. 2013). Among nonbreastfed children, the lower the ω-6 fatty
acid/ω-3 fatty acid ratio in the maternal diet, the higher the psychomotor
development scores in children at the ages of 2 and 3 years. Moreover,
even if mothers have a diet rich in ω-6 fatty acids in late pregnancy, better
language development was observed in children at the age of 2 years
when breastfeeding was practiced longer.
Ethically acceptable ways to estimate the importance of arachidonic
acid in the presence of DHA include the comparison of dietary treatments
with DHA only and with DHA and arachidonic acid or the comparison of
treatments with various ω-6/ω-3 fatty acid ratios. The latter option was
adopted in a study of very preterm infants (<1500 g at birth) comparing
two levels of arachidonic acid with constant DHA. The outcomes were
that infants consuming formulas with greater arachidonic acid (twofold)
had better psychomotor development at 2 years of age (Alshweki et al.
2015). Furthermore, the psychomotor development of the former group
was similar to that of comparable infants who were fed exclusively with
breast milk. As emphasized by the authors, these results may be explained
if it is recalled that arachidonic acid is a key component of cell membranes,

serving as a precursor to prostaglandin formation, and being involved in
the signaling systems of the brain. Generally, the weight of existing clini-
cal evidence favors arachidonic acid inclusion with DHA.
Therefore, these important findings suggest that the ω-6/ω-3 fatty
acid ratio in the maternal diet may directly influence the development
of children’s brains, mainly during pregnancy, but that breastfeeding
can still overcome nutritional mistakes of the mother, at least for the qual-
ity of lipids.
In the future, the monitoring of children up to the age of 5 years will
enable clinicians to examine the persistence of the beneficial effects of a
steady ω-3 fatty acid intake.
These early results showing all the beneficial effects in newborns of
a natural diet “for their growth, development and short, medium and
long term health” echo the international recommendations made by
WHO in 2007 advocating an exclusive breastfeeding up to 6 months
(http://whqlibdoc.who.int/publications/2008/9789241596664_eng.pdf).
It does not seem possible to doubt the long-term effects when taking
into account the results obtained in Brazil from a study of about 3500 new-
borns (Victora et al. 2015). This study has indeed verified, on the basis of the
IQ estimated between 6 months and 30 years after birth, that breastfeeding
improves intellectual performance. That improvement may have a signifi-
cant impact detectable 30 years later by a higher level of education and even
a higher income in adulthood. Victora et al. (2015) determined that children
breastfed for 1 year have an IQ that is 4 points higher than that measured
in children breastfed only 1 month. These results therefore confirm the
findings reported by the WHO after an analysis of 14 studies published
from 1988 to 2011: “This meta-analysis suggests that breastfeeding is asso-
ciated with increased performance in intelligence tests in childhood and
adolescence, of 3.5 points on average” (Horta and Victora 2013). Many
studies of brain imaging have confirmed these findings, stating that breast
milk allows the brain to develop faster. In addition, at Brown University
(Providence, Rhode Island), Deoni et al. (2013) established that breastfeed-
ing promotes myelin development, especially in brain areas related to
language, emotions, and cognitive abilities. Also, a 7-year longitudinal
study in Australian preterm infants determined that a predominantly
breast milk feeding in the first 28 days of life was associated with greater
gray matter volume and better IQ, academic achievement, working
memory, and motor function at 7 years old (Belfort et al. 2016).
It is surprising that the recommendations made in the early twenty-
first century correspond to the conclusions made almost a century ago
in the United States after a study of a “socially disadvantaged group”
(Hoefer and Hardy 1929). In France, the National Program for Nutrition
and Health has recommended breastfeeding “exclusively up to 6 months
age and at least up to 4 months age for health benefits” (Hercberg et al.
2008). In addition, to the increase in the breastfeeding frequency from
birth, that program recommended to increase its duration, if possible over
6 months, even during food diversification, a time when foods and bev-
erages other than milk are introduced. Similarly, WHO recommended that
breastfeeding be initiated within the first hour of birth and be exclusive for
6 months, with the introduction of complementary food after 6 months
and continued breastfeeding up until 2 years or beyond.
Despite these common sense recommendations that are also based on
corresponding findings in a multitude of scientific work, postnatal feed-
ing, although improving in all countries, is still far from matching recom-
mendations of the official texts.
In the United States, according to the Department of Health and Human
Services, breastfeeding rates continue to rise. In 2011, 79% of newborn infants
started to breastfeed, but breastfeeding did not continue for as long as recom-
mended. Of infants born in 2011, only 49% were breastfeeding at 6 months
and 27% at 12 months.
In Europe, WHO has estimated that only 25% of infants were exclu-
sively breastfed for the first 6 months during a 2006–2012 study, compared
with 43% in South East Asia. WHO has recommended that breastfeeding be
initiated within the first hour of birth and be exclusive for 6 months, with
the introduction of complementary food after 6 months and continued
breastfeeding up until 2 years or beyond. In Europe, the country with the
highest rate of breastfed babies is Norway: 99% of new mothers initiate
breastfeeding at the hospital and 80% still do it after 6 months.
In France, the Epifane 2012–2013 study (Perinatal and Nutritional
Monitoring Unit, Institute of Health Monitoring, Uspen) revealed that at
birth 59% of infants are breastfed. However, 3 months later, no more than
39% were breastfed, with only 10% exclusively. After 6 months, 23% of
children were still breastfed, but only 1.5% exclusively. Thus, the median
value of breastfeeding is 15 weeks and that of the exclusive breastfeeding
is only 24 days. As noted by the authors of that report, it seems imperative
to better spread and adapt the messages on infant feeding during the first
year of life.
To avoid the problems associated with analytical costs, and lengthy
and cumbersome food surveys, other investigators have used an “ecologi-
cal” approach, already adopted in various epidemiological studies such
as those aiming at the determination of the incidence of disease in differ-
ent geographical regions. This compelling approach was adopted by
Dr. W. D. Lassek at the University of Pittsburgh, Pennsylvania. This work
(Lassek and Gaulin 2014) has taken into account the national data pub-
lished in 28 countries worldwide on the fatty acid composition of breast
milk and the intellectual scores of students at the end of the compulsory
education (at the age of 15 years) (Figure 2.2). These data were measured
China
Hong Kong
550 Singapore
Korea
Finland Japan
Canada
The Netherlands Taiwan
Germany
Australia
Average PISA score
United Kingdom Norway

500 United States Denmark
Sweden France
Hungary
Italy Portugal
Spain
Israel
Turkey
450
Chile
Thailand
Mexico
400 Brazil
Argentina
–2.2 –2.0 –1.8 –1.6 –1.4 –1.2 –1.0

log DHA/LA
Figure 2.2 Relationship between the PISA test score in 15-year-old children and
the docosahexaenoic/linoleic acid (DHA/LA) ratio in breast milk for 28 countries.
1: Argentina, 2: Australia, 3: Brazil, 4: Canada, 5: Chili, 6: China, 7: Denmark,
8: Finland, 9: France, 10: Germany, 11: Hong Kong, 12: Hungary, 13: Israel,
14: Italy, 15: Japan, 16: Korea, 17: Mexico, 18: The Netherlands, 19: Norway,
20: Portugal, 21: Singapore, 22: Spain, 23: Sweden, 24: Taiwan, 25: Thailand,
26: Turkey, 27: United Kingdom, 28: United States. (Modified from Lassek
W.D., and Gaulin, S.J., Prostaglandins Leukot. Essent. Fatty Acids, 9, 195–201,
2014. With permission.)
by the Program for International Student Assessment (PISA). Notably, PISA,

managed by the Organisation for Economic Co-operation and Development,
aims to follow every 3 years the evolution of the performance of education
systems in member countries and 60 partner countries. The results are also
widely disseminated and discussed in the press, with each country trying
to understand and analyze its place in the general classification. The inves-
tigations of W. D. Lassek have taken into account the assessments of the
three skills measured in 2009 and 2012: reading, mathematics, and science.
The authors have decided to consider the quantitative ratio of the two
major milk fatty acids, DHA and LA, rather than to consider only the
DHA levels. In fact, the scientific community agrees that the physiological
importance of DHA closely depends on the concentration of LA, the major
component of the ω-6 fatty acid series (Section 7.1).
The main result of this large survey is that a tight correlation exists
between the PISA test scores in the 28 countries and the values of the
DHA/LA ratio in maternal milk. It is clear from this study that the
increase in cognitive performance in school-age children may be obtained
not only by increasing dietary DHA levels, but also mostly by decreasing
LA levels, as LA is the major fatty acid component of our modern foods.
Importantly, when the social level of the children estimated through the
gross domestic product and the education spending per student are taken
into account in the statistical calculation, the findings were not altered.
These results confirm those made in very young children and even in ani-
mals, showing that an excess of dietary LA has a negative effect on the
cognitive development. Although all work in this area did not lead to
the same conclusion, none brought evidence of opposite outcomes. This
should be of interest to medical professionals and especially pregnant
women so that they receive recommended dietary advice to optimize
the motor and cognitive development of their children. It is therefore pru-
dent to not exceed the stated recommended daily allowance for LA, as
indicated by the competent French authorities (Section 7.2). As wisely
highlighted by the French National Agency on Food Safety, Environment,
and Workplace Security (Agence nationale de sécurité sanitaire
de l’alimentation, de l’environnement et du travail [ANSES]), these values
(calculated as the percentage of the child’s total energy intake) must be
regarded as maximum and not optimum because they are the results of
studies showing that excessive LA intake is associated with a decrease
in the beneficial effects of ω-3 fatty acid (Leray 2015). The Nutrition
Committee of the French Pediatrics Society endorsed these conclusions
in 2014 by publishing on its website a detailed report on lipid intakes in
children under 3 years of age (http://www.sfpediatrie.com).
The most efficient dose of DHA to be added to the diet of pregnant or
breastfeeding women is yet to be defined, mainly in relation to their eating
habits. Admittedly, the pharmaceutical industry fully understood the
messages published by scientists, and it is pleased that it is possible
now to get infant formulas containing up to 20 mg of DHA per 100 mL
of reconstituted milk. The European Union and the US Food and Drug
Administration have set up milk composition standards and have also
recommended production methods preserving the added essential fatty
acids. In France, ANSES has proposed new values for the recommended
dietary allowances (RDAs) (Section 7.2). Regarding pregnant and nursing
women, the RDA for DHA (250 mg/day) and the sum DHA plus EPA
(500 mg/day) “are based on epidemiological and clinical studies that have
evaluated the impact of food intake on pregnancy parameters and on
visual and cognitive development in young children. They are also based
on the values and the arguments for adult men or women, in terms of dis-
ease prevention.” For newborns and infants, the DHA concentration must
be at least 10 mg/100 mL of liquid formula. For children older than
6 months, the RDA must be between 70 and 250 mg according to age.
Advertising has naturally exploited this information; a manufacturer
has even used the following assertion: “breast milk contains mostly good
mono- and polyunsaturated fats essential for proper brain development
and vision. A polyunsaturated fatty acid deficiency could reduce the final
size of the brain by 40%!”
The epidemiological investigation of Dr. J. R. Hibbeln at the National
Institutes of Health (NIH) in Bethesda, Maryland, has shown that the ben-
eficial effects of ω-3 fatty acids on child development should only be
expected for a consumption of marine products exceeding 340 g/week
(Hibbeln et al. 2007). According to this specialist, the possible risk gener-
ated from the presence of potential contaminants is far outweighed by the
expected health benefits. If there is too strong of a reluctance or an inabil-
ity to eat that amount of fish, a supplementation with fish oil or purified
preparations of ω-3 fatty acids is needed.
Gynecologists and pediatricians seem to have understood the alert
messages from scientists specializing in this field because they frequently
prescribe dietary supplements to pregnant or breastfeeding women that
offer from 160 to 300 mg of EPA plus DHA per day (in the United States:
Prenatal DHA, Opti3, Coromega omega-3, Safe catch products; in France:
Femibion grossesse, Gestarelle G, Gynefam, Oligobs allaitement, Sérénité
grossesse).
The influence of the ω-3 fatty acids contained in our food on brain
development is the subject of numerous clinical and psychological studies
and gradually becomes a significant matter of importance to public health.
A concerted and large effort is needed to better understand the effects of
these nutrients on the brain, mainly emphasizing the nature of the mechan-
isms involved. Responses have been already provided on the possible role
of DHA in neurotransmission and neurogenesis and even in protection
against oxidation, a well-known chemical stress that tends to kill our very
active nerve cells.
Because considerable evidence has accumulated to show that genetic
variation has marked effects on polyunsaturated fatty acid metabolism
(Glaser et al. 2011), the study of specific gene variants should now be
included in all intervention trials addressing biological effects of ω-3
fatty acids on cognitive development.
The current research interest for ω-3 fatty acid supplementation to
improve offspring neurodevelopment seems obvious because 10 studies
in this area were listed in 2016 on the official website of the NIH Clinical
Trials (http://ClinicalTrials.gov).
Although the findings are relevant, it remains yet to inform pregnant

women as soon as possible about the beneficial effects of ω-3 fatty acids,
especially those of marine origin, on the brain development of their babies.
Present research results suggest the future of children depends on mater-
nal diet, so is it not worth it? It is certain that the first message to spread
to expectant mothers is to follow dietary recommendations that include a
regular and sufficient supply of ω-3 fatty acids of vegetable (canola, wal-
nut oil) and animal (marine fish) origin and avoid an excess of ω-6 fatty
acids from sunflower, corn, or peanut oils. Similarly, the current state of
research and recommendations by the official academic associations
should alert parents to keep their children until the age of 3 years on
an adequate supply of DHA and linolenic acid, while minimizing the lino-
leic acid contribution (Section 7.2).
2.2 Vitamin D
Vitamin D is a lipid that has been the target of considerable work in rela-
tion to nervous system development. That interest seems justified because
it has been shown that maternal vitamin D deficiency is linked to health
problems in children, affecting, in general, fetal development, skeleton for-
mation, and particularly the respiratory system. This deficiency is wor-
sened by a lifestyle avoiding sunshine for fear of skin cancer or through
clothing habits. Animal experiments verified that a prenatal vitamin D
deficiency clearly induced interference in nerve signals between neurons
and could cause impaired brain function in adults. All the physiological
and biochemical data have suggested that vitamin D is an important para-
meter to consider in studying infant development.
As for multiple sclerosis (Section 5.2.2), epilepsy (Section 5.3.2), schizo-
phrenia (Section 6.1.3.2), and autism (Section 6.1.5.2), cognitive development
during childhood seems to be dependent on the month of birth of the
subjects, giving additional evidence of a possible relationship with the synth-
esis capacity of vitamin D by the skin under the effect of solar radiation.
It has long been recognized that children born in winter or spring are
statistically heavier and larger than those born in summer or in autumn.
Academically, many studies have shown that children born in summer
had statistically more learning difficulties than others, with these differences
being persistent even until the age of 10 or 11 years (Martin et al. 2004).
These results suggest a link between cognitive development and sunshine,
and thus vitamin D. Therefore, a birth in summer implies that the first and
second quarter of pregnancy elapsed in winter or early spring, poorly sun-
ny seasons and therefore critical for vitamin D synthesis. From these obser-
vations, it is possible to deduce that a significant vitamin D supply in the
third trimester of pregnancy, in summer in the Northern Hemisphere, prob-

ably has no effect on child cognitive development.
The hypothesis of the influence of vitamin D through sunshine was
exploited by Dr. J. J. McGrath. McGrath et al. (2006) investigated the impact
of the birth season of children of approximately 50,000 women living in 11 dif-
ferent US sites on various anthropometric and cognitive characteristics. The
tests used were the Bayley Motor Test at the age of 8 months and the Wechsler
Intelligence Test at the age of 7 years (Section 7.9). The results of that large
survey have shown clearly that children born in winter and spring had
higher anthropometric measurements (height, weight, head circumference)
and cognitive scores than children born in summer and autumn, with these
score differences being still noticeable at the age of 7 years.
After analyzing these last two works, it seems logical to conclude that
vitamin D is involved for optimal physical and mental conditions in chil-
dren, with this vitamin being synthesized more abundantly during sun
exposure of pregnant women in summer or in early fall. Furthermore, it
is possible to conclude that optimal vitamin D levels are needed during
the first and second trimesters of pregnancy.
Would additional research determine more clearly the critical time?
Perhaps a response could come from comparing the state of vitamin D
found in the maternal blood at different periods with neurocognitive data
estimated in children. Despite the importance of this subject, little research
has been devoted to the relationship between vitamin D deficiency in
pregnant women and the delay in child cognitive development.
One group of researchers has explored vitamin D status at the end of
pregnancy, and another in early or the middle of the second quarter. In
the first group, Dr. C. R. Gale (University of Southampton, UK) and col-
laborators could not detect any correlation between vitamin D blood
levels measured in the third trimester of pregnancy and cognitive func-
tions as well as psychological health of children estimated at the age of
9 years (Gale et al. 2008). These results allowed again for the considera-
tion that the last trimester of pregnancy is not a critical period. These
findings were confirmed in Denmark (Strom et al. 2014) and in the
United States (Keim et al. 2014). In China, vitamin D determinations in
umbilical cord blood in parallel with the estimation of the cognitive
development of children aged 16–18 months have provided equivocal
results, probably as a result of a general vitamin D deficiency diagnosed
in mothers (6–24 ng/mL plasma) (Zhu et al. 2015).
In the second group, Dr. A. J. Whitehouse (Perth, Australia) and associ-
ates studied 743 mother–infant pairs; vitamin D was measured in mothers
in the second quarter of pregnancy, and the children were subjected to neu-
ropsychological testing at the ages of 5 and 10 years (Whitehouse et al.
2012). Results showed that the status of the maternal vitamin D was not
related to the children’s emotions or behavior but that it was statistically
related to their verbal and reasoning performances (Peabody Picture

Vocabulary Test, Section 7.9). Thus, a maternal vitamin D deficiency during
the second trimester of pregnancy increased the risk of troubles in language
development that were detectable up to 5–10 years after birth. The same
year, Morales et al. (2012) in Spain showed in 1820 mother–child pairs that
a high vitamin D concentration measured in the second trimester of preg-
nancy was significantly associated with better mental and psychomotor
development, estimated with the Bayley Scale (Section 7.9). Thus, mothers
with a sufficient vitamin D concentration (>30 ng/mL) had children who
displayed an advantage of almost 2.5 points compared to children from
vitamin D–deficient mothers (<20 ng/mL).
From these investigations, it may be concluded that an optimal vitamin
D intake must be maintained in pregnant women during the first months of
pregnancy, with an apparent consensus being settled around a critical win-
dow in the second quarter. It seems also important to consider the experi-
ment conducted in India by Mithal and Kalra (2014), demonstrating that it
is necessary and safe to administer to pregnant women between 1000 and
2000 international units (IU)/day of vitamin D from the second trimester
of pregnancy and even 4000 IU in case of deficiency. A study in new Zealand
has also shown that maternal vitamin D supplementation (100,000 IU/
month) in lactating women during the first 5 months of breastfeeding
improved the vitamin D status of the mother and are not only safe but also
may improve the vitamin D status of the breastfeeding infant and subse-
quently prevent a deficiency in the first 6 months of life (Wheeler et al. 2016).
Given the immaturity of the nervous system in newborns and its slow
development during the following years, it is imperative to follow pro-
phylactic measures recommended by the official organizations for fighting
against vitamin D deficiency, from birth to adolescence (Section 7.4).
All the research over the past decade suggests that a vitamin D intake con-
sistent with the recommendations made by the competent medical authori-
ties is a necessity in pregnant women, and then in the infant, to optimize
brain development, thus ensuring optimal motor or intellectual develop-
ment. Results obtained in adults in other neuropsychology areas should
be undertaken in pregnant or breastfeeding women to verify the impact
of vitamin D on child mental health.
2.3 Vitamin E
It is now recognized that vitamin E deficiency, more frequently accompa-
nying malnutrition, may lead to irreversible brain damage and severe cog-
nitive impairment (Levitsky and Strupp 1995). As shown in animals, these
disorders are the result of a neuronal destruction under the effect of oxi-
dative stress that was not counteracted by vitamin E, the natural lipid
antioxidant (Section 7.5). For that reason, the requirement of vitamin E
has been recommended in at-risk pregnancies, and sometimes also in
women with excessive smoking, to limit the harmful effects of free radicals
in the fetus (Gallo et al. 2010).
Alternatively, an excess in vitamin E may also have deleterious effects
on brain development, altering neuronal plasticity in important brain
areas (Salucci et al. 2014).
Early research attempting to link vitamin E to cognitive functions in
young children were carried out in parallel to an exploration of the appear-
ance of cystic fibrosis in patients aged 2–36 months (Koscik et al. 2005). By
studying several subjects in the control group, the authors found that chil-
dren with normal vitamin E blood concentrations (>30 ng/mL) had, after
psychological examination, a score about 15 points higher than children
with low vitamin E concentration (<30 ng/mL). These scores have been mea-
sured using a test of cognitive skills (TSC/2) considered as equivalent to IQ.
Similar results, but of smaller amplitude, have been obtained in China
after examining 120 mother–child pairs (Chen et al. 2009). The vitamin E
concentration was measured in umbilical cord blood, and cognitive devel-
opment was then determined in the children at the age of 2 years. The tests
were specific for the estimation of four types of operation: motor behavior,
language, adaptation, and social or personal behavior.
An interesting experiment conducted in Japan with children born
before term (gestation period of about 26 weeks) was reported by Kitajima
et al. (2015). They showed that supplementation with α-tocopherol, the
main component of vitamin E (Section 7.5), for more than 6 months
may induce an increase in cognitive performances (e.g., IQ) measured at
an age of 8 years. Despite the small number of individuals observed in
the study (34 treated and 121 controls), these results are promising. It is
hoped that further investigations including maternal treatment will
quickly provide new data in this complex area of relationships between
antioxidants and mental development.
These results are few, but overall they indicate that it is necessary to
look for “critical periods” in the life of an individual when it is essential
to provide adequate amounts of lipid molecules to influence cognitive
development and behavior. It is thus likely that antioxidants must be pre-
sent before or shortly after birth to prevent degenerative processes in the
brain in old age, a process that can no longer be slowed. Any demonstra-
tion may be made only after the continuous study of many individuals
from fetal life until several years after birth. The lack of interest from phar-
maceutical companies for this goal is understandable; however, it seems
desirable that the public authorities support this type of research to reduce
the heavy burden of mental illness in adulthood.
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chapter three
Cognitive development
Neurobiologists have long established that the interactions necessary to
develop both the organization and the function of the brain are present in
a complex environment, mainly organic but also “sociocognitive.” During
childhood and adolescence, the brain continues its organization and neuro-
biological adaptation to the surrounding world under the control of endogen-
ous and exogenous influences essential for regular development. The
question once asked whether cognitive functions are genetically determined
is no longer relevant; now, there must be added the questions of when and
how are they influenced by the environment and more precisely by nutrients.
For humans, the duration of brain development is particularly long.
Indeed, brain size increases nearly five times from birth to adulthood, and
if the formation of the nervous system is fast at the beginning, the organiza-
tion of synaptic connections and myelin sheaths is not complete until about
15–20 years. Similarly, some areas such as the prefrontal cortex and the basal
ganglia reach maturity at beyond 15 years and can even continue to change
throughout life.
Therefore, this slow brain maturation, mainly based on the addition
and remodeling of anatomical structures, may be modulated by lipid
nutrients, essential compounds for building cell membranes and synthesis
of several neurotransmitters. Thus, even in adults, the brain gifted with
plasticity and depending on food and environment will evolve toward a
progressive development of its cognitive abilities and will decline more
or less rapidly in disclosing various disorders during aging.
Among the lipid components of the human diet that may influence
cognitive development, the most advanced research has targeted ω-3 fatty
acids (Section 3.1); phospholipids (Section 3.2), in particular phosphatidyl-
choline and phosphatidylserine; and vitamin D (Section 3.3).
3.1 ω-3 Fatty acids

3.1.1 Epidemiological investigations
The results presented in Chapter 2 related to the effects of ω-3 fatty acids
carried by blood to the fetus or by milk during breastfeeding on brain
development have naturally led clinicians to undertake similar investiga-
tions in young children, adults, and the elderly.
27
The first indications of a possible link between these essential fatty

acids and brain function were reported in 1982 when Dr. R. Holman
described for the first time the effects of linolenic acid (18:3 ω-3) deficiency
in a young girl of 6 years old (Holman et al. 1982). This famous American
biochemist, and originator of the expression omega-3 or ω-3, noticed neu-
rological symptoms and psychological disturbances appearing in the child
after a 5-month ω-3 fatty acid deficiency. Subsequently, many studies have
been done, but they could not lead to a clear understanding of the influ-
ence of these fatty acids on the cognitive capacity of the human brain,
whether in young children or in adults. In 1994, at the beginning of this
research, and during roughly the next 10 years, all of the meta-analyses
have avoided the conclusion of any beneficial effect of these fatty acids
on the improvement of cognitive performances in children older than
2 years (Eilander et al. 2007).
Most disagreements between the published reports are certainly
attributable to many experimental inaccuracies and to the use of differ-
ent neuropsychological tests. Thus, clinicians use comprehensive tests
exploring various cognitive functions, such as the battery of tests accord-
ing to Kaufman for children 3–18 years old, to Wechsler for 6–16 years
old, or to Bayley from a few months to 3 years old (Sections 7.9–7.10).
Other tests may be used to target more specific functions such as lan-
guage, communication, recognition, and problem-solving. The number
of tests currently available is very important and increases every year;
18 tests using computers were already listed by 2008 (Wild et al. 2008).
Moreover, in these experiments the participants consumed for differ-
ent times various amounts of foods with qualitative properties validated
by biochemical analyses. These cross-sectional studies are the most com-
monly used in an overall population (or a representative sample or cohort)
and at a given time. They thus provide a snapshot image of the population
studied. The results obtained by that technical approach are sometimes
considered approximate or inconsistent, even when positive trends are
detected. To improve the accuracy of the results, researchers have adopted
more specific procedures using numerous and homogeneous groups and
analytical methods less prone to criticism.
Investigators tackling these difficult psychophysiological problems fre-
quently try to appreciate the main cognitive functions in children and adults
by recognized methods. Thereafter, they compare these quantitative results
to the amounts of fatty acids ingested one or more days before having a neu-
ropsychological test(s). Because hundreds of data must be acquired, these
explorations are long and expensive, but they are essential for the precise
knowledge of the relationships between nutrients and brain function.
Determining cognitive performances in selected individuals is usually
directed at various aspects such as perception, language, memory, reason-
ing, and movement, all clarifying the operation of different types of memory
Chapter three: Cognitive development 29
that are necessary for a broad knowledge. The determination of amounts of

ingested fatty acids is carried out using a questionnaire on the type and
weight of the foods consumed some time before. The estimated amounts
of ingested fatty acids are then calculated from these weights with the aid
of official food composition tables.
Among the most compelling recent explorations is that of Dr. W. D. Lassek
(University of Pittsburgh, Pennsylvania), who involved more than 4000
children (equal number for each sex) aged 6 to 16 years and diverse ethnic
groups (Lassek and Gaullin 2011). In all selected subjects, four cognitive
tests were used: mathematics, reading, and estimation of spatial percep-
tion and numbers memory (Wechsler Test). The average scores for these
four tests were taken as a measure of the cognitive performance of the
children studied.
After eliminating statistically all possible bias (social and biological
factors, or otherwise), this work led to the following results:
• The scores of cognitive tests were positively related to the amount of

ω-3 fatty acids ingested by the subjects, boys or girls. In girls, the
relationship had a magnitude about two times greater than in boys,
the latter seeming less sensitive to the dietary ω-3 fatty acids.
According to the authors, this sex-related difference could reflect a
greater need of ω-3 fatty acids in girls for a future pregnancy and
breastfeeding. This aspect has only rarely been taken into account
in similar studies.
• The ω-6-to-ω-3 fatty acid ratio in the foods was inversely related to the
scores obtained for cognitive measures, but the correlation was signifi-
cant only in girls. The authors suggested that the high ω-6-to-ω-3 ratio
in the American diet might contribute to the relatively low ranking of
American children in international testing compared to children living
in countries such as Japan with lower ratios. As emphasized by
Dr. Lassek, these conclusions could lead to findings of consider-
able potential public health significance.
To understand this research, remember that the groups of subjects are het-
erogeneous and that the assessment of the average food intake from each
subject gives an approximate value. Is the knowledge of the meals the day
before a correct estimate of the nutritional status in the long term? Many
clinicians doubt it. The cost of several food surveys for years would
obviously be prohibitive.
Moreover, it is likely that the high significance of the ω-3 fatty acid
effects reported in the previous study is related to the low consumption
of these fatty acids by American children and to their excessive ω-6 fatty
acid intake interfering with the ω-3 fatty acid effects. These characteristics
could explain the unconvincing diversity of the results reported in several
studies carried out in various regions and with subjects selected in differ-
ent sociological categories.
It can also be speculated that improving the ω-3 fatty acid status could
be more effective on cognitive performances in studying very young chil-
dren during the period of the highest brain growth.
The great difficulty of such investigations is now clearly emerging.
As highlighted by Dr. Lassek, the dietary situation of the subjects enrolled
in that major study is probably related to the low score level obtained
by the American children in international rankings (National Center for
Education Statistics, Washington, DC). If that relationship is confirmed by
similar studies in different countries and social groups, it would be possible
to better appreciate the potential capacity of governments to improve the
intellectual status of children going to school.
Interestingly, a further study by Dr. K. W. Sheppard (University of
Carolina North, Chapel Hill) has confirmed these results in children aged
7–9 years after recording the meal composition three times per week
before psychometric testing (Sheppard and Cheatham 2013). In that
experiment, the most significant results were obtained with a spatial ability
test, a subset of the Cambridge Neuropsychological Test Assessment Battery
providing information on the contribution of the brain frontal lobes. In
2012, Prof. R. de Groot (Open Universiteit, Heerlen, the Netherlands) had
already shown that among students aged from 12 to 18 years, fish con-
sumption was positively associated with knowledge acquisition in three
key disciplines. Notably, some adverse effects were detected for high fish
intake and were probably related to the presence of toxic substances in
that kind of food (de Groot et al. 2012).
A study by Dr. C. L. Baym (University of Illinois, Urbana) has offered
a new perspective on the relationships between ω-3 fatty acids and a spe-
cific type of memory, relational memory, responsible for linking facts and
events (Baym et al. 2014). This ability is known to be generated in a spe-
cific area of the brain, the hippocampus, a region belonging to the limbic
system and located in the medial temporal lobe. The study demonstrated
that the performances of relational memory in children 7–9 years old
were proportional to the intake of ω-3 fatty acids. Conversely, the
amount of ingested saturated fatty acids seemed to be associated not
only with reduced performances of the relational memory but also of
the visual memory (i.e., memory independent of the hippocampus, but
located in the right prefrontal cortex).
To overcome the inaccuracy of food surveys, some studies have
applied fatty acid analysis in blood plasma or in erythrocytes (ideal
because they are long-lived cells) to estimate more accurately, but indir-
ectly, the dietary ω-3 fatty acid intake.
Among these studies, attention must be given to the research by
Dr. P. Montgomery (Oxford University, UK) who enrolled 493 children
aged 7–9 years with a reading level lower than the national average
(Montgomery et al. 2013). All children were analyzed for their blood ω-3
fatty acid content and underwent psychometric testing to estimate their
reading ability and the level of their working memory. Montgomery et al.
(2013) observed that the lowest erythrocyte concentrations of docosahexae-
noic acid (DHA) were closely associated to the weakest reading ability and
especially to the lowest efficiency of their working memory. They con-
cluded that the eicosapentaenoic acid (EPA) plus DHA amount in erythro-
cytes, already considered a reliable health marker for the cardiovascular
system, may now be used for the prediction of behavior and mental health
in young children.
In addition, the research team of Prof. R. de Groot has confirmed these
results, indicating that in subjects aged 13–15 years, the highest values of
the “ω-3 Index” (Section 7.1) measured in the blood were correlated to bet-
ter scores estimated with several psychometric tests. The most significant
outcome was the observation of a positive relationship with the speed of
information processing and a negative relationship with the impulsivity of
the subject (van der Wurff et al. 2016a). To supplement these investiga-
tions, it is important to take into account research by the same team focus-
ing on school performance instead of general cognition. Thus, it seems
noteworthy that at age of 7, in 150 children, significant associations
between DHA level measured in plasma phospholipids and both reading
and spelling were found (van der Wurff et al. 2016b). Unexpectedly, it was
also shown that maternal plasma DHA levels were negatively associated
with arithmetic scores of children at age 7 years. No biochemical explana-
tion for these outcomes could be evoked, but as emphasized by authors,
one could speculate that this is because these different skills are located
in different brain regions. Consequently, this observational study requires
prudence when considering DHA supplementation during pregnancy.
Studies based on adult subjects aged between 20 and 60 years are scarce
in comparison with studies with older subjects suffering from cognitive
decline. Most observations using dietary surveys have led to the conclusion
that there is an absence or a weak correlation between cognitive perfor-
mances and DHA intake (e.g., Joffre et al. 2014). A study using blood tests
has shown no effect or even a negative relationship between DHA erythro-
cyte concentration and learning speed (de Groot et al. 2007). Particularly,
these authors selected young women about 30 years old who did not con-
sume more than one fish serving per week.
Similarly, an original work (Johnston et al. 2013) was done by the
medical services of the US Army after enrolling soldiers aged 20–54 years
that were deployed during Iraq operations. The authors observed that the
levels of total blood ω-3 fatty acids, estimated by the ω-3 Index (Section 7.1),
were directly associated with better cognitive performances (flexibility,
executive functions). The results have been even more convincing in subjects
suffering sleep problems. It is easy to understand the value of such studies

as part of a program of improving cognitive performances in a theater
operation. Moreover, the US army is undertaking investigations to check
whether a regular supplementation with ω-3 fatty acids may be beneficial
for that category of personnel.
Regarding children, it seems evident that the prevention of school fail-
ures could include, without excessive costs, a dietary analysis leading
when necessary to an increase of their daily intake of essential fatty acids
including ω-3 fatty acids, while ensuring a control of their ω-6 fatty acid
intake. These contributions could be exercised, for example, through the
menu planning in school cafeterias, without neglecting simple advice to
families for dining at home. The financial investment in this area would
certainly be very profitable for the future health of schoolchildren and stu-
dents generations. It is likely that the results would be most effective if
these measures would be taken earlier in school years.
All these observations enlarge the set of data strongly suggesting
that the dietary intake of ω-3 fatty acids in children consistent with offi-
cial recommendations is beneficial to the acquisition and preservation of
a “normal memory,” even though all aspects have not yet been fully
explored. Although the intake of these fatty acids has been proven effec-
tive in pregnant or nursing women or in neonates (Section 2.1), what
happens in young children, especially if their nutritional status is unfa-
vorable? Research involving nutritional interventions is thus needed to
elucidate all possible effects of a change in the fatty acid status on cog-
nitive performance.
3.1.2 Intervention studies

Supplementation experiments are obviously more difficult to organize
than the epidemiological surveys described above; however, several
teams have examined the possible beneficial effects of an ω-3 fatty acid
supplementation in children, mainly if they displayed a current nutritional
deficiency.
But how can we correct mental deficiencies or improve a mental state
even considered “normal” with an ω-3 fatty acid fortification? Many stu-
dies have tried to answer these questions, so it seems necessary to analyze
the most important, although few having ended in failure.
Below are some of the more recent experiments that have led to equi-
vocal conclusions:
• In 2009 in Bangalore, India, 600 children aged 6–10 years were supple-
mented daily with or not supplemented with 100 mg of DHA and
930 mg of linolenic acid (Muthayya et al. 2009). No effect on cognitive
performance could be detected after a 9-month supplementation.
• In 2010 in Newport, UK, 500 children aged 8–10 years were supple-
mented daily or not supplemented for 4 months with 200 mg of
DHA and 28 mg of EPA (Kirby et al. 2010). No convincing neurop-
sychological outcomes could be detected.
• In 2012 in Oregon, Dr. J. E. Karr administered fish oil daily (480 mg
DHA and 720 mg EPA) for 4 weeks to students about 20 years old
(Karr et al. 2012). No cognitive benefits could be noted.
Fortunately, for the future of treatments with these compounds, now

called “nutraceuticals,” several studies have reached less pessimistic con-
clusions likely to be considered by the general population. It may be
assumed that these results were obtained by better equipped investigators
who can appreciate subtle changes in cognitive functions.
Below are some experiments that led to definite conclusions, otherwise
indisputable, on various physiological and neuropsychological aspects:
• In 2010, one of the most comprehensive studies was conducted by a

specialist of these questions, Dr. R. K. McNamara of the University of
Cincinnati, Ohio (McNamara et al. 2010). Boys between 8 and 10 years
old took 400 or 1200 mg of DHA/day or a placebo. After an 8-week
treatment, the erythrocyte DHA was analyzed and hemodynamic
changes related to brain activity were monitored by functional magnetic
resonance imaging (fMRI). For the first time, it could be shown that a
DHA supplementation increased the activity of a specific brain area
(dorsolateral prefrontal cortex) during vigilance and attention exercises,
with that change being positively correlated with the erythrocyte DHA
content. This study confirmed and completed a former study done in
2005 by Dr. G. Fontani (University of Siena, Italy), showing that a fish
oil supplementation (4 g/day for 35 days) was associated with an
improvement in attentional and physiological functions, particularly
those involving complex cortical processing (Fontani et al. 2005).
• In 2012 at the University of Oxford, UK (DOLAB study), 360 chil-
dren aged from 7 to 9 years with difficulties in reading were supple-
mented daily with 600 mg of DHA from algal origin (Richardson
et al. 2012). After a 16-week treatment, the authors found that com-
pared with control subjects, the supplementation improved reading
significantly (an advance of almost 1 month), as well as the students’
behavior toward teachers. At the same time, an improvement of the
working memory was detected by a team at the University of Pitts-
burgh, after subjects aged 18 and 25 years had taken 750 mg of DHA
and 930 mg of EPA daily (Narendran et al. 2012).
The fMRI technique combined with neuropsychological tests has allowed

Dr. I. Bauer (Swinburne University of Technology, Hawthorn, Australia)
to conclude that in adults aged 24 years, an EPA-rich supplementation

was more efficient that DHA for the participants’ brains as they worked
“less hard” and achieved a better cognitive performance compared to
before supplementation (Bauer et al. 2014). The effect of a fish oil supple-
mentation (1 g/day for 12 weeks) was also explored in connection with
the estimation of the intensity of cerebral hemodynamics by using a non-
invasive technique based on the penetration of infrared radiations through
the skull (Jackson et al. 2012). Despite the lack of effect on cognitive per-
formances in students (aged from 18 to 29 years), fish oil intake has greatly
increased the amount of oxygenated blood in the prefrontal cortex while
performing various cognitive tasks. These results confirm that dietary
DHA probably influences brain function by modulating the bloodstream,
thus neural tissue oxygenation. It is likely that the high intellectual level
of the subjects and the short duration of that experiment were responsible
for the lack of direct effect of the ω-3 fatty acids on cognitive functions.
Curiously, the same laboratory did not detect any hemodynamic effects
in the elderly (Jackson et al. 2016).
A study conducted among young aboriginal Australians aged 7 to 12
years that consumed very little fish rich in DHA and EPA also revealed
that a moderate daily intake of fish oil may improve, in less than 5 months,
maturity and intellectual capacity through nonverbal cognitive develop-
ment (Draw-A-Person Test) (Parletta et al. 2013). A similar but more com-
prehensive study was undertaken in 2014 at Universidad Autónoma de
Ciudad Juárez, Mexico, by Dr. V. Portillo-Reyes (Portillo-Reyes et al.
2014). Children selected in a population suffering from malnutrition were
treated daily for 3 months with 180 mg of DHA and 270 mg of EPA. The
use of 15 psychometric tests highlighted a significant improvement in sev-
eral parameters (speed processing, visual-perceptual coordination, atten-
tion and executive functions) in more than 70% of treated children. In
contrast, no memory type was improved, suggesting that it is imperative
to extend in future research the range of tests and duration of treatments
to better detect some specific effects of ω-3 fatty acids.
In adults ingesting low ω-3 fatty acid amounts, Dr. W. Stonehouse
(University of Auckland, New Zealand) showed that a dietary supple-
mentation with about 1 g of DHA daily for 6 months improved markedly
episodic memory performances (a form of declarative memory) in women
and working memory in men (Section 7.9) (Stonehouse et al. 2013). This
experiment demonstrated that the results are modulated by the subject’s
sex (male or female); therefore, it seems necessary to better adapt the psy-
chophysiological tests. Thus, future research could perhaps adapt the sup-
plementation according to the subject’s sex in addition to the nutritional
status to improve especially one specific memory type.
Although clinical data are still limited, it seems that DHA-based treat-
ments are more promising than those involving EPA or other ω-3 fatty acids
for improving memory and learning in individuals suffering only from mild
cognitive impairment (Dyall 2015). Notably, the results are, in general, more
significant when subjects are not carriers of the apolipoprotein E (ApoE4)
isoform, a major risk factor for several nerve diseases (Section 7.8). It is
clear that in the early years of childhood there is an important maturation
of the nervous system detectable at the level of neurons and their increasing
number of synaptic contacts. All of these changes are accompanied by a
characteristic DHA enrichment, due partially to the synthesis from precur-
sors, such as linolenic acid, but mostly directly from the diet. The low
DHA concentration in common foods consumed by children and adoles-
cents in developed or developing countries certainly explains the effective-
ness of DHA supplementation in subjects aged less than 10 years. For
older subjects, several experiments have shown little effect except some
changes in cerebral blood flow that are, however, important for enhancing
brain metabolism. Despite the limited number of studies and the diversity
of protocols, the investigators generally concluded that an EPA deficiency,
DHA deficiency, or both is harmful for learning in young children.
The accuracy of the results and their significance could certainly be
improved after investigations of the optimal doses of ω-3 fatty acids, the
duration of clinical trials, the nutritional status of participants, or the speci-
ficity of the various psychometric tests. One of the important points to take
into account seems to be a possible iron deficiency, very common in devel-
oping countries. Indeed, in children suffering from iron deficiency anemia,
the administration of both iron and ω-3 fatty acids seemed to be necessary
for the restoration of optimal cognitive functions (Baumgartner et al. 2015).
Since 2005, investigators have known that people are not genetically
equal with regard to dietary treatments. Indeed, as noted above, the presence
of different alleles of the gene encoding the synthesis of ApoE must be added
as a determining factor (Section 7.8). The presence of the ApoE4 isoform has
been associated with the onset, progression, and severity of many diseases,
but above all, dementia or Alzheimer’s disease (Huang et al. 2005). To clarify
the importance of that genetic equipment, it may be simply considered that
in the elderly (>64 years), healthy and without memory complaint, the
amount of ω-3 fatty acids in erythrocytes was correlated with cognitive per-
formance, but only in people lacking the ApoE4 gene (Whalley et al. 2008).
In summary, the current state of research on the relationships between diet-

ary ω-3 fatty acids and cognitive performances in children should suggest
that parents ensure a supply of these fatty acids close to the recommenda-
tions made by the medical agencies, i.e., 250 mg of EPA and DHA for chil-
dren 3–9 years old and 500 mg for young people 10–18 years old
(Section 7.2). Unless the child consumes one or two fatty fish servings a
week, the current intake will remain low and then after medical advice
the child must be regularly supplemented with ω-3 fatty acids commonly
sold in capsules. The emphasis should be on the requirement to supplement
children as soon as possible, and the short-term benefits will be even more
evident. Parents should acknowledge rapidly the effects on educational out-
comes concerning memory and attention, such as computation and reading.
3.2 Fatty acids

3.2.1 Phosphatidylcholine
The lipid phosphatidylcholine (Section 7.7.1) is ingested by humans from
either meat or plants, or in the form of commercial products known as
lecithins. Besides fatty acids, it represents a good source of choline, an
essential substance involved in the building of cell membranes and also
in many methylation reactions for the synthesis of acetylcholine, a very
important neurotransmitter. The richest foods in choline are calf liver (about
400 mg/100 g) and eggs (about 250 mg/100 g). Apart from choline, phos-
phatidylcholine may be also a carrier of long-chain ω-3 fatty acids, as in krill
oil. In that case, it will be difficult to attribute any effect to the presence of
choline or to the fatty acid moieties. Despite that reservation, Japanese
authors have recently awarded to ω-3 fatty acids the effects of a modest
intake of krill oil (0.28 g/day of EPA + DHA) on brain function (Konagai
et al. 2013). Furthermore, considering equal amounts of ω-3 fatty acids, krill
oil, rich in phosphatidylcholine, proved to be more effective than a trigly-
ceride-rich sardine oil on cognitive functions in healthy elderly.
In the 1980s, phosphatidylcholine was considered as a choline poten-
tial donor enabling the improvement of cholinergic systems that were
weakened in patients suffering from dementia. It was early reported that
the administration of phosphatidylcholine could improve the memory of
patients suffering from Alzheimer’s disease. Thereafter, many investiga-
tors explored the possible effects of the administration of this phospholi-
pid on other cognitive functions.
Considerable research was carried out in rats with some success, either
on brain development or behavior or memory. Unfortunately, little work
has been done in humans, and mainly in elderly patients or patients with
memory loss or dementia. Curiously, a positive result on explicit memory
(or declarative memory, Section 7.9) was reported in students only 90 min-
utes after ingesting 25 g of phosphatidylcholine, providing 3.75 g of choline
(Ladd et al. 1993). Is there a real effect or a placebo effect? It is too early to
choose the explanation.
In 2003, a review by M. A. McDaniel in the United States reported
some positive results, but the analysis remains questionable given the
age of the patients, their nutritional history, the diversity of the selected
populations, or their brain damage. A meta-analysis conducted in 2003

by the Cochrane Collaboration (UK) with 12 clinical trials involving
patients with various memory impairments, but also with Alzheimer's
or Parkinson’s diseases, failed to demonstrate any benefit from phospha-
tidylcholine administration.
Some work in Japan by T. Nagata may initiate a new approach (Nagata
et al. 2011). Following basic research on acetylcholine receptors in rat brain
hippocampus, they obtained in humans surprisingly positive results on
moderate memory loss and learning. The oral administration consisted of
two types of phosphatidylcholine: one type containing palmitic and oleic
acids and the other type containing only linoleic acid. The study highlighted
the difficulty to draw meaningful conclusions after using complex lipids
with an origin and composition poorly known, even if they are extracted
from plants.
Despite uncertainty about the validity of many results, food supple-
ments containing large amounts of plant phosphatidylcholine (soy lecithin)
are available on the market with the claims of beneficial effects for memory,
concentration, or sleep. These allegations concerning neurological disorders
are questionable and are often based on confusion between phosphatidyl-
choline and phosphatidylserine, both phospholipids being present together
in all natural raw extracts, but in varying proportions.
3.2.2 Phosphatidylserine
Phosphatidylserine (Section 7.7.2) is found in all plant and animal cell
membranes. Its characteristic is to be located in the inner leaflet of the cell
membranes where it exerts multiple functions, such as the regulation of
receptors, enzymes, and ion channels. In animals, this phospholipid is
mainly concentrated in the brain (about 15% of total phospholipids in
humans). Many studies have shown that it plays a major role in the com-
munication between neurons, allowing assignment to that lipid the possi-
bility to modulate cognitive functions.
So, considering numerous encouraging findings in animals, several
trials to improve memory by supplementation with phosphatidylserine
have been undertaken in young children or in the elderly. The first tests
were carried out in 1990 by Maggioni and co-workers in Italy. They
experimented with an oral treatment with phosphatidylserine isolated
from beef brain that seemed successful in improving depressive symp-
toms in older people as well as some cognitive parameters (Maggioni et al.
1990). Later, other researchers showed that the administration of phospha-
tidylserine was effective in improving memory and learning in seniors
suffering from declining memory.
Early research in this area used a product extracted from beef brain, but
a possible contamination by prions causing spongiform encephalopathy
(“mad cow disease”) has led governments to specifically prohibit the con-
sumption and use of bovine nervous tissues. These prohibitions were
initiated in 1986 in the United Kingdom and adopted in 1989 in France
and in 1996 in the United States and in many other countries. Yet, it has
been admitted that these animal fats should be treated by ultrafiltration
and sterilization at 133°C for 20 min before their use in food products. This
major crisis has led researchers to use an alternative source, if possible from
plant origin, such as soy lecithin. It was therefore necessary to reactivate all
investigations with that new product because it has a very different fatty
acid composition (lack of long-chain ω-3 fatty acids such as EPA or DHA).
What are the recent results obtained with phosphatidylserine? A moder-
ate improvement of short-term memory performances has been repeatedly
observed in the elderly suffering with some cognitive deficits. A Japanese
study of 78 subjects ranging from 50 to 69 years old and supplemented daily
with 300 mg of soya phosphatidylserine showed a significant improvement
in memory performances (Kato-Kataoka et al. 2010). However, it should be
noted that phosphatidylserine did not generally bring any improvement in
patients having an early degenerative dementia or Alzheimer’s disease.
Experiments reported in 2010 by V. Vakhapova in Israel, using phos-
phatidylserine enriched in marine EPA and DHA (100 mg/day), showed
after a 15-week treatment a significant improvement in short- and long-
term memory in the elderly (Vakhapova et al. 2010). The improvement
seemed more significant when the cognitive status of the persons was
minimally affected before the treatment. Therefore, the outcome advocates
the necessity of an early treatment of memory complaints.
An assay carried out in 2011 by A. G. Parker with 18 American students
clearly showed an improvement of cognitive function (subtraction test)
after a daily ingestion of 400 mg of soybean phosphatidylserine for 2 weeks
(Parker et al. 2011). A similar experiment had been conducted in 2008 by
J. Baumeister in Germany but this author was unable to detect any effect
on cognitive functions. However, specific changes were observed using
electroencephalography, indicating a new relaxation state after a period
of stress. These effects may be helpful to people preparing for intellectual
events requiring concentration.
A Japanese laboratory looked for the effect of a daily intake of 200 mg
of soybean phosphatidylserine for 2 months in young children (average
age 9 years) (Hirayama et al. 2013). The researchers demonstrated a ben-
eficial effect only for short-term auditory memory, with the test consisting
of measuring a repeated series of increasingly longer numbers. The result,
although modest, should be considered important in a school setting for
young children, with the effect of phosphatidylserine being able to
improve, for example, the study of reading.
It is obvious that these experiments do not definitely allow the results
to be associated to a specific phospholipid constituent (serine, fatty acids)
or to the whole lipid molecule. The mechanism of the phosphatidylserine

action remains unknown, despite numerous assumptions.
Given the published results, the US Food and Drug Administration
recognized in 2003 that phosphatidylserine added to food could improve
cognitive functions and slow their deterioration in the elderly. Despite few
new studies since then, the European Commission decided in 2011 that
soybean phosphatidylserine could be used in food for special medical pur-
poses (Decision 2011/513/EU of 19 August 2011). A review of all the
scientific work on the effects of phosphatidylserine on human brain con-
cluded that phosphatidylserine is useful in improving various forms of
memory, the ability to focus attention and concentrate, the ability to reason
and solve problems, language skills, and the ability to communicate (Glade
and Smith 2015). Although these memory effects are usually modest, they
would benefit greatly from investigations over long periods (ca. 1 year)
with chemically defined products, psychologically well-controlled patients,
and several memory tests. On these issues, it would be important to define
the effectiveness of a phosphatidylserine supplementation as a preventive
or curative treatment. The abundance on the market of food supplements
fortified with phosphatidylserine from various origins should motivate spe-
cialized laboratories to initiate serious behavioral and neuropsychological
studies. Such work could clearly inform consumers about the potential ben-
efits of such lipid supplementation marketable at a reasonable price.
3.3 Vitamin D
As for multiple sclerosis (Section 5.2.2), epilepsy (Section 5.3.2), schizo-
phrenia (Section 6.1.3.2), and autism (Section 6.1.5.2), cognitive develop-
ment during childhood seems to depend on the month of birth of the
subjects, additional evidence of a possible relationship with the vitamin
D production by skin under the effect of solar radiation (Section 2.2).
Recall that on an academic basis, many studies have shown that children
born in summer had more learning problems than children form in the
other seasons, with these differences persisting until the age of 10–11 years
(Martin et al. 2004).
A systematic review of 10 human studies has shown that only subtle
cognitive impairments were observed in offspring of vitamin D–deficient
mothers (Pet et al. 2016). However, validations of these findings are
required.
Outside the context of pregnancy, very few studies have been devoted
to the relationship between vitamin D and cognitive functions in children
or adolescents. This is an unfortunate situation because no hypothesis
may be proposed for possible improvements of such higher brain
functions with that vitamin, a guarantee of better health in adulthood. The

interest of such studies in young age is to avoid the interference from other
factors such as the consumption of alcohol, drugs, or tobacco, behaviors
known to impair cognitive performances.
The limited research performed with adolescents has failed to highlight
an association between cognitive performances and vitamin D blood levels.
One of the first investigations recruited almost 1700 teenagers as part of the
great American survey on health and nutrition program (National Health
and Nutrition Examination Survey), several psychometric tests, and a blood
analysis being processed in each subject. Contrary to expectations, the
results suggested that the vitamin D status was not related to cognitive per-
formances in young subjects (McGrath et al. 2010). Similar outcomes were
reported based on a study of a second sample of about 1800 teenagers as
part of the same American survey (Tolppanen et al. 2010).
Besides these negative results, interestingly, an investigation was done
on English teenagers comparing the educational outcomes and the serum
levels of the two types of vitamin D, ergocalciferol (vitamin D2) and chole-
calciferol (vitamin D3) (Tolppanen et al. 2012). Recall that vitamin D2 comes
from dietary sources (plants), whereas vitamin D3 is mainly synthesized by
the skin under sunlight exposure (Section 7.4). Tolppanen et al. (2012)
showed that in contrast to vitamin D3, the concentration of vitamin D2
was inversely related to academic performances. Unfortunately, no hypoth-
esis has been proposed to date to explain these results. A verification with
further research could have important implications for vegetarians or
vegans excluding any consumption of fish or egg, but depending only on
a regular sun exposure to provide them vitamin D3.
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chapter four
Cognitive decline and

Alzheimer’s disease
The cognitive decline that accompanies aging of all individuals is a normal
and complex process, but slow and progressive, and probably a conse-
quence of many factors. Some of these factors are known to facilitate the
decline as hypertension, whereas others show it as a decline in physical
activities or some hormonal treatments. In certain individuals, these disor-
ders have a more rapid time course leading to very important cognitive
disturbances, frequently marked by memory problems and sometimes
accompanied by a worsening of executive functions. This stage is called
mild cognitive impairment (MCI). Some of these problems will evolve into
a state of mental disorganization, also known as dementia, with Alzheimer’s
disease being one of the main forms. The diagnosis of MCI is increasing in
older people, and its incidence often follows simultaneously the increase in
life expectancy. Thus, it is assumed that the incidence of this disease gen-
erally increases exponentially with age: 1 person in 10 at 65 years old and
1 person in 3 at 85 years old. This acute health problem requires the rapid
identification of factors that could allow for control of its development,
such as food constituents.
MCI, which affects a significant portion of the elderly population,
has been explored to slow the decline progression, mainly via examining
the influence of ω-3 fatty acids (Section 4.1.1), vitamin A, or carotenoids
(Section 4.1.2).
Increasing research effort also has been devoted to the dementia
syndrome of the Alzheimer’s type. Indeed, this disease has been largely
investigated in the field of ω-3 fatty acids (Section 4.2.1), vitamin A
(Section 4.2.2), vitamin D (Section 4.2.3), vitamin E (Section 4.2.4),
and cholesterol (Section 4.2.5).
4.1 Age-related decline

The first symptoms appear probably at the age of 45, as shown by a
recent Franco–British study of the Whitehall II cohort (Singh-Manoux
et al. 2012), and then become obvious at 65–70 years old. The decline
clearly results from numerous structural and functional modifications
45
in the brain. Alterations of the interactions between the subject and the
activities of everyday life, and especially with the environment, may
also be important.
It is now well established that aging is accompanied by a decrease
of cognitive performance in most areas, with these decreases comparable
to the decline observed in sensory functions. This decline of age-related
cognitive capacities results from biological alterations of cerebral tissue.
Indeed, the brain volume is progressively decreasing in parallel with
important cellular changes, such as loss of dendrites and synapses. Mod-
ification of the cerebral microcirculation also is observed, leading to a
decreased blood flow in the trophic capillary bed. Similarly, microvascular
accidents and cerebral atherosclerosis have been found to induce neuronal
loss in strategic areas.
Other less known factors were also discussed, such as an alteration of
the transports through the blood-brain barrier or the disturbance of neu-
rotransmitter systems, optionally combined with a demyelination process.
It must be emphasized that these biological phenomena related to aging
are not automatically accompanied by cognitive losses, many elderly hav-
ing no cognitive impairment or they do not complain. Modern ima-
ging techniques have helped explain these issues by brain plasticity, a
recently known phenomenon that contributes to adapt the elderly to his
environment.
The memory disorders observed in the elderly, who are considered
otherwise healthy, are usually benign, simple memory lapses but whose
frequency could increase with aging. These minor problems lead, in
general, to complaints, but they do not necessarily correspond to an
objective memory issue. It was known that in this field the age-related
decline relates to working memory (particularly spatial memory), atten-
tion, and especially episodic memory (Ronnlund et al. 2005). Conver-
sely, other forms of declarative memory, such as those concerning
vocabulary and verbal IQ, seem to remain relatively intact in the elderly.
In a poorly defined part of the population, the loss of mental abilities
during aging is more important than commonly found in most situations;
we are dealing here with MCI. The proportion (prevalence) of affected
individuals is currently high, between 3% and 22% annually according
to the studies. This means that from 10% to 25% of individuals more than
70 years old in most countries are suffering from MCI. Overall, these
troubles are constantly growing due to the aging of population, thereby
stimulating the interest to better understand the pathological conditions
involved. The MCI concept corresponds to a confounding zone between
cognitive changes linked to normal aging and early stages of dementia.
The distinction between normal aging and MCI remains difficult to estab-
lish and requires the use of clinically valid tools. In addition, there is
controversy about the need to distinguish MCI subgroups based on the
Chapter four: Cognitive decline and Alzheimer’s disease 47
number of affected cognitive domains. Concrete progress is therefore

expected to better predict the evolution of these disorders and define
the future experimental protocols.
That step in the evolution of disorders is marked by a worsening
memory complaint from the patient and from family. Although difficult
to characterize, these troubles have anatomical features in common with
the state of dementia, such as the presence of amyloid deposits and a
volume reduction of the hippocampus. At this stage of the disease, these
anatomical lesions are rarely revealed by the use of medical imaging tech-
niques (especially MRI). In current practice, the doctor verifies whether
the patient’s memory complaints (or those around him or her) are indeed
associated with real memory disorders that could be later detected with a
clinical examination based on more or less specialized tests such as the
Mini-Mental State Examination (MMSE) or the Trail Making Test (TMT)
(Section 7.9). These assessment tools are selected to estimate the global
intellectual efficiency and help the clinicians monitor the development
of the disease.
The presence of MCI, affecting mainly the episodic memory (memory
of autobiographical events), and sometimes also the executive memory,
actually corresponds to an early stage of nervous degeneration, but it does
not consistently move toward a state of dementia. Thus, it was observed
that approximately 7%–12% of the subjects by year displaying these trou-
bles will progress toward Alzheimer’s disease. Four years after making
the diagnosis of MCI, approximately 50% of the patients will be suffering
from dementia.
As for Alzheimer’s disease, the MCI condition is characterized by
significant and irreversible brain alterations in defined areas.
No current therapy exists to fight against MCI. However, this disease
is considered as the optimal stage for interventional studies aimed at
delaying the onset of dementia. Given the importance of lipids in the
structure and functions of the brain, it seems urgent to consider nutrition
as an opportunity to slow the progression of the age-related cognitive
disorders to reduce or even offset the risk of developing dementia. Among
nutrients, several lipid compounds have already been the target of inves-
tigations: ω-3 fatty acids (Section 4.1.1) and vitamin A and carotenoids
(Section 4.1.2).
4.1.1 ω-3 Fatty acids

Scientists began in the early 1980s to study the role of nutrition in cognitive
processes. But it was not until the late 1990s that essential advances were
made with the so-called “Rotterdam” study. That important survey study
demonstrated that the consumption of ω-3 fatty acid–rich fish enhanced
cognitive performances in the elderly, whereas an excess linoleic acid
(precursor of ω-6 fatty acids) had the opposite effect (Kalmijn et al. 1997).
This thesis, although still disputed, has since been verified many times
by independent research teams fighting against dementia and Alzheimer’s
disease. Several researchers have also discussed the possible action of ω-3
fatty acids on the brain vascular system, as it has long been demonstrated
for the cardiovascular system (Leray 2015).
In the elderly, what are the possible relationships between ω-3 fatty
acids and cognitive functions? Could nutrients delay the alteration of
these functions or affect that development throughout life in maintaining
nerve structures? What is known about the effects of the supplementa-
tion with docosahexaenoic acid (DHA) combined or not with eicosapentae-
noic acid (EPA)? Clinicians are interested in the population aged over
50 years, because complaints of memory loss are becoming more and more
frequent.
4.1.1.1 Epidemiological investigations

Since the beginning of the twenty-first century, numerous studies have
shown that fish consumption would help to prevent the age-associated
cognitive decline and perhaps even the dementia that is often associated
with it. Meanwhile, it has been verified that the ω-3 fatty acid content
in brain tissue decreased with advancing age. This poorly explained
phenomenon could be not only connected to a reduction in the transport
of these fatty acids from the blood to the brain but also to an alteration of
their metabolism in the brain tissue itself. It can also be hypothesized that
the elderly, living at home or in nursing institutions, progressively
decrease their seafood consumption or have less and less efficient intest-
inal absorptive capacity. These changes could thus contribute to reducing
the DHA brain concentration. It has been demonstrated that older animals
have a specific reduced DHA concentration in the hippocampus, the brain
location known to play a key role in memory and spatial orientation.
Thus, the links between the chemical composition of nervous tissue and
memory capacities are becoming clearer.
In the fight against the cognitive decline associated with age, the
benefits brought about by fish consumption are difficult to estimate,
although a trend is gradually emerging. Some work concerning MCI
details the benefits of frequent or continuous consumption of marine
fish that could help adults remain healthy. MCI is a syndrome defined
by clinical, cognitive, and functional criteria that implies, according to
specialists, a predementia condition (Section 7.9). This syndrome affects
almost exclusively the memory and was found to be a good predictor of a
progression to dementia (10%–15% of cases) during the year after diagnosis.
The clinical diagnosis of dementia is retained only when the cognitive
or behavioral disorders seriously disrupt the patient’s daily life. Some
epidemiological and neuropsychological studies in many patients have
shown that fish consumption was associated with a reduced risk of cog-
nitive function loss (memory, comprehension, psychomotor speed). Of
course, as very often in clinical research, other studies did not fully con-
firm this association, but fortunately detected no particular negative
effect.
One of the studies showing the most favorable effects of a fish-enriched
diet on the cognitive capacities of the elderly is that achieved in Norway
in 2007 through a collaboration between Bergen and Oslo universities
(Nurk et al. 2007). An accurate survey of dietary habits and examinations
with appropriate psychometric tests (including MMSE and TMT,
Section 7.9) were performed on nearly 2000 individuals aged from 70 to
74 years. The results showed that the subjects consuming an average of
more than 10 g per day of fish or seafood had significantly higher scores
in six tests, thus they had better cognitive performance than subjects con-
suming lower amounts. This daily 10-g threshold corresponds in reality
to only one fish meal per week. The results also showed that maximum
effects are associated with a consumption of about 75 g of fish per day.
Conversely, other studies did detect some positive effects for a more limited
number of neuropsychological tests.
More recently, four investigations have been done in France, the USA,
and China:
• The French study, published in 2009, is part of a wide epidemiologi-

cal investigation on women registered in a mutual life insurance
company (Mutuelle Générale de l’Education Nationale [MGEN])
(Vercambre et al. 2009). Approximately 4800 women aged 76–82
years filled out a self-administered questionnaire and underwent neu-
ropsychological tests. Outcomes clearly supported the hypothesis of
a beneficial effect of foods rich in ω-3 fatty acids in the prevention
of the cognitive decline observed during aging. That outcome was
confirmed by another interesting multidisciplinary study of about
3300 subjects of both sexes and 64 years average age. They were
selected from the French study SUVIMAX (Supplementation with
Vitamins, Minerals and Antioxidants) (Kesse-Guyot et al. 2011).
• The American study, published in 2013, recruited 6000 women, with
mean age of 72 years who worked in the health field (Women’s
Health Study) (Kim et al. 2013). The authors observed better cogni-
tive capacities, mainly in verbal memory, in people consuming one
or more fish servings weekly. The fish in question were dark-meat
fish (e.g., tuna, mackerel, sardines, salmon, or swordfish). All of
these species are particularly rich in ω-3 fatty acids. Conversely,
no benefit was observed with light-meat fish (e.g., cod, haddock,
or halibut) as well as shellfish (e.g., lobster, scallop, or shrimp), all
of which are very poor in ω-3 fatty acids.
• The Chinese study, published in 2014, was realized by two

American teams that specialized in human nutrition and psychiatry
(Qin et al. 2014). The results were obtained from approximately
1600 community-dwelling adults older than 55 years, with a mean
follow-up of 5.3 years in nine Chinese provinces. They observed that
a weekly consumption of more than one fish meal (about 100 g) in
subjects older than 65 years reduced the mean annual rate of global
cognitive decline by 0.35 point, a gain equivalent to the disparity
associated with 18 months of age.
An original approach also has been carried out by a research team in

Uppsala, Sweden, that established a positive correlation between EPA
and DHA dietary intake, overall cognitive performances, and the gray
matter volume measured by MRI (Titova et al. 2013). The objectivity of
the imaging measurements in the brain demonstrated at least an unques-
tionable anatomical effect, even if the results of exploration are still the
subject to discussions. These results were confirmed 1 year later with the
same techniques by clinicians at the University of Pittsburgh, Pennsylvania
(Raji et al. 2014). This work showed with more fish consumption, there
was a greater mass of gray matter (neurons) in areas responsible for
cognition. Actually, nothing can proved regarding the direct influence
of ω-3 fatty acids on these anatomical variations. Apart from differences
in lifestyle among fish eaters, no serious hypothesis can now explain these
results. Very similar results on the volume of the whole brain and the
hippocampus together with the average cortex thickness were recently
published by a team from Columbia University, New York (Gu et al.
2015). The authors calculated that in the elderly, a weekly consumption
of 90–150 g of fish would provide significant protection against brain
atrophy, a benefit equivalent to 3–4 years of aging. Thus, an effortless
dietary modification may ensure a significant effect of maintaining cogni-
tive functions.
This subject remains highly topical and of such importance that two
major analyses were published in early 2015. One analysis of more than
20 studies done over about 15 years in this field allowed the conclusion
that ω-3 fatty acids provided by fish have a more or less important bene-
ficial effect on cognitive activity during aging (Denis et al. 2015). The other
analysis of 15 studies selected among 1034 publications revealed that
adults taking at least 1 g/day of an EPA plus DHA mixture improved
episodic memory, with DHA being specifically effective for semantic
memory (Yurko-Mauro et al. 2015). These results are important because
they help us to understand why many investigators have detected no effect
with smaller fatty acid amounts. Notably, this threshold of 1g/day is not
excessive; it corresponds to a daily consumption of 50 g of salmon or 100 g
of sardines.
As for many other physiological aspects of dietary lipids, it is neces-

sary to consider the relative amounts of the ω-6 fatty acid intake in addi-
tion to that of ω-3 fatty acids (Loef and Walach 2013). Indeed, many
studies have shown that the absolute amount of ω-3 fatty acids is a less
important marker than the ω-6-to-ω-3 fatty acid ratio, an index measured
in diet or in blood. This concept is not new for nutritionists (Leray 2015),
but it has only recently been applied to the relationships between dietary
lipids and cognitive decline or dementia. Among the first work raising
this issue is the French study “Trois-Cités” (Bordeaux, Dijon, Montpellier).
The study enrolled around 10,000 subjects and showed that a high con-
sumption of ω-6 fatty acid–rich oils was associated with a higher risk of
dementia and even Alzheimer’s disease. Notably, these adverse effects
are all the more marked in that the intake of ω-3 fatty acids is low, and
even more pronounced among the apolipoprotein E4 (ApoE4) noncarriers
(Barberger-Gateau et al. 2007).
Given the well-known metabolic competition between these two fatty
acid series, it is not surprising that in human history the change from a
prehistoric diet (with a ω-6/ω-3 fatty acid ratio close to 1) to a modern diet,
or “Western” diet (with a ω-6/ω-3 fatty acid ratio sometimes close to 30),
may influence brain function. Although it is not currently possible to
make specific recommendations, it seems more desirable to first decrease
the intake of vegetable sources providing too much ω-6 fatty acids before
increasing the intake of ω-3 fatty acids.
Unfortunately, epidemiological studies have usually resulted shown
great variability of results, likely arising from the poor reliability of the infor-
mation provided by consumer food surveys. The estimation errors were
often placed on the account of the failing memory of surveyed subjects,
the imprecision of food composition tables, and the culinary practices being
different between countries and people. The protective effects of DHA and
EPA may be also insidiously underestimated due to an increased mortality
from cardiovascular disease in people consuming only small amounts of
fish. This indirect consequence of a diet deficient in ω-3 fatty acids could thus
reduce the chances of observing cognitive issues in the elderly, who some-
how died prematurely.
These approximations and some others may be the cause of the
finding of an absence of relationships between the oily fish consumption
and cognitive performances among US veterans, despite a 3-year follow-up
and the use of a large number of psychometric tests (van de Rest et al.
2009).
Regardless, these epidemiological studies cannot eliminate the possi-
bility of an association between fish consumption and socioeconomic
level, which led to select subjects accustomed to a balanced diet and
having a lifestyle without any excess. These factors are well known to
minimize the risk of cognitive impairment.
To complete this aspect of research, the detrimental consequences of

pollution by fish mercury must also be considered. Indeed, such pollution
has recently been evoked to explain some adverse effects of a high fish con-
sumption on the cognitive performances in the elderly living in Adelaide,
South Australia, an area known for its high pollution rate (Danthiir et al.
2014). However, this risk may be minimized as a recent study conducted
at the Rush Medical University of Chicago, United States, clearly showed
that for a moderate consumption of fish (up to three servings weekly),
the brain mercury levels were not correlated with any neuropathological
marker (Morris et al. 2016). Similarly, mercury exposure was found to have
little impact on cognitive performance in elderly men and women from
Kuopio, Finland (D’Ascoli et al. 2016).
As shown by the ω-3 fatty acid analysis in plasma or red blood cells, it
becomes possible to reduce the sources of error related to dietary ques-
tionnaires. Thus, a study of 246 participants aged 63–74 years living in
Nantes, France, showed after a 4-year follow-up that a higher proportion
of DHA (as opposed to EPA) in erythrocyte membranes was significantly
associated with a lower cognitive decline (Heude et al. 2003). In addition,
a similar study conducted in the United Kingdom confirmed that high
levels of ω-3 fatty acids in erythrocytes were closely correlated with a
slowdown of cognitive decline, but only in individuals not carrying the
ApoE4 gene (Whalley et al. 2008). Comparable results were published
from a recent Japanese study of 400 subjects aged 60–79 years and fol-
lowed up for 10 years (Otsuka et al. 2014). Conversely, the finding of a
similar relationship, but only in relation to the ApoE4 gene carriers,
may result from not taking into account the dietary supply of ω-6 fatty
acids (Morris et al. 2016). That explanation may also be valid for the obser-
vation of slower rates of decline in global cognition with weekly seafood
consumption in elderly of average age 81 years (van de Rest et al. 2016).
An interesting aspect is that addressed by the Brain Institute at the
University of Oregon in Portland (Bowman et al. 2013). The team of
Dr. J. F. Quinn showed that in older people (about 74 years old) followed
up for 4 years, the executive function decline (estimated by the TMT,
Section 7.9) was associated with a low concentration of blood ω-3 fatty
acids and a higher volume of subcortical white matter. That volume
increase has long been considered as a marker of cognitive decline
and motor dysfunction. They were thus able to estimate that for each
100 μg/mL increase of plasma ω-3 fatty acids, the age-related cognitive
decline is delayed by 1 year, without alteration of verbal memory or
MMSE test scores.
Recent work has shown that in elderly people without mental disabil-
ity, a high blood level of ω-3 fatty acids was accompanied by a higher cog-
nitive flexibility and a greater gray matter volume in the anterior cingulate
area, known to be important for that function (Zamroziewicz et al. 2015).
A more recent study was done in Finland with 768 participants with a
mean age of 68 years, but without cognitive impairment, who were exam-
ined at baseline for their cognitive function and serum fatty acid composi-
tion and then reexamined 11 years later (D’Ascoli et al. 2016). The authors
have found that people with higher serum EPA plus DHA, reflecting
mainly fish consumption, had better performance in the TMT (Section 7.9)
and the Verbal Fluency Test, with both tests being specific for frontal lobe
functioning. Notably, the associations with DHA were stronger and the
ApoE4 phenotype had little impact on cognitive performance. These studies
are the first involving the precision of ω-3 fatty acids as specific factors link-
ing nutrition and cognitive functions.
Many other studies have been devoted to this problem, but the varia-
bility in results and the diversity of the psychometric tests used require
caution in interpreting the findings and announcing recommendations.
The importance of the dietary ω-6 fatty acid supply in the scale and diver-
sity of the outcomes remains a frequently topic of discussion. Despite these
reservations, it seems that the blood ω-3 fatty acid composition is a reliable
biochemical marker of the cognitive impairment related to aging, even in
the absence of dementia or cardiovascular disease (Tan et al. 2012).
It is evident that the meaning of the blood DHA status remains
unclear: is it a reflection of the nutritional intake or that of the metabolism,
or a better intestinal absorption, or a lower cellular catabolism? These ques-
tions are fundamental for studies related to the elderly. Future research in
this area should take into account these physiological aspects while com-
paring them with the genetic characteristics of the selected participants.
Despite the reservations expressed by some authors and the lack of con-
sensus on the positive effects of ω-3 fatty acids, it seems wise to advise the
entire population to increase the presence of fish meals on the family table
so that parents and children can benefit from a sufficient ω-3 fatty acid con-
tribution. By simply following the recommendations of the French National
Plan of Nutrition and Health, consumers will obtain substantial health
benefits for cognitive aging (PNNS 2011-2015 report, available at http://
www.sante.gouv.fr/programme-nationalnutrition-sante-2011-2015.html).
The US Food and Drug Administration and the US Environmental
Protection Agency recently issued updated advice on fish consumption.
The two agencies have concluded that pregnant and breastfeeding women,
those who might become pregnant, and young children should eat more
fish with low mercury content to gain important developmental and health
benefits. The updated advice recommends pregnant women eat at least
224 g (8 ounces) and up to 336 g (12 ounces) per week (2–3 servings) of a vari-
ety of fish that is known to be lower in mercury to support fetal growth and
development. These weakly polluted species include some of the most com-
monly eaten fish, such as pollock, salmon, canned light tuna, tilapia, catfish,
cod, and even shrimp (http://www.ncbi.nlm.nih.gov/books/NBK305180/).
Despite the presence of contaminants, the belief of many experts has been
that consuming fish is beneficial for health. The “Dietary Guidelines for
Americans, 2010” also recommends a consumption of 227 g (ca. 8 ounces)
of seafood per week.
4.1.1.1.1 Intervention studies Given the existing problems limiting

fish consumption (e.g., availability, pollution, taste), investigators have
experimented with alternative sources such as fish oils or purified ω-3 fatty
acids. So, what have we learned from that approach, the aim of which is to
reduce efficiently the cognitive decline in aging?
Admittedly, intervention studies are not sufficient for clarifying
the subject, likely because of the wide variety of selected protocols, the
difficulty in evaluating neuropsychiatric symptoms, and their evolution
during a relatively short time. A recent meta-analysis of three clinical
trials by the international Cochrane Center pointed out that, given the
results published from 2008 to 2011, a ω-3 fatty acid supplementation
provides little profit for the cognitive function of the elderly in good
mental health, as indeed for those suffering from dementia (Dangour
et al. 2012).
Recently, thanks to the exceptional advances in human genetics, biol-
ogists better understand the complex mechanisms involved in how our
cells absorb nutrients and react to food. Nutrigenomics is the result of that
new alliance between genomics and nutritional sciences. This approach
allows a better understanding of how nutrients influence the expression
of our genome and also how the genome itself can influence the metabo-
lism of these nutrients.
Thus, concerning the ω-3 fatty acids, it has been shown that the
presence in the genetic heritage of an individual of the allele encoding
the protein apolipoprotein epsilon 4 (or ApoE4 isoform) was closely asso-
ciated to a high risk of cognitive decline and especially of Alzheimer’s
disease. As mentioned by A. M. Minihane in England, the ApoE4 gene
could indeed interact with ω-3 fatty acids and promote the genesis of car-
diovascular diseases and secondarily of brain function disorders (Minihane
et al. 2000). The potential impact of this gene in the status of the cognitive
performances in the elderly has been mentioned previously. Thanks to a
large number of results, there is no longer any doubt that genes interact
with the environment regarding cognitive functions (Small et al. 2004).
The validity of this explanation is based on the observation of a close
association between the level of ω-3 fatty acids in red blood cells and
the preservation of the cognitive performances in patients not carrying
the ApoE4 gene (Whalley et al. 2008). Interestingly, it has been proved that
only the individuals with mild cognitive decline, but lacking the ApoE4
gene, might benefit from fish oil ingestion to improve their cognitive
status (Daiello et al. 2015).
Nevertheless, the mechanisms involved in the interactions among

genes, foods, and cognitive performances are still poorly understood.
Moreover, the influence of compounds other than lipids should not be
ruled out. Future research should consider not only the nature and the
amount of the ingested fatty acids but also the genetic status of ApoE in
the patients examined. If these approaches are confirmed, any attempt
to prevent a loss of the age-related cognitive performances should be pre-
ceded by a genetic study to increase the prevention efficiency. Actually,
clinicians undertake these analyses only in the context of research on
the treatment of a declared Alzheimer’s disease, but it is likely that work
carried out with ω-3 fatty acids will encourage health authorities to
expand in the near future the indication of such investigations.
The variability of results reported in the scientific press is likely the
cause of the heterogeneity of the participants of clinical tests. Thus, a
British study in 2010 did not detect any change in cognitive performances
in 800 subjects with a mean age of 75 years after a daily intake of 500 mg
of DHA and 200 mg of EPA during 2 years (Dangour et al. 2010). Similarly
in 2015, Dr. E. Y. Chew, as part of the Age-Related Eye Disease Study 2
(AREDS2), could not detect any beneficial effect after prescribing 350 mg
of DHA and 650 mg of EPA for 5 years to a large number of individuals
about 73 years old. These patients were selected for a general study of
retinal disorders (Chew et al. 2015).
In fact, Dr. Chew noted that the dosage could be one of the factors that
affected their findings. Importantly, the vast majority of studies using less
than 700 mg of DHA daily have concluded no benefit, whereas studies
using higher amounts indicated beneficial effects on cognitive function in
adults ranging from healthy individuals to those having mild Alzheimer’s
disease (http://www.goedomega3.com/index.php/blog/2015/08/omega-
3s-and-cognition-dosage-matters). However, the cause of the negative out-
comes is probably multiple: advanced age of subjects, adequate dietary
ω-3 fatty acid intake, or inadequate psychometric tests.
As for other experiments, the large number of enrolled patients does
not always provide greater experimental rigor.
A remarkable investigation in this area was conducted in 19 US sites
involving 485 healthy subjects, aged more than 55 years, with half being sup-
plemented daily for about 6 months with 900 mg of DHA, and the others
receiving a placebo (Yurko-Mauro et al. 2010). This large clinical trial, con-
ducted with the help of Martek Biosciences Corporation that produced a sea-
weed DHA extract, has shown a remarkable beneficial effect on learning and
episodic memory (verbal recognition), but not on spatial memory or pattern
recognition. In addition, the cognitive test scores were significantly correlated
with the blood DHA concentrations. The authors of this extensive work con-
sidered that the improvement observed after 6 months in individuals receiv-
ing DHA corresponded to the state observed in 3.5-year younger subjects.
Other work carried out on a smaller group of individuals receiving

DHA daily for 3 months (Rondanelli et al. 2012) or on a larger group
receiving fish oil for 1 year (Lee et al. 2013) has demonstrated the useful-
ness of such treatments in improving cognitive performances in the elderly
suffering from MCI.
A rigorous meta-analysis of eight investigations in the same field done
between 2006 and 2010 came to the same conclusions: the supply of ω-3
fatty acids is capable of inducing beneficial effects on the memory charac-
teristics in healthy subjects having only memory complaints or scores indi-
cating only a mild cognitive decline (Mazereeuw et al. 2012).
The subject remains highly topical and of such an importance that a
new meta-analysis was published in early 2015. This analysis, encompass-
ing 15 investigations selected from 1034 publications, found a real improve-
ment in the episodic memory of adults taking at least 1 g/day of an EPA
plus DHA mixture, with the DHA being particularly efficient for semantic
and working memory (Yurko-Mauro et al. 2015).
To conclude the survey of this field of investigation, it is also necessary
to take into account the results of rigorously designed clinical research
recently performed in Germany at the Leibniz University of Hanover (Witte
et al. 2014). The authors clearly showed that a treatment with ω-3 fatty acids
from fish oil (2.2 g/day for 6 months) led to positive effects in brain function,
mainly on its executive functions (TMT, Section 7.9) in the elderly without
neuropsychological disorders (score MMSE >26). The treatment also
showed a beneficial effect on the blood levels of neurotrophic factors and
on the nerve microstructure appreciated by MRI techniques.
As was previously described for young adults (Section 3.1), new
studies demonstrate that 24 weeks of fish oil supplementation (2.4 g/day
of EPA plus DHA) increases prefrontal cortical hemoglobin oxygena-
tion (blood oxygenation level–dependent signal) in healthy older adults
(62–80 years), together with their working memory performance (Boespflug
et al. 2016). These findings suggest that increasing dietary long-chain ω-3 fatty
acids intake may help to reduce neurocognitive decline and more importantly
neurodegenerative processes when initiated early in their onset.
Moreover, it has been proven that after a treatment with fish oil, unlike
patients with Alzheimer’s disease, only patients with a light cognitive
decline, but lacking ApoE4, displayed improvement in their cognitive con-
dition (Daiello et al. 2015). These results are in agreement with the conclu-
sions reported by J. F. Quinn that people suffering from Alzheimer’s disease
(MMSE score between 14 and 26) and treated with 2 g of DHA/day did not
see a slowdown of their cognitive decline (Quinn et al. 2010).
Despite certain limitations, all the research cited above suggests that
a dose ranging from 1 to 2 g of DHA per day can slow cognitive decline
in healthy subjects and also in those with mild forms of dementia.
The mechanisms involved are poorly known, but they seem to aim
specifically at the modulation of inflammation and apoptosis. This

hypothesis is supported by a study proving that DHA is more effective
than EPA in modulating specific markers of inflammation in humans
(Allaire et al. 2016).
It is unfortunate that no treatment with purified EPA has been initiated.
Although the state of research in this field does not allow targeting of particu-
lar populations according to their genetic or physiological predispositions, it is
essential to maintain from a very young age an ω-3 fatty acid intake consistent
with the most recent recommendations (Section 7.2). As emphasized by
Dr. P. Barberger-Gateau at the University of Bordeaux in France, it is certain
that upcoming experimental research will consider more parameters to target
better defined populations on the point of view of cognition, nutrition, and
genetics to optimize the future prescriptions (Barberger-Gateau et al. 2013).
Five clinical projects are about to be completed or were still recruiting in
2016 in various research centers targeting the effects of ω-3 fatty acid supple-
mentation on age-related cognitive decline (http://clinicaltrials.gov).
In conclusion, all this research generates new ways or means to prevent or

delay the devastating effects of time on our cognitive performances. All authors
invested in this fight emphasized the need to set up an early prevention, based
on a regular consumption of fish and, if necessary, a daily intake of at least 1 g of
purified ω-3 fatty acids. Any fatty acid supplementation should be applied well
before the onset of dementia symptoms; it should be recommended from the age
of 40 or 50 years for people at risk, knowing that clear criteria of the disease can
be established only after the progression of the underlying disease remaining
silent during several years.
4.1.2 Vitamin A and carotenoids

4.1.2.1 Vitamin A
Laboratory experiments over time have shown that retinoic acid, one of the
forms of vitamin A (Section 7.3), plays a key role in the developing nervous
system. In the Laboratory of Cognitive Neuroscience at the University of
Bordeaux, Dr. F. Mingaud has shown, in animals, that vitamin A is involved
in the regulation of synaptic plasticity (Mingaud et al. 2008). This plasticity is
now taken into account to explain the modifications in learning and memory
functions mainly by means of the expression of target genes. Other experi-
ments conducted at the same university in young rats have shown that a
dietary vitamin A supplementation improved the neuronal dendritic arboriza-
tion and especially the spatial memory in older animals (Touyarot et al. 2013).
Despite these encouraging results, the actual role of retinoids in the
human cognitive functions remains enigmatic, although the intervention
of these lipid compounds in the emergence of dementia is now an undis-

puted fact (Section 4.2.2).
4.1.2.2 Carotenoids
Lutein, a widespread carotenoid in plants (Section 7.3) seems to be a com-
pound potentially very important for cognitive functions. As zeaxanthin,
it is known to cross readily the blood–brain barrier and accumulate in all
nerve tissues, and specifically in the region of retina called the macula.
Thus, the measurement of macular pigment concentration by photometric
methods has been proposed to replace in blood the complex determina-
tion of these pigments.
The academic interest for that molecule is new; it originated more
than 10 years ago during a US epidemiological study (Kang et al. 2005).
This large trial (Nurses Health Study), involving more than 13,000
women, revealed that subjects consuming the greatest amount of green
vegetables (lutein rich) had a cognitive decline less pronounced that sub-
jects consuming green vegetables only rarely. The authors were able to
estimate the gain in terms of “cognitive age” equivalent to about 2 years.
More recently, the laboratory of Dr. Elizabeth J. Johnson, a recognized spe-
cialist in this issue at Tufts University in Boston, studied lutein as well as
zeaxanthin and β-carotene in an important number of seniors and even in
centenarians living in the US state of Georgia (Johnson et al. 2013). These
investigations showed that the cognitive performances of all subjects were
directly correlated with the blood levels of these three carotenoids, with
lutein characterizing more particularly octogenarians. Similar results were
obtained after analysis of brain samples taken from people who died
during the study. These results have been repeatedly confirmed in many
elderly after research based on the oral intake of β-carotene (Dutch study)
or on the plasma concentration as well (Swiss study).
It is even more interesting to learn that in people older than 50 years
the lowest macular pigment concentrations are correlated with the lower
cognitive performances (Feeney et al. 2013). It is therefore possible to say,
show me your eyes, and I shall tell you how your brain works.
Dr. E. J. Johnson published the results of a supplementation trial of
10 women, aged about 67 years and who were in good mental health, with
lutein at 12 mg/day for 4 months. At the end of that study, the subjects
receiving lutein showed a significant improvement in verbal fluency
scores, unlike subjects receiving a placebo (Johnson et al. 2008). The test
used allowed the assessment of long-term memory of subjects by asking
them to list the greatest number of names belonging to the same category
(flowers, animals, etc.) for 1 minute. Although these results were obtained
with only a small number of individuals, they seemed encouraging to
initiate further research on the therapeutic use of lutein, perhaps synergis-
tically with other treatments such as ω-3 fatty acids.
However, an experimental study performed by Dr. E. Y. Chew, within

the general American AREDS2 program, could not highlight any benefit
after 5 years with a daily intake of 10 mg of lutein and 2 mg of zeaxanthin
in people of average age 73 suffering from mild retinal disorders (Chew
et al. 2015).
No specific carotenoid intake has been recommended in humans,
but the few data collected to date on the effects of lutein, and perhaps
zeaxanthin, on various forms of memory may only encourage all of us
to consume, as much as possible, green vegetables such as kale and spi-
nach, which are particularly rich sources of these compounds (Leray
2015). Recall that French people ingest with their food, on average,
2.5 mg/day lutein and zeaxanthin (Section 7.3), whereas 6 mg was asso-
ciated with a reduced risk of age-related macular degeneration (AMD).
Similar low dietary intakes of these carotenoids have been determined
in Americans from Indianapolis, Indiana (Curran-Celentano et al. 2001).
Efforts remain to be done to achieve the threshold dose that could be defi-
nitely beneficial to many functions, both in the visual field and the cogni-
tive field.
4.2 Dementia and Alzheimer’s disease

MCI progresses to dementia frequently. The clinical situation is then
characterized by significant cognitive deficits, severe enough to affect
family, social, or professional life. Thus, a progressive loss of memory
is recorded, but also an alteration in motor movements and language
and difficulties with thinking or problem-solving. The disease has been
associated specifically with a loss of executive functions that character-
ize the execution of tasks requiring a goal or defined objectives. These
high-level functions are involved in many forms of cognitive activities
(Section 7.9).
Among dementias, a distinction should be made between Alzheimer’s
disease, frontotemporal dementia (Pick’s disease), vascular dementia,
and other dementia associated with certain diseases (Creutzfeld–Jacob,
Parkinson, Huntington). Certain neurologists even argue that the majority
of dementia in the elderly would be a trouble combining degenerative dis-
ease and vascular pathology. The term “senile dementia” was used when
it was thought that memory loss and confusion were a normal part of
aging. It is more common now to refer to dementia, or early-onset demen-
tia, if the person is under 65 years old.
As Prof. Roger Gil (2010) said: “It is difficult to have an unitary
approach of a set as disparate as organic dementia. This disparity is due
to the symptomatology of dementia syndrome that is not one but is plural;
it also lies in the diversity of all etiologies as well as to the heterogeneity of

clinical presentations within a same etiology.”
Thus, in the absence of reliable biomarkers, clinicians must unfortu-
nately wait for the full establishment of the disease before characteriz-
ing with success an advanced dementia, a time that can delay any
intervention. Following the works of Prof. Bruno Dubois, Pierre and Marie
Curie University in Paris, the current trend is to clinically characterize an
Alzheimer’s prodromal phase after a preclinical phase, a period still cur-
rently poorly characterized that lasts from 15 to 20 years. The prodromal
stage shows symptoms including impairment of episodic memory of the
hippocampal type that does not yet alter daily life and the presence of bio-
markers detected in the cerebrospinal fluid (β-amyloid peptide) or by MRI
(hippocampal atrophy, senile plaques).
The “World Alzheimer Report” estimated that in 2010 the number of
people affected in the world by dementia was 35.6 million and will reach
66 million in 2030 and more than 115 million by 2050 if no medical treat-
ment reduces the incidence of this disease. Globally, the costs incurred by
dementia have been estimated at more than US$600 billion dollars.
The US Alzheimer’s Association has estimated that more than 5 million
Americans are living with Alzheimer’s disease, with approximately
200,000 individuals being under 65 years. Notably, one in three seniors
dies with Alzheimer’s or another dementia. In 2015, the cost of the unpaid
care for patients has an estimated economic value of more than US$220
billion. As emphasized by the association, Alzheimer’s takes a devastating
toll, not just on those with the disease but also on entire families. These
numbers will increase rapidly in coming years, because the baby boom
generation has begun to reach age 65 and beyond, the age range of great-
est risk for the disease.
In Europe, all dementias affect about 6.4% of the population, with
this figure being 1.2% between 65 and 69 years and nearly 30% after
90 years.
In France, there are currently about 900,000 patients, with an inci-
dence of more than 100,000 new cases per year. The prospects for the
coming years are quite dark because, considering the current trends, an
INSERM epidemiologist team has estimated a 75% increase in dementia
cases in the French population between 2010 and 2030 and 200% in peo-
ple more than 90 years (Institut National de la Santé et de la Recherche
Médicale [INSERM] Unit 897/Université Victor Segalen, Bordeaux 2).
These alarming estimates are nevertheless necessary to anticipate the
needs and manage this relentless evolution in our society. Ignoring the
financial burden for families, the annual fee for the French patients is cur-
rently close to €19 billion (0.6% of gross domestic product). Despite these
alarming figures, it has been estimated that if it were possible to delay the
onset of the disease a year, more than 9 million people would avoid the
disease in the world in 2050 (Wimo and Prince 2010).
The diagnosis of Alzheimer’s disease is currently unclear and long
to establish, because it is based solely on the use of neuropsychological tests
to evaluate the patient’s cognitive functions, and at different times of the
evolution of the pathology. Frontotemporal dementia could represent about
20% of the degenerative dementia (about one third of the cases diagnosed
in people under 65 years old) and 30% of patients would in fact suffer from
vascular dementia, especially for the early cases. Recall that the increasingly
frequent MRI scans show that 30% of patients older than 65 years have
signs of cerebral infarction. The imprecision of diagnosis, due to the overlap
of symptoms, makes the estimation of the contribution of each type of dis-
ease to the cognitive decline difficult, likely contributing to the dispersion
of the results registered during epidemiological or clinical work.
In neuropsychology, Alzheimer’s disease differs from mild cognitive
decline by a movement toward a loss of autonomy followed by disability.
In both cases, the first signs are identical, and the same psychometric tests,
such as the MMSE and the TMT (Section 7.9), are often used to establish
a diagnosis. Some patients have a rapid decline (loss of at least 3 MMSE
points in 1 year) that has a poor prognosis, whereas others have a slower
decline. The diagnosis of the disease may be established not only on the
basis of an evolution of cognitive functions, by using, for example, the spe-
cific Alzheimer Disease Assessment Scale-cognitive (ADAS-cog, Sec-
tion 7.9), but also more recently through imaging techniques
(computerized tomography, MRI). These new procedures allow to
appreciate a possible atrophy of specific brain areas, such as the hippo-
campus, but they will be soon complemented by positron emission tomo-
graphy scans enabling the quantification of amyloid deposits and thus a
more accurate diagnosis. Analysis of blood and cerebrospinal fluid may
also be used. Research is nevertheless required to establish the validity
of these promising new tools.
After the appearance of a mild cognitive decline, some patients pre-
sent a progressive worsening of their cognitive functions, such as memory,
judgment, decision-making, language, and orientation. Added to that list
several must be behavioral issues such as anger, aggression, greed, dis-
trust, depression, delirium, or hyperphagia. The neuropathologists add
to the clinical picture many neuronal plasticity alterations, such as a selec-
tive loss of neurons and synapses, an intracellular deposit of insoluble
fibrillar proteins (tau protein), and the formation of extracellular senile
plaques (amyloid plaques). In most cases and as for cognitive decline
(Section 4.1.1), the presence of the ApoE4 gene (in approximately 15%
of the population) is a genetic predisposition factor that increases by about
four times the risk of developing Alzheimer’s disease. For a long time this
genetic equipment was indeed said to be the cause of amyloid deposits,

and more recently the reduction of cerebral metabolism and hippocampus
volume (Liu et al. 2015).
Among the nutrients that may influence the evolution of dementia
syndromes, several lipid compounds have already been investigated,
and the results deserve to be known by everyone. The main targeted
lipids are ω-3 fatty acids (Section 4.2.1), vitamin A and carotenoids
(Section 4.2.2), vitamin D (Section 4.2.3), vitamin E (Section 4.2.4), and
cholesterol (Section 4.2.5).

In the absence of efficient pharmacological treatments, it is possible to
consider for Alzheimer’s disease, as for the normal cognitive decline, a
therapeutic solution using specific lipid supplies that influence the pro-
gression of the disease up to an old age. Through animal models and cul-
tured cells, it has become increasingly clear that a supplementation with
EPA and DHA can lower amyloid plaque formation, likely through their
protective roles in reducing β-amyloid accumulation via mediating the
glymphatic system function in the brain (Ren et al. 2016). Neuroinflamma-
tion plays an important role in the onset and also in the advancement of
the disease, with ω-3 fatty acids being involved in both the reduction and
resolution of inflammation. Several new approaches seem to prove that
the origin of these effects may be lipid mediators (oxylipins) derived from
ω-3 fatty acids (EPA and DHA) in fish oil (Devassy et al. 2016). Numerous
studies have also shown that in addition to its anti-inflammatory role,
DHA could improve neuronal survival. α-Linolenic acid could also posi-
tively impact Alzheimer’s disease.
Considerable research has considered that the late expression of
Alzheimer’s disease results from an interaction between genetics and
environment. These positive developments have naturally lead clinicians
to explore the relationships between dietary intake of ω-3 fatty acids and
the incidence of the disease. Faced with this developing disease, it seems
urgent to define simple and inexpensive therapies applicable quickly and
safely as early as possible and preferably in subjects genetically predis-
posed to the disease.

After the observation of a lower concentration of DHA in the brain tis-
sue in patients with Alzheimer’s disease, several epidemiological stu-
dies were carried out to make a link between the fatty acid status and
the symptom onset. Before 2005, the number and the quality of the pub-
lished work was not an incentive to relevant conclusions; thus, in 2005,
the US Agency for Healthcare Research and Quality made no clear
recommendation on the effects of ω-3 fatty acids on cognitive functions

and their pathological degradation (http://www.ncbi.nlm.nih.gov/
books/NBK11853/#__NBK11853_dtls__).
Since this hardly exciting review, nine large epidemiological studies
were performed in a dozen countries. They all established with more
certainty that the intake of ω-3 fatty acids of marine origin, attested and esti-
mated by blood concentration, decreased significantly the risks of cognitive
decline, dementia, or Alzheimer’s disease (Cunnane et al. 2009). Nineteen
reliable studies were published between 1997 and 2008 on the same subject.
It must be noted that if two of them have shown no effect, the other 17
reported that the risk of Alzheimer’s disease increased when the nutritional
intake of ω-3 fatty acids decreased. Several other epidemiological studies
recently published led to the same conclusions. Very recently, it has been
shown that a low level of EPA, but not DHA, in the red blood cells was
the best indicator of an increased risk of cognitive performance degradation
(Street et al. 2015).
From an analysis of numerous publications, it has been estimated that
a large weekly consumption of fish (500 g or more) was associated with a
36% lower risk of suffering from Alzheimer’s disease. A statistical calcula-
tion allowed for the estimation that for each additional intake of 100 g
of fish per week, the risk of developing the disease was reduced by 11%
(Wu et al. 2015).
In France, two studies have contributed to the understanding of
the effects of this specific diet. The vast PAQUID study coordinated by
INSERM in southwestern France has shown a close association between
an important and regular consumption of fish and a lower risk of develop-
ing dementia or cognitive decline when measured after 7 years (Barberger-
Gateau et al. 2002). The second major French study, a part of the COGINUT
program coordinated by the National Institute of Agronomic Research,
aimed at analyzing the relationship between diet and intellectual perfor-
mances among the elderly, emphasizing the role of ω-3 fatty acids and
antioxidants. This project was developed in 1999 within the Study of
Three Cities, including more than 9000 people aged over 65 and studied
for 7 years in Bordeaux, Dijon, and Montpellier (Barberger-Gateau et al.
2007). At the end of the program, it seemed that old subjects eating fish
at least once weekly, in combination with daily consumption of fruits
and vegetables, had a 30% lower risk of developing dementia in the next
4 years, but only in subjects not carrying the ApoE4 gene. The regular
use of linoleic acid–rich oils (sunflower, peanut, grape seed) in the absence
of a compensation by α-linolenic acid–rich oils (rapeseed or walnut) was
associated with a two times greater risk of dementia, but only in noncar-
riers of the ApoE4 gene. However, it seemed that the regular consumption
of various sources ω-3 fatty acids should be associated with an antioxi-
dant supply (fruits and vegetables) for a significantly decreased risk of
dementia, with the presence of only one of these healthy eating habits not
being sufficient for brain protection. An encouraging support for that
approach was recently provided by the demonstration of a reduced inci-
dence of Alzheimer’s disease associated with a modified Mediterranean
diet (Mediterranean-DASH Intervention for Neurodegenerative Delay
[MIND] diet) (Morris et al. 2015b). That prospective study of 923 aged par-
ticipants living in retirement communities and followed, on average,
4.5 years has suggested that reducing the risk of developing Alzheimer’s
disease may be obtained with even modest dietary adjustments. For exam-
ple, the MIND diet score specifies just two vegetable servings per day and
both two berry servings and one fish meal per week.
4.2.1.2 Intervention studies

It is regrettable that the use of EPA and DHA as dietary supplements has
so far provided little in the way of conclusive results, probably because of
the variety of the lipids used and a lack of discrimination in the selection
of participants in these clinical trials. The interpretation of the positive
results obtained with various ω-3 fatty acids raises several questions about
their analysis or discussion (Cunnane et al. 2009). Nevertheless, all studies
have suggested that the achieved effects were highly dependent on the
state of disease development, with these fatty acids being more effective
in the early stages of disease. The assessment of the first symptoms (pro-
dromal phase) thus seems essential to ensure the success of this nutritional
therapy. This is also true for the current pharmacological or behavioral
treatments.
This is the point of view adopted by one of the most renowned spe-
cialists of this question, Prof. Greg Cole, of the University of California-
Los Angeles, who acknowledged that DHA is able to slow several molecular
mechanisms deleterious for the nervous system at the beginning of a disease
(Cole and Frautschy 2010). This clinician argues openly in favor of an early
nutritional intervention including the administration of DHA and antioxi-
dants, especially in subjects at risk.
These recommendations can only encourage investigators to imple-
ment all biochemical, anatomical, and neuropsychological aspects to pre-
dict as accurately as possible the risk of transforming a simple state of
weak memory into an irreversible dementia. In the absence of reliable
markers, it is advisable to follow the nutritional recommendations for
lipid intakes by selecting foods that meet the individual requirements.
Several studies have concluded that there was no evidence of any
usefulness of a ω-3 fatty acid supplementation to improve the cognitive
decline or dementia in the elderly (Dangour et al. 2012). Despite these con-
clusions, an extensive study carried out in the United States in year 2000
has definitely turned upside down the organization of the future clinical
research in this area (Quinn et al. 2010).
This study, among the most serious in recent years, was carried out
under the sponsorship of the National Institutes of Health by a group of
cooperative research on Alzheimer’s disease. This large trial involved 51
research centers gathering together 402 patients divided into two groups:
one group received 2 g of DHA daily for 18 months and the group (con-
trol) received a mixture of vegetable oils. In addition to numerous psycho-
metric tests, the distribution of ApoE4 gene carriers was investigated.
The overall result of this immense work that lasted several years was a
little disappointing because the DHA supplementation led to no detect-
able benefit with selected tests, but the treatment did not cause unpleasant
side effects. Conversely, the noticeable result of this work comes from the
comparison of subjects carrying the ApoE4 gene with those who did not.
Indeed, only the subgroup without the ApoE4 allele could benefited after
an 18-month treatment of a highly significant slowing down of their cog-
nitive decline. It seems, as it has often been reported in other studies, that
ApoE4 is a potent regulator agent of the DHA effects on the emergence
of dementia (Huang et al. 2005). However, some authors contested these
findings, showing that unanimity is not yet fully established for the invol-
vement of that genotype in specific neuropathological risks. These discre-
pancies may result from several factors affecting the DHA metabolism,
such as sex, age, body weight index, and alcohol consumption.
These issues obviously pose a lot of questions because DHA may pos-
sibly inhibit the generation of amyloid plaques and slow the cognitive
decline in patients lacking the ApoE4 gene, although the intimate mechan-
isms of this regulation remain unknown (Salem et al. 2015). These results
should be related to the recent data indicating that the presence of the
ApoE4 gene is the most prevalent risk factor for Alzheimer’s disease,
because this lipoprotein is expressed in more than half of the patients
(Michaelson 2014). The role of the gene coding the protein in the onset of
Alzheimer’s disease is predominant and indisputable because it is widely
associated in the brain, not only with hippocampus atrophy but also with
a deposit of amyloid substances (Liu et al. 2015).
It is hoped that future research will target rapidly these regulatory
mechanisms without missing the methods of dietary treatment in patients
carrying the ApoE4 gene. As it was stressed previously for the role of age
(Section 4.1.1), it seems important that everybody could know his or her
genetic composition to decide the merits of an early prevention based
on DHA supplementation, EPA supplementation, or both without waiting
for the first manifestations of a cognitive decline that may lead to an irre-
versible nervous degeneration. The generalization of this “nutrigenetic”
approach seems the most pragmatic, given its relative safety compared
to all pharmacological treatments, with their benefits being still very ques-
tionable. It must be emphasized that according to a large survey carried
out in 2014 by a mutual insurance company (MGEN), 62% of French
people have said they are interested in genetic testing and 84% would
change their lifestyle upon detection of a genetic defect. It is becoming
increasingly clear that a high risk of suffering from a serious cognitive
deficiency argues for detecting any specific predisposition to take place
as early as possible. That approach is not a bet on probable science pro-
gress because solutions already exist to delay or attenuate the manifesta-
tions of cognitive decline and dementia. These preventive means involve
only a small dietary change or possibly a supplementation with natural
products extracted and purified without any chemical modification.
It seems evident that genetic tests specific for the cholesterol and fatty acid
metabolism would be more widely practiced while remaining faithful to
the bioethic laws, because results of these tests could be associated with
potential nervous disorders.
Within the framework of the last French Alzheimer plan, a large
survey (Multidomain Alzheimer Preventive Trial [MAPT]) initiated by
the Toulouse University Hospital (Gérontopôle) was launched in 2008
with 1680 subjects more than 70 years old to determine whether preven-
tive measures, including the administration of ω-3 fatty acids, could pro-
tect against memory loss. Everyone hopes to know shortly the outcomes
of this vast trial.
Further research will certainly contribute to the discovery of addi-
tional therapeutic and especially preventive strategies for the various
forms of dementia, and to the knowledge of the biological mechanisms
and the treatment modalities convenient at each disease stage. Thus, the
future explorations involving ω-3 fatty acids should also consider the
recent discovery of Dr. F. Jernerén on the influence of B vitamin (Jernerén
et al. 2015). Indeed, in the context of the great OPTIMA (Oxford Project to
Investigate Memory and Aging) study, a remarkable new concept was
proposed suggesting future developments for a more efficient prevention
of Alzheimer’s disease. Investigators have shown that in elderly (70 years
or older) with mild cognitive decline, ω-3 fatty acid supplementation had a
beneficial effect only when there was a joint contribution of B vitamins.
Recall that the dietary B-complex vitamins, including B1 (thiamine),
B2 (riboflavin), B3 (niacin), B5 (pantothenate), B6 (biotin, folate), and
B12 (cobalamin), are important regulators of neurotransmitter function.
Vitamin B6, in particular, is an important cofactor for the enzymes
that synthesize serotonin, epinephrine, norepinephrine, and γ-aminobutyric
acid.
It had also been previously demonstrated that an important intake of
B vitamins could slow brain atrophy in this type of patients (Smith et al.
2010). This discovery led the project leader, Prof. D. Smith of the Depart-
ment of Pharmacology, Oxford University, to state in April 2015 in the
Daily Express that “it was the first treatment showing that brain altera-
tions associated with Alzheimer’s disease may be prevented. This means
that simply maintaining a high level of ω-3 fatty acids, associated with
a B vitamin supplementation, can greatly reduce the disease risks.”
Furthermore, Smith believes that this treatment should be administered
immediately after the first signs of dementia.
These new data will help in future experiments to form more consis-
tent groups of subjects to avoid result dispersion, thereby increasing their
meaning. An alternative could be to supplement subjects with a mixture of
B vitamins at appropriate doses before any supplementation with ω-3
fatty acids.
In this area, several new trials already look promising, for example,
the LipiDiDiet European project. Indeed, a new dietary supplement
(Nutritia Souvenaid®) providing 1200 mg of DHA and 300 mg of EPA
daily, vitamins (E, B6, B12), trace elements (selenium), and various meta-
bolites (uridine, choline) was administered to subjects from several
European countries who were exhibiting signs of Alzheimer’s disease.
Well-controlled experiments have demonstrated that this treatment
had beneficial effects on memory and patient behavior (Scheltens et al.
2014) and even on the organization of the neuronal networks (de Waal
et al. 2014). These trials provide compelling evidence that it is now
possible to improve cognitive functions by using a combination of nutrients
combining ω-3 fatty acids and several vitamins. Nonetheless, another trial
with the same product found no effect on the development of the cognitive
decline in subjects clearly affected by the Alzheimer’s disease (Shah et al.
2013). As noted, it is likely that the stage of progression of the disease in
these two trials is the source of these differences.
Further clinical trials are underway to evaluate all the possible effects
of this new product as able to maintain the integrity of synapses, a char-
acteristic that is essential for brain function, on account of ω-3 fatty acids
and other compounds.
In the absence of investigations on primary prevention, several basic
and clinical studies are needed before considering a widespread prescrip-
tion of DHA or EPA to prevent or first to treat Alzheimer’s disease. These
steps forward will benefit from related progress in the molecular diagno-
sis of the disease, thereby allowing early identification of individuals at
risk. They may encourage the support of long-term research with strict
protocols to get rapid solutions for fighting against all types of dementia.
Pending the outcomes of this future work and considering that the major-
ity of fatty acid supplementations give equivocal results, the main recom-
mendation is again to increase fish consumption, with supplementation of
purified ω-3 fatty acids as an alternative. It is regrettable that, in general,
academic authorities or care associations that are able to guide govern-
ment decisions are still very careful regarding support of “nutrigenic”
prevention of dementia. In focusing their interest on hypertension or dia-
betes, these organizations pay, in general, no attention to the influence of
essential fatty acids on brain function. However, in later publications,

INSERM acknowledged cautiously that “a broad preventive message
(more physical activity, better balance diet, a healthy lifestyle) could help
to delay the onset or expression of Alzheimer’s disease.” It is also regret-
table that even in the most recent books (Léger and Mas 2015) there is only
a discreet mention of a 2003 publication concluding ω-3 fatty acids have
beneficial effects on cognitive decline (Heude et al. 2003).
Compared with dementia of neuronal origin, vascular dementia
remains a poorly defined syndrome, despite research that began nearly
80 years ago. This pathology is clinically described most often as a cogni-
tive decline related to intracerebral vascular lesions caused by a stroke of
ischemic or hemorrhagic origin. Vascular dementia is the second type
of common dementia after Alzheimer’s disease, being found in 15%–30%
of cases; however, this pathology is underestimated in clinical diagnostics,
although the risk factors are the same for these two types of dementia.
Unfortunately, limited research has been devoted to the effects of ω-3 fatty
acids on vascular damage possibly causing dementia. Most epidemiologi-
cal studies still show an inverse relationship between fish consumption
and the incidence of the disease. A large epidemiological study concluded
that an increase in fish consumption (from one serving monthly up to four
servings per week) significantly lowered by 35% the risk of vascular
dementia, but only when consumed fish was not fried (Misner et al.
2001). Conversely, the important Italian study Gruppo Italiano per lo
Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione
was unable to detect any effect after a daily supplementation of 850 mg
of ω-3 fatty acids. The few in-depth studies and the small number of
dementia cases reported in each of these studies do not yet allow appropri-
ate therapeutic options to be determined. Further work on a larger scale is
needed to explore the complexities of vascular dementia, which is usually
difficult to diagnose with certainty.
Globally, 15 projects are underway or are about to be completed in
various research centers that have focused on the neuropsychiatric effects
of ω-3 fatty acid supplementation in patients suffering from more or less
pronounced dementia (http://clinicaltrials.gov). The prospective research
should now consider the ApoE polymorphism because it seems to closely
influence the DHA benefits either in epidemiological or experimental
investigations.
4.2.2 Vitamin A and carotenoids

4.2.2.1 Vitamin A
The importance of vitamin A for the nervous system was revealed in 1935
after the discovery of its role in eye function. Later, it was shown that the
brain needed an active form of vitamin A called retinoic acid not only for
the control of cell proliferation during brain development but also for neu-
roplasticity, a complex mechanism allowing neurons to alter their connec-
tions with other cells. Evidence from studies of animal models suggests
that vitamin A is essential for the cognitive functions of the brain (Stoney
and McCaffery 2016).
Around 2000, several studies performed with animals highlighted the
fundamental role of vitamin A (Section 7.3) in the development and the func-
tion of the adult brain. All of these studies emphasized the deleterious effects
of a vitamin A deficiency on the hippocampus, one important area for learn-
ing and memory (Misner et al. 2001). These outcomes have led researchers to
note this societal problem worldwide, because it involves the mental health
of hundreds of millions of adults and children deficient in vitamin A.
Several studies have shown that dysregulation in vitamin A supply was
well related to the onset of Alzheimer’s disease (Goodman and Pardee 2003).
Such a conclusion was confirmed by animal experiments establishing a close
link between vitamin A deficiency, loss of various memory types, and espe-
cially appearance in the brain of β-amyloid peptide, an indisputable marker
of Alzheimer’s disease (Sodhi and Singh 2014). Conversely, a vitamin A
treatment of these animals was able to reduce the accumulation of this pep-
tide and also improve memory performances (Ding et al. 2008). Specific
research carried out in vitro was able to clarify the molecular mechanisms
leading to these effects (Ono and Yamada 2012).
Other observations were added to the clinical description of the dis-
ease, such as low vitamin A blood content in patients with the Alzheimer’s
disease, with the results being more significant in the late form (or spora-
dic form) of the disease. It is possible that much of the effects of vitamin A
(or retinoids), as carotenoids, could be attributed to their antioxidant
actions, thus fighting against the formation of free radicals known to be
highly toxic for brain tissue (Smith 2006).
Unfortunately, clinical studies are desperately needed in this field,
with only one being officially launched worldwide in 2012; this study used
a form of vitamin A prescribed for the treatment of psoriasis (Acitretin).
Trials are under way using a synthetic analogue of vitamin A, Targretin®
(bexarotene). This retinoic X receptor agonist was shown to decrease brain
amyloid formation and to improve synaptic and cognitive functions in
animal models of Alzheimer’s disease. The treatment of one patient with
mild Alzheimer’s disease (6 months with 300 mg bexarotene/day) induced
a 40% memory improvement and a 20% decrease of the tau protein in
the cerebrospinal fluid, whereas no significant side effects were noticed
(Pierrot et al. 2015). This observation indicates that bexarotene may
improve memory performance and biological markers at an early stage
of Alzheimer’s disease. It is hoped that ongoing clinical trials will provide
much more consolidated data to validate that vitamin A analogue as a
potential drug in the treatment of neurodegenerative diseases.
In conclusion, a therapy with vitamin A should lead to major benefits in

the evolution of the Alzheimer’s disease, particularly by modulating the
β-amyloid synthesis, a step that is not the target of the current treatments.
Moreover, all results support the beneficial role of retinoids through their
antioxidant and antiapoptosis activities and by their role in cellular differ-
entiation and activation of cholinergic functions. Retinoids may be an
important repair factor for the nervous system by activating cell protection
and regeneration.
In the absence of other information, the issue can once again be raised
regarding the lack of interest of the pharmaceutical industry for medications
producing little return on investment. In future research, it should be
necessary to better understand the involvement of vitamin A in the signal-
ing pathways and possibly the oxidative reactions within the brain. These
pathways are now well known to play an active role in the genesis of patho-
logical lesions in patients with the Alzheimer’s disease.
4.2.2.2 Carotenoids
As for vitamin A, it was frequently observed that patients with Alzheimer’s
disease had lower carotenoid blood levels than healthy subjects. Among
carotenoids (Section 7.3), lutein and zeaxanthin displayed the most impor-
tant decreases. This relationship was also observed in the retina (macula),
wherein the progression of the disease can be monitored by a photometric
examination of the ocular fundus. All these outcomes are consistent to
explain the higher frequency (about two times) of AMD in patients with
Alzheimer’s disease (Nolan et al. 2014).
Thus, carotenoids seem to be very active agents in lowering manifes-
tations of Alzheimer’s disease, and future research could lead to the pro-
posal of a natural means to fight against this disease, likely by starting
dietary supplementation very early. Pending more efficient and more spe-
cific treatments, the regular consumption of vegetables rich in carotenoids
may currently be considered an effective prevention.
4.2.3 Vitamin D
Historically, vitamin D is considered responsible for calcium homeostasis
and thus key for bone metabolism. Gradually, over the past 30 years, phy-
siologists have shown that this vitamin also has functions in cell prolifera-
tion and differentiation, immunity, and many other metabolic systems
(Leray 2015).
Long after its discovery in 1920 by the American chemist E. V. McCollum,
vitamin D gained notice in neurochemistry, soon after the synthesis in the
1970s of its active form, calcitriol, and especially after the discovery in
1987 of its receptor in the brain. In the past 15 years, the importance of this
lipid vitamin in brain function has continuously grown to the point where
it is now considered as a hormone and classified among neurosteroids
(McGrath et al. 2001).
As with all vitamins, progress came from the study of deficiency
states in animals and in humans. Recently, it became increasingly clear
that levels of vitamin D that were too low in blood of adults were
correlated with serious neuropsychiatric problems and sometimes with
symptoms of neurodegenerative diseases (Eyles et al. 2013). In terms of
brain structure, the observation of an abnormal increase in the white
substance volume, measured by MRI in the vitamin D–deficient elderly,
characterized their motor and cognitive decline (Annweiler et al. 2015a).
This observation is fully consistent with that of an inverse relationship
for the gray matter (Brouwer-Brolsma et al. 2015).
These findings can only suggest to correct any vitamin D deficiency,
considering the importance of the induced pathologies and the extent of
the population concerned, not to mention the huge financial consequences.
The numerous studies conducted in animals have all led to the conclu-
sion that vitamin D plays the role of a neuroprotective actor, able to fight
against the age-related cognitive decline in improving learning and mem-
ory (Latimer et al. 2014). Even more interesting and yet known for nearly
30 years is that vitamin D can accelerate acetylcholine synthesis in some
brain areas. A low synthesis of this neurotransmitter is recognized as fun-
damental in the development of dementia (Sonnenberg et al. 1986). The
recent demonstration of control of serotonin biosynthesis by vitamin D
provides insight into the modulation of behavior and cognitive functions
by this vitamin (Patrick and Ames 2015). In addition, research on animal
models has demonstrated that vitamin D not only improves synaptic plas-
ticity but also reduces amyloid deposits. This knowledge makes it possible
to hypothesize that vitamin D may be effective in patients at risk or with
an Alzheimer’s disease in progress.

Nearly 100 trials were carried out in the past 10 years to explore the poten-
tial role of the vitamin D status on the cognitive decline leading to demen-
tia and more specifically to Alzheimer’s disease. These investigations
consisted either of observing a group of several subjects (a cohort) during
a short time (observational studies) or of following a population for the
longest time possible (prospective studies). In both cases, the results gen-
erally led to the conclusion that subjects with vitamin D blood levels lower
than the current recommendations (less than 30 ng/mL or 78 nmol/L)
had a greater risk of developing a dementia condition than subjects with
higher levels (equal or greater than 30 ng/mL).
An example of a typical observational study is that of Llewellyn et al.

(2009) at the University of Cambridge, UK. They selected 1766 British
subjects of both sexes, aged 65 years or more (mean age 80 years). A blood
vitamin D determination and a psychometric test similar to the MMSE
(Section 7.9) were processed in each participant. Statistical analysis of all
the results showed that subjects having a vitamin D concentration in the
range of 17–25, 12–17, and 3–12 ng/mL had a risk of cognitive disorder
multiplied by 1.1, 1.4, and 2.3, respectively, compared to subjects with a
vitamin D level greater than 25 ng/mL.
This work proved that a decreased vitamin D level in blood was
associated with an increased risk of developing dementia, with the more
deficient subjects having a two times higher risk than control subjects of
the same age group.
To illustrate an example of a prospective study, the work done at the
University of Minnesota, Minneapolis, is considered (Slinin et al. 2012).
This study followed 6257 female participants, with a mean age 77 years,
for 4 years. Besides vitamin D determination in the blood, they proceeded
with a test of global (MMSE) and executive (TMT) function (Section 7.9).
At the onset of the study, the authors found an association between vita-
min D and cognitive impairment similar to that detected in the previous
study. After 4 years, a new psychometric examination in the same subjects
showed that those initially deficient in vitamin D (concentration less than
10 ng/mL or 26 nmol/L) had a risk of cognitive disorders two times higher
than that of the subjects having levels above that threshold.
The study of D. L. Llewellyn, comparable to the previous study,
provided finally comparable results after 6 years: the risk of a significant
decline (3 points on the MMSE test) in subjects with vitamin D blood
levels below 10 ng/mL was 30% higher than in subjects having a level
above 28.5 ng/mL (Llewellyn et al. 2010). A recent cohort study (Littlejohns
et al. 2014) in the United States by the same team involving 1658 elderly
people monitored for a mean of 5.6 years found an incident Alzheimer’s
disease for those with vitamin D <25 nmol/L two times higher than for those
with vitamin D >50 nmol/L. Similar results were obtained after following
more than 10,000 Danes during 30 years (Afzal et al. 2014); 412 Koreans aged
over 65 years for 5 years (Moon et al. 2015); and 382 Americans with a mean
age of 75.5 years (Miller et al. 2015).
These examples illustrate clearly the hypothesis prevailing among
specialists of an adverse effect of vitamin D deficiency in maintaining
the cognitive status during aging, a situation that may even lead to demen-
tia. It is necessary to emphasize that although most of the elderly have a
vitamin D deficiency, not all will develop Alzheimer’s disease. Hypovita-
minosis cannot alone explain the occurrence of the disease, thus suggest-
ing that a vitamin D supplementation may not be sufficient in each case
for an effective prevention.
To broaden the field of study and open discussion, an awareness of

two recent reviews of published communications on this subject over
the past decade is needed.
The first review, conducted at the Department of Geriatrics at Utrecht
University, The Netherlands, selected 28 communications combining
the observations on nearly 57,000 people (van der Schaft et al. 2013).
The review revealed that almost 72% of the work found an association
between low vitamin D levels and cognitive decline, thus indicating a
higher risk of dementia. But no study showed any negative effect for a
high vitamin level.
The second review was done at the Department of Geriatrics,
Angers University, France (Annweiler et al. 2013). The results of 14
research programs confirmed the previous findings indicating that
the executive functions are particularly sensitive to the plasma
vitamin D concentration. Subsequent to that final review, the same
team has shown that a vitamin D deficiency (serum concentration
<28 ng/mL) was significantly associated with more subjective memory
complaints (Tot Babberich Ede et al. 2015). Recall that memory com-
plaint is a light but frequent subjective issue in normal aging because
it affects up to half of subjects aged over 50 years. Recent findings have
shown that the vitamin D threshold associated with cognition issues is
likely around 10 ng/mL. Subjects with concentrations lower than
10 ng/mL have important risks of cognitive disorders, whereas the
risks become lower when the concentrations are higher than 30 ng/mL
(Annweiler 2016).
A meta-analysis of five more recent epidemiological surveys confirms
that vitamin D deficiency increases of more than 20% the risk of develop-
ing dementia or Alzheimer’s disease (Shen and Ji 2015).
These studies are clearly unable to definitively establish a causal rela-
tionship between vitamin D and cognitive decline. Many factors can be
invoked to weigh the results, but the overall trend of a correlation between
the two settings does not seem to be challenged, despite the diversity of the
analytical approaches. When asked whether hypovitaminosis D precipi-
tates cognitive disorders or vice versa, Dr. Annweiler (Annweiler 2016)
answered: “Longitudinal prospective studies have provided possible
answers by showing that older ethnically diverse groups of individuals
with hypovitaminosis D have a significantly increased risk of cognitive
decline, Alzheimer’s disease, and all-cause dementia, compared to those
with higher vitamin D concentrations.” No relationship has been reported
after some trials, but a close examination of the conditions of these tests
easily reveals that several uncontrolled biases often distort the conclu-
sions. Indeed, authors emphasize frequently the difficulty of achieving
global analyzes from several investigations, considering the diversity of
the measurements and the psychometric tests. It must be remembered
that the transition between a subjective cognitive complaint and a charac-

terized Alzheimer’s disease is progressive and that no specific biological
marker can be used to characterize any intermediate step. Moreover, the
most recent large French study (SU.VI.MAX 2, Supplementation in Antiox-
idant Vitamins and Minerals) has shown that positive effects of vitamin D
on some cognitive performances were demonstrable only in uneducated
subjects (Assmann et al. 2015).
The importance of the contribution of genetic factors in the modula-
tion of cognitive functions, as for the vitamin D status, must not be
underestimated (Maddock et al. 2015). Whereas individuals carrying
the ApoE4 gene may have some risk having reduced cognitive perfor-
mances (Section 4.2.1), they show higher circulating vitamin D levels
(Egert et al. 2012). Unexpectedly, these findings are more numerous in
black-skinned people and are found even more frequently in the highest
latitudes. Much work has also emphasized the importance of the genetic
polymorphism of the vitamin D receptor in connection with a premature
neuronal aging.
These complex relationships between genes and environment, yet
poorly explored by clinicians, are undoubtedly relevant to the evolution
of our species, with their knowledge also being essential to develop
and improve new therapeutics to fight efficiently against Alzheimer’s
disease.

For vitamin D, as with all vitamins or hormones, the study of the causal
links between that compound and the physiological effects requires pre-
cise intervention studies. The experimental design of these trials should
include a random distribution of subjects between a control group receiv-
ing no treatment or a placebo and an experimental group supplemented
with a defined dose of vitamin D precisely administered. At the end of
the experiment, the evaluation of both groups is carried out using bio-
chemical analysis combined with a neuropsychological assessment of each
subject. That approach, however, presents some limits for the interpreta-
tion of results because the protocol is often designed in well-controlled
experimental conditions, but it does not reflect a diverse population
commonly encountered on the ground.
Little experimental work has been done to date to elucidate the
effects of a correction of too low vitamin D levels on dementia. This
lack is probably a consequence of the difficulty of implementation of
these trials and their cost. The very low added value of the product
may also contribute to the scarcity of such research in the pharmaceu-
tical field.
The first attempt was made in 2008, but the authors have not reported
any positive effect on cognitive performances and behavior in 25 nursing
home residents aged about 86 years and deficient in vitamin D (Przybelski

et al. 2008). No doubt, this is on the account of the use of ergosterol
(vitamin D2), a plant analogue of cholecalciferol (vitamin D3) known to
be biologically less active. A 4-week trial seems also too short to observe
significant changes in the brain.
A large trial was undertaken with nearly 4000 American women of
average age 70 years, half of which were supplemented with 400 IU/day
of vitamin D (Rossom et al. 2012). After a 3-year treatment, no advantage
over cognitive decline and dementia incidence could be found. The use of
an insufficient amount of vitamin D, a small number of reported neuropsy-
chological incidents, and the unique selection of women probably explain
this lack of effect.
The most encouraging trial was reported by Annweiler et al. (2012a).
Twenty patients, with a mean age of 82 years, received a supplementation
of 800 IU/day of vitamin D for 16 months. During the study, the blood
level of vitamin D increased from 6 to 11 ng/mL, and all the psychometric
tests displayed improved global and executive cognitive functions.
Despite the use of small cohorts, this work confirmed the assumptions
made from the epidemiological studies summarized above: it helped to
demonstrate that dementia does not cause a hypovitaminosis, but rather
the reverse.
Future treatment of cognitive decline and dementia therefore needs
the use of a section including vitamin D. The vitamin supply may be car-
ried out through the diet, as a nutritional supplement or possibly by its
natural synthesis during prolonged sun exposure, although that last source
is recognized as inefficient in the elderly. Such therapy may be also consid-
ered in conjunction with conventional treatments, because Annweiler et al.
(2012b) has shown that the efficiency of a treatment with memantine,
a dementia symptomatic treatment, was potentiated by the addition of
vitamin D.
Other recent data reinforce the hypothesis of a role of vitamin D
in the maintenance of cognitive functions. Among them, are noteworthy
the high amounts of the vitamin D transport protein in the cerebrosp-
inal fluid in individuals with Alzheimer’s disease. The transport pro-
tein status may thus contribute to decrease the cellular availability of
vitamin D.
For ω-3 fatty acids, research is still necessary before proposing a
vitamin D treatment in healthy individuals to prevent illness or to limit
the worsening of preexisting cognitive issues. It is desirable that the pre-
viously published work can used actively to encourage more researchers
to explore the various aspects of vitamin D activities.
All critical aspects between vitamin D and cognitive abilities were
analyzed in early 2013 by a group of 12 international experts grouped
as a task force focusing on key questions related to the role of vitamin D
in Alzheimer’s disease and related disorders (Annweiler et al. 2015b). The

following questions were addressed:
To the questions:
• Can hypovitaminosis D be considered as a risk factor for cognitive

disorders or Alzheimer’s disease (decline and dementia)? All experts
answered yes. The experimental evidence for an action of vitamin D
on the brain is clear enough at the present time to justify that
opinion.
• Can serum vitamin D status be considered a useful biomarker for
the diagnosis of Alzheimer’s disease and related disorders? All
experts except one agreed to answer no. The main argument is that
vitamin D deficiency is too common in the elderly and is not specific
for any cognitive disorder.
• Can serum vitamin D status explain part of the variability in symp-
toms of Alzheimer’s disease and related disorders in older adults?
All experts agreed that vitamin D can explain, at least in part, the
diversity of symptoms. Hypovitaminosis D affects many organs
other than the brain and has been associated with numerous dis-
eases. These conditions may be found in patients with both hypovi-
taminosis D and Alzheimer’s disease and related disorders, thus
affecting a patient’s functional independence and the clinical status.
• Should vitamin D supplementation be part of the care management
of older adults with cognitive disorders or with Alzheimer’s disease
and related disorders. All experts except one agreed to answer yes.
The main argument was that the clinical results are generally favor-
able. Indeed, vitamin D has positive effects on the brain, but also on
many other organs including bones. In addition, this supplementa-
tion is without risk.
Why did the health ministers in several countries not impress more
upon their agri-food industries the need to speed the enrichment of most
common foods (dairy products, bread, cereals, oils), enrichment that
was already allowed in many countries, as in France, since the 2006 law
(Leray 2015)? Even if this allows only a maximum intake of 5 μg/day of
vitamin D. It seems now appropriate to take into consideration the official
scientific studies that revealed that the average vitamin D intake was
corresponding to half of that value as in France, hence confirming the
predominance of a deficiency state in several populations.
Furthermore, one can manifest astonishment when the French High
Authority for Health published in 2013 that the usefulness of blood vitamin
D analysis is not demonstrated. That authority has retained only partially
the osteoporosis pathology. In 2014, the National Health Insurance decided
to abolish the reimbursement of expenses associated with these analyses.
The same high authority has curiously also acknowledged that a vitamin D
supplementation could be established and maintained without a prior
biochemical determination.
Despite the weight of the scientific information, it is surprising that
health authorities do not presently envisage some preventive measures
encouraging vitamin D supplementation, at least for populations at risk.
Indeed, that kind of decision could delay by at least by 1 year the appear-
ance of any dementia if individuals over 65 years were supplemented.
The total prevention cost (approximately €140 million for 100,000 IU every
2 months) would be amply compensated by cost savings estimated to
about €2 billion for Alzheimer’s disease (on an annual total of €16 billion),
but also for those related to fractures, infections, and many chronic dis-
eases (Leray 2015).
Globally, 19 projects that are declared completed were still recruiting
in 2016 in various research centers targeting the neuropsychiatric effects of
vitamin D in patients suffering from various types of dementia, including
Alzheimer’s disease (http://clinicaltrials.gov).
In conclusion, with an increasing number of people affected by cognitive

decline usually leading to Alzheimer’s disease, and with the broad spectrum
of activity of vitamin D, it seems appropriate to undertake a large deficiency
screening plan for this vitamin. The expected results will be clearer if the
screening is carried out as soon as possible. This plan must be followed by spe-
cific advice to restore vitamin levels greater than 30 ng/mL blood through diet,
sun exposure, or possibly with the intake of pharmaceutical supplements.
Despite uncertainty about the most effective doses and the influence of the
genetic terrain of individuals, it is imperative to raise the awareness of people
on the importance of vitamin D, especially if one estimate that 80% of adults
are now insufficient (10 ng/mL < blood levels <30 ng/mL) or deficient (blood
levels <10 ng/mL) in the majority of countries is accurate. The focus should
therefore be on the need for a vitamin D daily intake consistent with the
recommendations of medical authorities (1000–1500 IU/day after 50 years
old, Section 7.4). This is particularly important for populations recognized
as deficient in vitamin D, such as the elderly, young children, and people with
much pigmented skin or living mostly out of direct sunlight.
4.2.4 Vitamin E
The term “vitamin E” is not equivalent to α-tocopherol, despite the large
amount of work devoted to that chemical form (Section 7.5). The other
forms belonging to the vitamin E group must not be ignored because
they are also the subject of an increasing number of investigations in the
brain area. It is significant, for example, that barely 1% of the literature on

vitamin E concerns the tocotrienols.
The importance of vitamin E for the central nervous system seemed
evident as early as at the beginning of the twentieth century when
H. M. Evans and G. O. Burr described the presence of paralysis in young
rats born from vitamin E–deficient females.
Vitamin E is the most abundant lipid antioxidant in the human body,
with that property probably explaining its well-known protective effects
on biological membranes and therefore nerve cell membranes. These
effects are also potentiated in the presence of vitamin C that regenerates
α-tocopherol after its inactivation by free radicals, a property explaining
the joint use in some experiments of both vitamins.
The frequent demonstration of a close association between oxidative
stress, aging, and some nervous pathologies, such as Alzheimer’s disease,
has emphasized the possible use of antioxidant compounds in the preven-
tion and treatment of these areas. Therefore, antioxidants may be also
useful in the fight against memory loss and dementia, because they have
proven to be beneficial for the cardiovascular system (Leray 2015), itself
involved in cognitive disorders.

It was not until 1999 that a link between vitamin E (and not vitamin C or
β-carotene) and memory performances was clearly established in consider-
ing a vast multiethnic US population (Perkins et al. 1999). A year later,
work including blood analysis in many centenarians confirmed this infor-
mation (Klapcinska et al. 2000). The hypothesis of a possible protective
effect of vitamin E on cognitive capacities could be issued.
Here, only the best-documented effects of only some components of
the vitamin E complex on cognitive decline and dementia are reported,
with further data summarized in a review by La Fata et al. (2014).
Many studies based on dietary surveys have attempted to reveal a pos-
sible association between antioxidants and memory. The specific contribu-
tion of the dietary vitamin E remains difficult to estimate, because it is
regularly ingested with many other natural antioxidants, such as vitamins
A and C, carotenoids, and several polyphenols. The role of each compound
and the importance of the mixtures remain undetermined. Among the epi-
demiological studies open to debate, a US survey conducted in 2002 fol-
lowed nearly 2900 individuals aged 65–102 over 3 years (Morris et al.
2002). The statement of the vitamin E intake and the use of four different
psychometric tests allowed to correlate the high doses of vitamin E with a
reduced cognitive decline. A similar study conducted in The Netherlands
in 1996 (Rotterdam study) did not reveal any correlation. The extension
of that study for 6 years on the risk of dementia and Alzheimer’s disease
has nonetheless revealed a modest, but significant beneficial effect of
vitamin E, with that effect being more pronounced in smokers. Another

extension of the same study for 10 years has confirmed these results,
eliminating the interferences of the β-carotene and vitamin C effects
(Devore et al. 2010). The large French SUVIMAX2 study came to similar
conclusions after a follow-up of 10 years (Peneau et al. 2011).
These examples show the difficulty of these approaches, facing a time
scale often not compatible with investigations requiring a wide financial
support. Furthermore, a possible reason to justify the inconsistencies is
the multifaceted feature of Alzheimer’s disease with a progressive devel-
opment and different levels of severity.
A Swedish team conducted a clinical examination of patients with
moderate-to-severe cognitive disorders (Alzheimer’s disease) by performing
MRI investigations in the brain and determination of various circulating
forms of vitamin E (Mangialasche et al. 2013a). The authors concluded that
it should be possible to use serum vitamin E as an indicator of the severity of
disorders, as the vitamin concentration was lower when the disease was
more pronounced. They also noted, throughout a period of 8 years that
older subjects with elevated blood levels of γ-tocopherol and tocotrienols
developed less cognitive impairments (Mangialasche et al. 2013b). The
importance of γ-tocopherol seems to be supported by the discovery of a link
between its high brain level and a reduced deposition of amyloid plaques
between neurons and neurofibrillary tangles within the neuronal cells
(Morris et al. 2015a). These results demonstrate the complexity of the studies
in the elderly dealing directly with the prevention of cognitive decline, but
they should already be encouraging people to diversify their dietary plant
sources to ensure a regular intake of the different vitamin E forms (Section 7.5).
Precise measurements of vitamin E could thus help to establish a diag-
nosis that remains still difficult to provide. Although the link between the
vitamin E status and the cognitive decline level is still unclear, it is inter-
esting to note that the blood vitamin E level does not seem to be connected
to a patient’s nutritional status (Lopes da Silva et al. 2014). This could
remove from the debate a dietary default in subjects known to be often
struck by malnutrition.

Early research on the joint evolution of the vitamin E status and the sever-
ity of cognitive impairment have led some clinicians to evaluate the effect
of a vitamin supplementation on these disorders. Studies using moderate
doses of vitamin E have failed to demonstrate any effect on cognitive
performance; however, doses up to 1340 mg/day have yielded positive
results in one laboratory, but not in another (Farina et al. 2012). It took still
20 years to detect a beneficial effect of a regular supplementation with
vitamins E and C on cognitive function after examining nearly 15,000
aging women (Grodstein et al. 2003). In a randomized trial conducted
in the United States, a high daily dose of vitamin E resulted in a slowing of

the functional decline in patients with a mild-to-moderate Alzheimer’s
disease and was also effective in reducing caregiver time in assisting
patients (Dysken et al. 2014). In the group supplemented with α-tocopherol,
a delay in the annual rate of clinical progression of 19% or approximately
6.2 months was observed over the follow-up period (5 years). The
discrepancies observed between these investigations cannot be explained;
however, it is possible that the controversy over a beneficial effect of
vitamin E in Alzheimer’s pathology is based on the observation of
positive effects only when they are accompanied by a decrease in the oxi-
dative stress. In contrast, the refractory subjects who experience no change
with that antioxidant have an unfavorable evolution of their cognitive sta-
tus, even faster than in subjects receiving a placebo (Lloret et al. 2009).
The comparison between studies done in different countries is often
made difficult by the various chemical forms of the vitamin ingested
naturally by patients. Thus, Europeans mostly absorb α-tocopherol from
sunflower and olive oils, whereas Americans absorb mainly γ-tocopherol
from soy and corn oils. Similarly, for intervention studies, the administered
form is mainly α-tocopherol found commonly on the market worldwide,
but until now no studies have considered the other forms, tocopherols or
tocotrienols, isolated or as mixtures. Research undertaken on cellular mod-
els have already provided sufficiently encouraging results to consider, in
the near future, the development of effective treatments involving specific
forms of vitamin E that have not as yet been explored in clinical research.
In addition, results obtained in animals suggest that sesame oil consump-
tion could strengthen the effects of vitamin E on slowing nervous degenera-
tion processes, a combination likely at the origin of the low development of
Alzheimer’s disease in the Indian population.
In conclusion, the positive effects obtained in several studies and the rela-
tive safety and low cost of its supplementation suggest vitamin E as a
nutritional compound to promote healthy brain aging and to delay
Alzheimer-related functional decline. Despite the still discordant results
provided by clinicians (La Fata et al. 2014), it seems wise to maintain a per-
manent dietary vitamin E intake at least equal to the recommendations
made by the medical authorities (12 mg/day for an adult) (Section 7.5). That
daily intake is easily covered by consumption in moderate amounts of vege-
tables, such as spinach, cabbage, pepper, and pumpkin, but also meat and
fish. An addition of oil, if possible from corn or seeds (almond, hazelnut, pea-
nut) may achieve much higher vitamin E levels. For therapeutic doses of
vitamin E, such as those used in some work, plant sources are no longer
suitable, and it is necessary to use commercial vitamin supplements.
These preparations are either of chemical origin, containing only one form
of vitamin E, or of natural origin, mostly as concentrates from palm oil

refining. Vitamin supplements have the advantage of containing high con-
centrations of almost all vitamin E forms (Leray 2015).
4.2.5 Cholesterol
The brain is the richest organ containing cholesterol (Section 7.6). Although it
is about 1/50th of the body weight, it contains about one quarter of all the
body’s cholesterol amount. Brain cholesterol, which exists in a free state,
mainly occurs in myelin, astrocytes, and nerve cell membranes. It has long
been known that nerve cells synthesize their own cholesterol, being virtually
independent of blood supply (Morell and Jurevics 1996). Brain cholesterol is
thus mainly synthesized in situ, but mainly in astrocytes and oligodendro-
cytes. In contrast to developing neurons, mature neurons can synthesize only
a small amount of cholesterol. It is well-known that cholesterol plays a major
role in the properties of neuronal membranes by modulating the functions of
enzymes, receptors, and ion channels.
Since the discovery of the cholesterol transport protein ApoE and the
potential links between cholesterol and Alzheimer’s disease, major efforts
have been devoted to that problem (Canevari and Clark 2007).
Animal studies have shown that a cholesterol-enriched diet is almost
always associated with a deposit in the brain of an Alzheimer’s disease
marker, the β-amyloid peptide; conversely, the inhibition of cholesterol bio-
synthesis reduces the production of that peptide. For the first time in 1994,
a possible link between cholesterol and Alzheimer’s disease was proposed
in rabbits (Sparks et al. 1994). Later, other work carried out using animal
models for the disease found that a cholesterol-rich diet caused not only
atherosclerosis, as expected, but also a learning disability in space perception
(Li et al. 2003). One of these models lead to stronger evidence of a causal link
between the neuronal accumulation of cholesterol and that of the tau protein,
a marker of Alzheimer’s disease (Burlot et al. 2015).
In addition, it was often stressed that the appearance of atherosclerosis
in humans was frequently accompanied with neuropsychological disorders,
thus resulting in a poor oxygenation of the nervous areas mainly involved
in memory mechanisms. That harmful role of cholesterol on memory
received a beginning of an explanation by noting it was correlated with a loss
of dendrites and cholinergic dysfunction, and with increased inflammation
(Granholm et al. 2008). All these disturbances clearly evoke some typical
effects detected in Alzheimer’s disease.
Although the relationships between blood cholesterol and disease
onset are poorly defined, there is no doubt that cholesterol promotes
the genesis of the β-amyloid protein whose metabolism is controlled by
the amyloid precursor protein (Allinquant et al. 2014). This complex field
is being explored and new strategies for prevention or treatment of the
neuronal degeneration will emerge within a short time.
The various assumptions involving cholesterol and dementia are
mainly the result of epidemiological studies attempting to link the inci-
dence of the disease to high cholesterol levels (Xue-shan et al. 2016).
The extremely widespread use treatment of hypercholesterolemia with
statins has prompted clinicians to explore the possible effect of the inhibi-
tion of cholesterol synthesis on Alzheimer’s disease incidence.
In epidemiological investigations, many studies have shown that high
cholesterol levels are harmful for learning and memory and also contribute
to the development of MCI and Alzheimer’s disease. That was the conclu-
sion arising from the large Finnish study led by Dr. M. Kivipelto, a specialist
in this area at the University of Kuopio (Solomon et al. 2007). The authors of
this important work, spread over 21 years, have followed nearly 1500 old
persons living in the eastern part of Finland. First, they found that, com-
pared to control subjects, cholesterolemia was higher in people with light
cognitive impairment and even higher in subjects with dementia. Indeed,
it became clear that a high cholesterolemia (>2.5 g/L) around the age of
50 years represented an increased risk of greater cognitive impairment in
later life. Conversely, a lower cholesterolemia between 50 and 70 years
was often accompanied by an aggravation of neuropsychological disorders.
These observations are problematic to understand. Are the disturbances a
reflection of a lifestyle change during advancing age? This is unlikely
because low cholesterol levels were also recorded in members of aging twin
pairs having a severe cognitive decline at approximately 56 years of age
(Swan et al. 1992). It is also possible to hypothesize that low cholesterol
levels may be related with other pathologies associated with poor cognitive
performances. Pending further clarification, it seems wise to ensure and
maintain around the age of 50 years a total cholesterol level lower than
2 g/L in agreement with the medical authorities (Leray 2015), to reduce
the risk of cognitive decline at an advanced age.
All research in this area has not led to the same conclusions; some
research has found no relationship between blood cholesterol and mem-
ory disorders. After detailed analysis of negative reports, it seems that
these studies focused on the very elderly, whereas studies reporting a
positive correlation were performed in younger subjects. This relation-
ship is consistent with the observation of a direct correlation between
cholesterol and the presence of amyloid deposits identified in the brain
at autopsy, but in subjects under 55 years old only. Through the
Maine-Syracuse study, Dr. G. E. Crichton showed that although total
cholesterol was not correlated to the cognitive function of people over
60 years, the situation was different for the “good” cholesterol, included
in the high-density lipoprotein (HDL) (Crichton et al. 2014). In fact,
subjects aged 60–98 years having an acceptable HDL cholesterol level

(>600 mg/L) had the highest scores for several psychometric tests; that
was not the case for total cholesterol, low-density cholesterol, cholesterol,
or triglycerides.
It is obvious that any causal relationship between cholesterol and
dementia is far to be demonstrated, because the cerebral metabolism of this
lipid is still poorly known. The relationships between the blood compart-
ment and nerve cells, with these being partially protected by the blood–brain
barrier, are also not well understood. These reserves are strengthened by
the demonstration of a close connection between the inhibition of the neuro-
nal cholesterol synthesis and the resistance to growth factors associated with
an increase of apoptosis in the presence of β-amyloid peptide (Fukui et al.
2015). All these effects could contribute to accelerate the neurodegeneration
processes, such as those characterizing the Alzheimer’s disease.
These results suggest a very relative importance of the circulating
cholesterol, related directly to the dietary cholesterol, in the deposition
of β-amyloid peptide and thus in cognitive impairment.
The problem is even more complex because many studies have con-
firmed the hypothesis of an important role of oxidized derivatives of cho-
lesterol in the development of dementia and the progression of the
Alzheimer’s disease (Gamba et al. 2015). Several studies have emphasized
the involvement of these derivatives in brain inflammation, accumulation
of β-amyloid peptide, and neuronal death.
The widespread treatment of hypercholesterolemia with statins has
pushed epidemiologists to examine the effects of these drugs, largely used
worldwide, on age-related cognitive decline and the onset of dementia.
Prof. A. Solomon of the University of Kuopio confirmed previously
achieved outcomes in studying nondemented patients, taking or not tak-
ing statins during almost 21 years. The conclusion was that a high blood
cholesterol level around 50 years old led to a high risk of cognitive decline
observed 20 years later, with these risks being nonexistent in patients
treated with statins (Solomon et al. 2009). But it must be remembered that
beneficial effects of statins on cognitive performances were often reported
in older but nondemented subjects (Yaffe et al. 2002). The mechanisms
involved are poorly understood, but in addition to the inhibition of cho-
lesterol metabolism, statins may have many other targets in the brain
(Crisby 2006). Among the benefits, there is a lowering of the reduction
of β-amyloid production, a peptide known to be at the origin of neuro-
nal degeneration (Carlsson et al. 2008). Similarly, the administration of
probucol, another cholesterol-lowering drug, to subjects with a mild-
to-moderate sporadic Alzheimer’s disease led to a significant increase
of ApoE levels and to a decrease in the β-amyloid and tau protein con-
centrations in the cerebrospinal fluid (Poirier et al. 2014). These changes
were also correlated with an improvement in cognitive performances.
All this initial work has prompted clinicians to use statins in the treat-
ment of neurodegeneration diseases such as Alzheimer’s disease. Unfortu-
nately, the results are still very controversial, but some works suggested a
long-term beneficial effect on the development of memory disorders and
even on the progression of dementia. Thus, a large meta-analysis has shown
that the temporary or continuous use of statins would be responsible for a
reduction of 48% or 76%, respectively, of the risk of developing Alzheimer’s
disease (Xu et al. 2015). However, other studies indicated an absence of
effect. A few studies have even set focus on the possibility of harmful effects.
For example, in 2014 the US Food and Drug Administration advised doctors
and statin users to use great caution in their treatment and that all patients
should be cautioned about the possibility of memory loss or confusion at all
ages and for all forms of statins. Although these symptoms are not severe
and are reversible, the problem of the effects of these inhibitors of cholesterol
biosynthesis on brain function and Alzheimer’s disease remains open
(Wanamaker et al. 2015).
Statins undoubtedly have a pharmacological interest in the incessant
fight of medicine against atherosclerosis, but their side effects in the brain
are at present poorly understood and therefore should make patients cau-
tious. It is hoped that the research developments in this area may quickly
provide valuable insight for preventive treatments of important degenerative
diseases. Another way of investigation was opened by researchers who
explored the effects of plant sterols, lipids naturally included in our diet.
These sterols, known as inhibitors of cholesterol absorption, are able to cross
the blood–brain barrier, to accumulate in nerve cell membranes and to reduce
the generation of the β-amyloid peptide in cultured cells (Vanmierlo et al.
2015). Among these sterols, the most therapeutically convenient could be
brassicasterol and sitosterol, with their concentrations being lower in
the cerebrospinal fluid of patients with Alzheimer’s disease than in
healthy subjects (Vanmierlo et al. 2011).
Globally, 22 clinical projects are about to be completed or were still
recruiting in 2016 in various research centers targeting the importance
of cholesterol in patients suffering from more or less pronounced demen-
tia (http://clinicaltrials.gov).
In conclusion, it seems prudent to strictly observe the recommenda-

tions from health authorities on the consumption of cholesterol-rich
foods and the upper limits for circulating cholesterol (approximately
2 g/L). In the absence of data on specific biochemical mechanisms invol-
ving cholesterol in brain functions, these standards remain favorable for
the cardiovascular system. Maintaining a healthy vascular network,
including that supplying the brain, should certainly participate in main-
taining an optimal cognitive function.
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chapter five
Other neurological diseases

Neurological disorders discussed in this chapter are considered as integral
part of the nervous system diseases. They most often affect the brain, but
they also the spinal cord and nerves. Besides Alzheimer’s disease (Chapter 4),
three other major neurological diseases show motor and sometimes mental
aspects at different times in life: Parkinson’s disease (Section 5.1), multiple
sclerosis (Section 5.2), and epilepsy (Section 5.3).
These disorders affect directly nerve cells, their structure or their function,
and are very diverse in their mode of expression, with some of them being
associated with aging. Unlike other disorders, the origin of their outbreaks
is increasingly well understood, thus explaining the development of new
pharmacological treatments. As the influence of the environment is more
and more taken into account, the progressive introduction of nutritional
aspects may be exercised for therapeutic as well as preventive purposes.
5.1 Parkinson’s disease

Parkinson’s disease is a chronic neurodegenerative disorder that is slowly
changing and that has a poorly understood origin. It reaches first an area
of a few millimeters located at the base of the brain and rich in dopamine
neurons (locus niger or substantia nigra), the latter being also abundantly
supplied with vitamin D receptors. The death of these cells is associated
with disturbances in all the neural networks associated with other brain
areas (striatum, thalamus, subthalamic nucleus). These neurons are spe-
cialized in manufacturing dopamine, a neurotransmitter involved in the
control of the body movements, mainly those that are automatic such as
walking. Nonmotor symptoms are also observed; they are associated with
various disorders such as sleep problems, smell loss (anosmia), cognitive
troubles, poor balance, pain, and depression, all associated in neural net-
works located in nondopaminergic central structures.
Next to Alzheimer’s disease, Parkinson’s disease is the second most com-
mon neurodegenerative disease. Described in 1817 by Dr. James Parkinson,
it was redefined and named for its discoverer by Dr. Jean-Martin Charcot
in late nineteenth century. This pathology has benefited from an effective
treatment only in 1967 with the introduction of L-DOPA (or levodopa),
an intermediate substance in the catecholamine synthesis. Curiously, there
is no simple definition of the disease.
95
Neurologists diagnose the disease by noting the presence of the fol-

lowing symptoms: walking difficulty; slowness of movement (bradykine-
sia or akinesia); unilateral resting tremor of the hand, foot, or both; and
stiffness or poor muscle relaxation (hypertonia). Importantly, however,
these cardinal symptoms are not always associated with the disease.
A positive response to L-DOPA treatment confirms the diagnosis that
could be more difficult to make by the existence of nontypical or very
diverse signs, such as depression, pain, and fatigue.
Each patient is a particular subject with his or her own clinical symp-
toms, with the evolution of the disease being unique and depending on
many factors. Some signs such as difficulty in speaking may appear after
several years or remain insignificant.
Parkinson’s disease mainly affects people older than 60 years (mean age
58 years); 10% of them have symptoms at less than 50 years old, but the dis-
ease process begins actually 5–10 years before the first symptoms appear.
Men are slightly more affected than women (55 men for 45 women). Evidence
suggests that in some cases the disease may be inherited. An estimated
15%–25% of people with Parkinson’s have a known relative with the disease.
The etiology of the majority of cases of the disease remains unknown, with
multifactorial theories suggesting genetic and environmental interactions.
Globally, more than 6 million people are affected; the disease is diag-
nosed in more than 300,000 people each year. However, it is difficult to
know exactly how many have developed the disease because many peo-
ple think their symptoms are due to normal aging (Campenhausen et al.
2005). Furthermore, the figures are likely influenced by design differences
in studies, such as diagnostic criteria and methods of case ascertainment.
In the United States, there are about 1 million people (0.37% of the popu-
lation) with the disease, but 3 million people could be undiagnosed. It seems
that the incidence is higher in whites than in blacks, Hispanics, or Asians,
with the latter having the lowest rate. Using US Medicare data, it has been
established that Parkinson’s disease prevalence (per 100,000) was 2170 in
white men, but 1036 in blacks and 1140 in Asians (Willis et al. 2010).
In China alone there are more than 1.7 million people with Parkinson’s
disease. The prevalence per 100,000 of population is the highest in Albania
(800), Egypt (557), Canada (317), Israel (256), and Japan (193), but the
lowest in Norway (102), Thailand (95), Sweden (76), and Poland (66)
(Pringsheim et al. 2014). In France, about 100,000 people are affected, with
8000 new cases reported each year.
In all countries, given the aging population, the incidence of the dis-
ease can only progress. As such, it has been estimated that the number
of individuals affected worldwide will double by 2030.
Among the tests used for screening the pathology, the Unified Parkinson
Disease Rating Scale is the most used and best validated tool for measuring
the overall status of patients with Parkinson’s disease.
Chapter five: Other neurological diseases 97
This test includes examinations in four main sections:
• Mental and behavioral status

• Activities in daily life
• Motricity examination
• Responses to treatment

As outlined in Chapter 1, the long-chain ω-3 fatty acids, mainly eicosapen-
taenoic acid (EPA) and docosahexaenoic acid (DHA), are major constitu-
ents of the nervous structures and are known to play an important role
in cognitive function (Section 3.1). These components have also obvious
neuroprotective properties in inhibiting programmed cell death (apoptosis)
of neurons, but also in promoting neurogenesis and myelination. Impor-
tantly, these properties are particularly affected in the Parkinson’s disease.
In animals deficient in ω-3 fatty acids, there is a major disturbance of the
dopaminergic signaling, also known to be altered in Parkinson’s disease
(Zimmer et al. 2002). Conversely, in animal models DHA supplementation
has led to an attenuation of the symptoms related to the disease and been
linked to physiological and molecular disorders (Agim and Cannon 2015).
This is consistent with the discovery in rats of toxic mechanisms triggered
by ω-3 fatty acid deficiency at the level of the substantia nigra (Cardoso
et al. 2014). Thus, it is hoped that such research will be extended to humans.
Even if everyone agrees to recognize that the consumption of ω-3 fatty
acid–rich foods is an important factor in reducing the risk of Parkinson’s
disease, the epidemiological studies thus far do not provide clear results.
More research is needed to clarify the specific role of these lipids. In some
patients, a few attempts have tried a supplementation with DHA and
have shown less depression symptoms that are often associated with
the disease, but no effect on motricity problems. At the initiation of treat-
ment, there is a need to determine the disease status, the optimal dose, and
the duration of treatment. Unfortunately, the conditions required for an
efficient supplementation are still hypothetical.
The complexity of Parkinson’s disease involving motor, and also
behavioral and cognitive symptoms, makes the investigation very difficult
and lengthy; therefore, a large scientific cooperation is required. As for
Alzheimer’s disease, the success is certainly conditioned by an early detec-
tion, so that tests are conducted before there is too much destruction of
dopaminergic neurons.
While waiting for more results, it is recommended to maintain an intake of ω-3

fatty acids of marine origin, not exceeding the recommended intake that can
occur with only the diet. Adopting a Mediterranean (or Cretan) diet represents
currently the best way to reduce the risk of developing Parkinson’s disease,
as for other degenerative diseases. If consumption of marine products is too
low, supplementation should be considered at an early age and followed
throughout life.
5.1.2 Vitamin D
As early as 1997, the observation of a vitamin D deficiency in patients with
Parkinson’s disease was reported by Y. Sato in Japan and was confirmed
much later in an European population (Evatt et al. 2008) and then in a
Chinese population (Wang et al. 2016). This condition seems undisputed
today as it is supported by all subsequent investigations carried out in
several countries (Zhao et al. 2013).
It has not been yet determined whether vitamin D deficiency is at the
origin or at the worsening of this debilitating disease, or conversely whether
it results from it. However, it is evident that the disease is often accompanied
by osteoporosis, a bone status causing frequent fractures and known to be
directly related to a vitamin D deficiency. If one considers the data confirm-
ing largely that this vitamin is an important actor in harmonious brain devel-
opment, the natural trend is to establish links between deficiency and onset
of the neurological disease. In Finland, where sun exposure is reduced and
vitamin D deficiencies are frequent, a large study conducted in 2010 by
P. Knekt tends to confirm the relevance of the previous hypothesis (Knekt
et al. 2010). Indeed, taking into account all other factors, the number of
patients who became ill over a period of 30 years was three times higher
in the group with the lowest vitamin level than in the group with the highest
vitamin level. Meanwhile, cognitive performances of nondemented patients
seem to be also affected by vitamin D levels as the scores estimated with
neuropsychological tests, including those for depression, are even better
when the vitamin levels are among the highest (Peterson et al. 2013).
As for multiple sclerosis (Section 5.2.2), it was observed that the
prevalence of Parkinson’s disease follows a geographic gradient. In the
United States, that prevalence rises gradually when patients are studied
from south to north (Lux and Kurtzke 1987). Unfortunately, there are few
systematic studies in very remote countries; therefore, it is too early to link
with certainty these observations to only a decrease in sun exposure, with
the latter being responsible for a decrease of the cutaneous vitamin D synthesis.
In the near future, research in this area will accelerate after the discov-
ery of a close association between the Parkinson’s disease and a poly-
morphism of the gene controlling the synthesis of the vitamin D
receptors. A genomic study published in 2011 has reinforced that working
hypothesis (Butler et al. 2011). Given the close relationships between

vitamin D and the capacity of dopamine synthesis by the brain,
vitamin D is now considered a neurohormone efficiently protecting nerve
cells in both human and animal models (Eyles et al. 2013).

What about a possible treatment of Parkinson’s disease with vitamin D?
When investigators have studied the effect of vitamin D in experimental
models, cells in culture, or animals, they always observed beneficial
effects. For example, an increased dopamine content in the striatum and
substantia nigra was observed after a vitamin D treatment in the brain
of rats with an early-onset Parkinson’s disease (Smith et al. 2006). In
humans, any hope is now admissible because a team from Tokyo Medi-
cine University in Shinjuku, Japan, has shown that the treatment of
patients with 1200 international units (IU) (30 μg)/day of vitamin D3 sta-
bilized the motor symptoms after 1 year (Suzuki et al. 2013).
It is hoped that other teams will contribute to that specific therapeutic
aspect of Parkinson’s disease. Currently, three trials involving vitamin D
in the treatment of the disease are reported on the official registry of the
National Institutes of Health (http://www.clinicaltrials.gov). Certainly,
much work is needed to clarify the role of vitamin D in the pathogenesis
and progression of Parkinson’s disease. Right now, sufficient data have been
revealed by clinicians to participate in combating the disease when blood
analysis indicates a vitamin deficiency. The low cost and the safety of the
treatment favor this approach, even if all evidence has not been yet provided.
In conclusion, it seems appropriate to advise people who seem to develop

Parkinson’s disease to request a blood analysis to establish their vitamin
D status. In case of insufficiency or deficiency, it is recommended that they
increase first sun exposure to correct that condition. If impossible or diffi-
cult, they must absorb regularly a vitamin D supplement. At the least, this
treatment will improve the bone condition of patients, even if the nervous
system remains an uncertain target. This advice is especially aimed at
patients in the symptomatic stage, also called the “honeymoon period,”
which lasts 3–8 years. Within the framework of a still hypothetical preven-
tion of Parkinson’s disease, as for osteoporosis or many other conditions
(Leray 2015), it seems prudent to recommend to the elderly, regardless their
lifestyle, a permanent and adequate vitamin D3 (cholecalciferol) intake.
Supply may be done classically with 25–50 μg of vitamin (1000–2000
IU) per day or more conveniently with 100,000 IU every month or every
2 months. The general practitioner should be asked to prescribe periodically
an analysis of the circulating vitamin D3 level.
5.1.3 Vitamin E
As with all neurodegenerative diseases (Section 4.2.4), oxidative stress
has been implicated in Parkinson’s disease. Thus, the use of vitamin E
(Section 7.5) as for other powerful antioxidants has been mentioned as a
possible therapy that may protect nerve cells (Sies et al. 1992). Vitamin E
is abundantly present in plants, especially in oils and derived products
from whole grains. It is the natural protection of lipids from oxidation,
the most efficient that humans can find in the diet.
Many studies have attempted to demonstrate a protective effect of
vitamin E in the context of Parkinson’s disease. This motivation is mainly
due to the high vulnerability to oxidative stress of the substantia nigra, a
brain area rich in dopaminergic neurons (Kidd 2000). Admittedly, the
results of epidemiological studies have suggested a protective effect of
vitamin E against the disease, even with moderate doses and often with-
out higher efficiency for higher doses (Etminam et al. 2005).
If we examine, for example, one of the largest studies carried out in
The Netherlands (Rotterdam Study) on more than 5300 individuals aged
55–95 years, the consumption of about 10 mg/day of vitamin E is asso-
ciated with about 40% lower risk of Parkinson’s disease (de Rijk et al.
1997). Conversely, other studies were unable to detect any effect.
In Japan, comparing patients with subjects without any neurodegen-
erative disease has shown that for an intake of plant vitamin E greater
than 7 mg/day, the risk to develop Parkinson’s disease was two times
lower than for lesser amounts of vitamin E. Curiously, women displayed
a still three times lower risk.
So far, the scientific literature seems to assign a unanimous protec-
tive role to vitamin E, at least to the forms included in the commonly
eaten plants.

Only one study performed over 20 years has been devoted to the vitamin
E supplementation, but it was not conclusive. Despite a daily treatment
with 1.34 g of tocopherol for over 1 year, no beneficial effect could be
detected in patients with a Parkinson’s disease diagnosed less than 5 years
ago (Shoulson 1993). Contrary to what the authors suggested at that time,
it seems difficult to assign this negative result to the doses used in the
study being too small. Thus, it seems more realistic to rely on an advanced
disease state for which it is known that more than half of dopaminergic
cells in the substantia nigra are already destroyed.
The majority of the work has mainly demonstrated that plant con-
sumption seems to be the most protective measure, but the assignment
of results only to vitamin E is probably too restrictive. Furthermore, sev-
eral authors have pointed out that the observed effects may also be due to
the presence of other antioxidant substances, or even to some substances

still unidentified in the vegetables consumed. Results obtained in animals
seem to show that consumption of sesame oil strengthens the vitamin E
effects on slowing the neurodegenerative process.
It seems therefore advisable to adopt the conclusions of the previous work

even temporarily in maintaining very early a consumption of vegetable pro-
ducts sufficient to supply the body with at least 12 mg/day of vitamin E, as
recommended by the medical authorities (Leray 2015). A larger intake of
about 50 mg/day as a pharmaceutical supplement is strongly recommended
for the elderly.
5.2 Multiple sclerosis

Multiple sclerosis (MS) was described for the first time in 1868 by Jean-
Martin Charcot, the founder of the modern neurology, at the Salpêtrière
Hospital in Paris, France. MS is an inflammatory and autoimmune disease
that affects the white matter in the central nervous system (brain, optic
nerves, and spinal cord). It results from a disruption of the body’s defense
system in which antibodies (auto-antibodies) against the antigens of the
same body are considered as foreigners (auto-antigens). The disease
involves inflammation mechanisms causing an early loss of oligodendro-
cytes, the myelin-producing cells, and a depletion of myelin in many axonal
fibers with formation of fibrous structures called MS plaques. These demye-
lination plaques cause secondarily motor, sensory, and cognitive impair-
ments because nerve impulses are slowed or blocked, depending on the
extent of demyelination. These disorders have an unpredictable progression
and often lead to an irreversible disability, altering gradually the function of
all nerve pathways. Motor disorders (decreased muscle strength), sensory
disturbances (e.g., hot–cold sensation, touch, tingling), balance disorders,
or visual disturbances are then observable. In 85% of cases, there is a suc-
cession of crises with neurological symptoms that disappear in two-thirds
of cases without late-occurring effects. In MS lesions, it has been shown that
remyelination occurs at the edge of the plaques, where oligodendrocytes
are numerous and may even proliferate. These observations have allowed
suggested a reorganization of the axonal membrane with appearance of
new ion channels along the nerve fiber. Nevertheless, a decrease in the
neuronal density has been demonstrated in certain brain areas (cortex,
thalamus). The attack frequency varies from one individual to another
(on average, an attack per year). The time sequence of these episodes of
relapses characterizes the form of the disease called relapsing-remitting.
This form is present in more than 85% of patients at the beginning of
the disease. Over the long term, the remitting stage turns into a progres-
sively chronic phase wherein the neurological discomfort settles over sev-
eral months without superimposed attack. Sometimes, this discomfort
settles regularly and is called the progressive primary form of MS. This
diversity of forms, originating probably from a diversity of causes, justifies
the difficulty to develop treatments and the diversity of results obtained
with environmental approaches (e.g., diet, sun exposure, vitamin intake).
Besides neurological phenomena, MS displays very frequently cognitive
disorders that are mainly related to memory deficits, spatial perception, rea-
soning, or attention. Unfortunately, these disorders have not been taken
into account in clinical studies related to food and environment.
Pharmacological treatments currently used reduce the inflammatory
attacks, but they cannot stop the progression of the disease. New thera-
peutic strategies slowing immune attacks and developing an onset of
myelination are being evaluated.
Worldwide, there are about 2.3 million people with MS, including
300,000 in Western Europe, although the number may be much higher
because it is likely that many ill people remain undiagnosed in certain parts
of the world. Likewise, estimated annual incidence rates ranged widely
from less than 1 to more than 10 in 100,000.
There has not been a scientifically sound national estimation of
the prevalence of MS in the United States since 1975. Currently, the inci-
dence or prevalence of this disease is not consistently reported. The US
Multiple Sclerosis Foundation relies on estimates based on the earlier
studies. It has been estimated that more than 400,000 people have the dis-
ease and that the average person has about a 1 in 750 chance (0.1%) of
developing it. It is noticeable that the rates of the disease are higher farther
from the equator: about 57–78 cases per 100,000 people in southern states
(below the 37th parallel) and about 110–140 cases per 100,000 in northern
states (above the 37th parallel). A very high prevalence was observed in
Canada (290 per 100,000)
In France, there are more than 80,000 patients. Each year, from 3000 to
5000 new cases are diagnosed in young people, two-thirds of which are
women. Nearly 70% of patients present the first symptoms between 20
and 50 years of age. MS is in the young the leading cause of acquired neu-
rological disability and is the leading cause of disability in young adults
after road accidents (French League against multiple sclerosis).
Genetic factors are thought to play a significant role in determining
who develops MS. The twin of someone with MS has a 25% chance of
developing the disease. The fact that the risk is only 1 in 4 demonstrates
that other environmental factors, including geography, ethnicity, or
nutrition are likely involved as well. Early on, diet was suspected as a
possible way to intervene in the development of the disease, with
the composition of dietary ω-3 fatty acids being considered a priority
(Section 5.2.1). The importance of sun exposure is another widely stu-

died factor; it has been the subject of many investigations because it
seems linked to statistically proven cyclic variations in the disease pre-
valence indicating clearly the existence of relationships with vitamin D
(Section 5.2.2).

In 1956, H. Sinclair, the discoverer of the concept of essential fatty acids,
expressed the assumption that MS could result from diets deficient in highly
unsaturated fatty acids, such as ω-6 or ω-3 fatty acids. Because a ω-6 fatty
acid deficiency is unlikely in Western countries, given the high consumption
of vegetable oils rich in linoleic acid (18:2 ω-6) and of meat rich in arachido-
nic acid (20:4 ω-6), the attention focused naturally on ω-3 fatty acids. Later,
analysis performed on postmortem brain specimens from patients with
MS showed ω-3 fatty acid levels decreased by 50% compared to con-
trols (Kishimoto et al. 1967). Already 50 years ago in the United States,
Dr. R. L. Swank recommended for a year a diet low in fat, but rich in fatty
acids derived from fish and plants to reduce the frequency and severity of
attacks observed in his patients with MS. He had the idea to recommend a
diet low in saturated fats (less than 20 g/day), but rich in vegetables and
fish and fortified with 5 g/day of fish oil. He observed that during the first
7 years, the frequency and inflammatory severity of the attacks were
reduced. He made a fundamental observation: the earlier patients adopted
this diet, the better were the results. Moreover, Dr. Swank reported that
after 4 years, only 8% of subjects had a worse situation if they had followed
very early the diet against 65% among those who had started too late.
Interestingly, a reactivation of the disease was observed in almost all cases
if the recommended diet was stopped even after 5–10 years. After these
results, Dr. Swank wrote his recommendations in the form of recipes in
the successful book The Multiple Sclerosis Diet Book, originally published
in 1972.
Some authors have used the geographical distribution of the disease
to reinforce the attractive hypothesis of a therapeutic effect of the lipid
constituents of fish oil. Thus, the lower incidence of the disease in Japan
or China compared to Europe or the United States could be a consequence
of higher fish consumption in the first two countries. The same difference
was found between the inhabitants of the coastal zones of Norway and
the rest of the population (Larsen et al. 1985). It is however not certain that
the dietary intake of ω-3 fatty acids is the only explanation, because fish
are also a vitamin D–rich source (Section 7.4). Moreover, a combined effect
of both lipid types may not be excluded.
Several authors observed that fish consumption also had favorable
effects on disease progression. For example, in Belgium, a study
demonstrated that in patients with MS, an important consumption of fish

decreased the attack severity, but it did not influence the slow evolution of
the disease between attacks (D’hooghe et al. 2012). These results prove
once again that the evaluation of the influence of the nutritional treat-
ments on the disease remains complex.
Despite sporadic studies supporting a beneficial effect of ω-3 fatty acids,
one of the largest clinical and nutritional investigations, done in Boston,
Massachusetts, on nearly 200,000 women followed for about 14 years,
was unable to detect any effect of these fatty acids and other lipids on
the incidence and progression of the disease (Zhang et al. 2000). In contrast,
an Australian survey of a 500-patient cohort showed that subjects consum-
ing the highest amount of fish had an improved quality of life, a lower risk
of attack, and less intense nervous disorders (Jelinek et al. 2013).

Considerable research has nevertheless shown that ω-3 fatty acids pro-
tected nervous tissue and were able to modulate the immune responses,
especially in animal models of the disease. Thus, it is understandable that
clinicians have attempted to verify whether the intake of these fatty acids, in
the form of dietary supplements, could favorably influence the evolution of
MS. Since the 1970s, many studies have been carried out, but they have gen-
erally produced few convincing outcomes. Among the encouraging results
is the research by I. Nordvik at the University of Bergen in Norway on
patients suffering from MS and who were newly diagnosed and immedi-
ately subjected to a treatment with 0.9 g of ω-3 fatty acids per day (Nordvik
et al. 2000). After a 2-year follow-up, the attack frequency was significantly
reduced and the neurological condition improved compared to the situa-
tion before treatment. It is regrettable that the size of the studied group
(16 patients) was too small to draw meaningful conclusions.
Another attractive study was done by Dr. B. Weinstock-Guttman at
Buffalo General Hospital in New York, with patients whose diagnosis
occurred during the last 3 years and who were supplemented daily with
6 g of fish oil for a year (Weinstock-Guttman et al. 2005). The authors
recorded moderate beneficial effects on clinical manifestations of the disease
and the quality of life. Notably, patients were instructed to have a diet with
a lipid content lower than 15% of their total energy intake. The previously
reported assumptions made by Dr. R. L. Swank are still found verified here.
Despite positive results, the authors emphasized the significant weight
losses in supplemented subjects. Other nutritional conditions should be
used in future investigations to optimize these early results.
The latest and most interesting progress in the treatment of MS with
fatty acids is the clinical work of Dr. M. C. Pantzaris at the neurological
clinic in Nicosia, Cyprus (Pantzaris et al. 2013). This doctor tested in
patients with a carefully characterized disease the combined effect of a
daily intake of ω-3 fatty acids (6.3 g of EPA plus DHA) combined with a
vitamin E component (760 mg of γ-tocopherol) compared to that of a pla-
cebo (olive oil). The major observation of this work was a significant 62%
reduction in relapses after 2 years and a lower progression of the disease.
The combination of ω-3 fatty acids and γ-tocopherol was the most success-
ful compared to fatty acids (18%) or γ-tocopherol alone (30%). These
results obtained in the absence of any pharmaceutical treatment highlight
the importance of a long-term administration of a mixture of ω-3 fatty
acids and a powerful antioxidant (γ-tocopherol). Many similar trials are
required to optimize an MS treatment based on dietary lipids. It also is
necessary to determine the efficiency of these supplementations in the pre-
sence of recent treatments, such as those involving monoclonal antibodies.
The analysis of positive results should not obscure studies that have
not allowed conclusions usable for therapy, even in using larger groups
of patients and similar supplementations. It seems inevitable that future
research should be designed using more patients who are clinically well
characterized and with better defined fatty acid mixtures. It is evident that
long-term research hold back the initiatives for such investigations, but it
would be desirable, in the interest of patients, that national support is
promptly assigned to teams already engaged in this research.
In conclusion, pending more accurate results, it may only be recommended, as

for other lipids, to maintain a dietary intake of ω-3 fatty acids of marine origin in
accordance with the recommendations of the medical authorities (Section 7.2).
The results reported above should only suggest to patients recently diagnosed
with MS to adopt a level of dietary ω-3 fatty acids significantly higher (Two
or three times) than that recommended for healthy people.
5.2.2 Vitamin D
The influence of vitamin D on the immune system has been studied for
more than 25 years; a comprehensive review of particular physiological
aspects is given by Schoindre et al. (2012). The evolution of our knowledge
is based on many epidemiological investigations linking vitamin D and
several autoimmune diseases and has also resulted from the demonstra-
tion of a vitamin D synthesis in immune cells.
In 1974, after some preliminary observations, Dr. P. Goldberg hypothe-
sized that subjects genetically predisposed to MS should have a vitamin D
supply higher than that of healthy subjects (Goldberg 1974). A vitamin D
deficiency during adolescence could thus lead to the formation of an abnor-
mal myelin or even to demyelination plaques followed by the neurological
symptoms specific of the disease. Therefore, a vitamin D supplementation
may well induce its beneficial effects in young adults where the myelin for-
mation is near completion. Goldberg applied his theory in treating young
subjects (22–37 years) with cod liver oil (20 g/day) (Goldberg et al. 1986).
The very positive results (2.4 times less relapses) after 2 years with an
intake corresponding to about 5000 IU of vitamin D per day led Goldberg
to put the benefit on the account of the vitamin D contained in cod liver
oil. Cautiously, he also spoke of a possible action of fish oil fatty acids.
Although valuable in the fight against the clinical manifestations of the
disease, these findings highlight the difficulty of this type of nutritional
study, especially when they involve complex natural products. The fact
remains that fish oil, whatever the responsible component, seems to have
a significant efficiency in limiting the progression of MS.
Since then and in many countries, several studies have confirmed that
vitamin D deficiency is one risk factor in the development of MS. Indeed,
as for other pathologies, one of the characteristics of the disease is its
geographical distribution, with a greater frequency in low sunshine areas
where the skin vitamin D synthesis is reduced and without any nutritional
influence.
As for the Parkinson’s disease (Section 5.1.2), the geographical distri-
bution of MS is not uniform worldwide: it is rare in equatorial regions,
with its incidence increasing gradually north from the equator. For exam-
ple, there are high-prevalence areas (100–300 per 100,000) in Scandinavia,
Scotland, northern Europe, Canada, and the northern United States; average-
prevalence areas (more than 30) in Europe, Russia, and Australia; moderate-
prevalence areas (5–30) around the Mediterranean basin, south of the
United States, and Africa; and low-prevalence areas (less than 5) in East Asia,
India, Africa, the Caribbean, and Mexico. However, geographical distribu-
tion depending on the latitude cannot be generalized to the entire world
population. Numerous exceptions show that other factors also are involved,
with ethnicity being the most important. Thus, exceptions to the latitudinal
gradient in the Italian region and northern Scandinavia are likely a result
of genetic and behavioral-cultural variations (Simpson et al. 2011).
The relationship between disease prevalence and sunshine has been
well studied in North America (Kurtzke et al. 1979) and France. In
France, Dr. S. Vukusic observed, by using the statistics established by
the insurance of farmers (Mutualité Sociale Agricole), that the distribu-
tion of patients was heterogeneous, but that it was correlated with lati-
tude. Indeed, the prevalence of the disease was twice as high among
farmers living in the northeastern areas (about 100 per 100,000 inhabi-
tants) compared to those living in the southwestern regions (about 50
per 100,000) (Vukusic et al. 2007).
Accurate surveys have even shown that subjects going out for
short times in the sun, either in summer in countries with little sunshine
(Norway) or year-round in sunny countries (Mexico, Italy), have a high risk
700
650
Multiple sclerosis births
600
550
500
450
1 2 3 4 5 6 7 8 9 10 11 12
Month of birth
Figure 5.1 Frequency of the number of births of Norwegians suffering from multi-
ple sclerosis and born from 1930 to 1979 based on the month of the year. (Modified
from Torkildsen, O., et al., Ann. Clin. Transl. Neurol., 1, 141–144, 2014.)
of suffering from MS. Other risks include the frequent use of sunscreens in
the young, the very fair skinned, and those with red or blonde hair.
After counting statistics for nearly 80,000 English, an even more
amazing relationship has been demonstrated (Dobson et al. 2013). This
work described that there was a greater risk of developing MS in adults
when the mother’s pregnancy took place during the autumn and winter,
periods of low sun exposure. A review of 15 studies published on this
topic and done in different countries confirmed that the month of birth
influenced distinctly the risk of developing the disease. As for schizo-
phrenia (Section 6.1.3.2), the effect seems amplified in less sunny areas
(Figure 5.1) (Torkildsen et al. 2014), but remains detectable as well in
very sunny countries such as Kuwait (Akhtar et al. 2015).
It has been repeatedly shown that the presence of MS is associated with
low vitamin D levels, with the deficiency resulting either from reduced expo-
sure to sunshine, an inadequate food supply, or both. Almost all the scientific
literature agrees on this association. One can find one confirmation in a review
made from 11 studies that highlighted the general consensus that patients
with MS have consistently low blood vitamin D levels (Duan et al. 2014).
Dr. E. Thouvenot in the Nîmes Hospital, France, also showed that the level
of the vitamin D deficiency was well correlated with the degree of patient
disability, thus upholding the interest for a supplementation to slow the dis-
ease progression (Thouvenot et al. 2015). A study of patients living in Poland
and receiving immune-modulating drugs has shown that hypovitaminosis D

is more prevalent during winter than summer, both in patient group and
the controls, especially in female patients with higher levels of disability.
Furthermore, low vitamin D levels were associated with a more severe course
of disease and an increased number of relapses (Brola et al. 2016).
To accurately investigate the possible links between the risk of devel-
oping disease and vitamin D deficiency, it is necessary to examine a large
population considered as healthy and to study it several years later when
some individuals have developed the disease. Such a study was carried
out by the team of Prof. A. Ascherio at Harvard Medical School, Boston,
Massachusetts (Munger et al. 2006). These researchers followed hundreds
of young soldiers recruited between 1993 and 2004. None of them was suf-
fering from neurological disease in recruitment before the age of 20 years,
all having a blood vitamin D analysis. After a little over 4 years and sev-
eral blood explorations, 257 cases of MS appeared. The authors of that
study observed that while comparing these subjects to healthy subjects, the
risk of MS significantly decreased with increasing levels of vitamin D.
However, the relationship was less clear among the African American
subjects, probably in connection with their very low initial vitamin D
level. Some years later, Dr. Ascherio established that about three quarters
of MS cases could be prevented if children and young adults were main-
taining a blood vitamin D level greater than 40 ng/mL (100 nmol/L).
In the past 5 years, several publications on that topic have focused on
the statistical evidence of a close correlation between vitamin D and MS.
Thus, Dr. Ascherio clearly showed that in patients treated with interferon
β-1b, the highest levels of vitamin D allowed to predict a reduced disease
activity and also the lowest progression rates (Ascherio et al. 2014). These
findings are more and more frequently noticed, although the nature of the
mechanisms involved are not fully elucidated.
A recent discovery has specified a missing link in these complex con-
nections between vitamin D and MS. Indeed, the study carried out by the
team of Dr. B. Richards at McGill University, Montreal, Quebec, focused
on the characterization of low vitamin D levels in subjects with specific
nucleotide polymorphisms and the likelihood of developing MS. That
study was conducted with 14,498 subjects with the disease and 24,091
healthy subjects (Mokry et al. 2015). It seemed that from birth, children
with genetically lower vitamin D levels had a risk two times higher for
developing the disease, with the latter being diagnosed 20–50 years later.

It is too early to assert that supplementing healthy children and adults
with vitamin D will reduce the risk of developing MS much later; the
clinical trials undertaken for the past 10 years remain still unconvincing.
A recent review of all the clinical studies in this area has highlighted the
ambiguity of the results.
What are the causes of these failures when the previously exposed
data suggested that we are getting closer to the goal? No serious leads
are currently considered. Given the diversity of protocols, it is possible
that the doses of vitamin D and the duration of treatment were insuffi-
cient. Moreover, the period of the start of treatment may be inappropriate.
It is certainly desirable that the prevention starts very early, in early child-
hood, and long before the first symptoms of the disease. In the subjects
genetically deficient in vitamin D, the results also suggested the interest
of preventive measures, adapted according to the genome or the examina-
tion of the vitamin status.
Several large clinical trials are studying whether adding vitamin D to
the treatment of patients with interferon may offer a therapeutic advan-
tage. In France, another way is being explored in the Programme Hospi-
talier de Recherche Clinique (PHRC). Dr. Eric Thouvenot at University of
Montpellier, thinks that the effect of interferon will mask that of vitamin D
during the disease treatment. So, he attempted to check whether vitamin D
administered when the first symptoms are reported could reduce the risks
that a disease not yet confirmed could be converted into MS. Initiated in
2013, that study is being conducted in 33 centers across the country; the
results will be known likely by 2018.
The French Society of Multiple Sclerosis ignores the research advances
on vitamin D, as does the Multiple Sclerosis Association of America, and
the US National Multiple Sclerosis Society. However, the Multiple Sclerosis
Society of Canada informs its members, gives some dietary advice, and states
that many doctors already prescribe a daily intake of 1000–2000 IU of
vitamin D. In addition, the society website said that any dietary modification
requires advice from a doctor or a nutritionist. The society funds several
research teams on that subject and gives its members ample information from
published work worldwide (https://mssociety.ca/). It clearly states that
“clinicians who treat people with multiple sclerosis should become familiar
with current vitamin D information so that they are able to educate their
patients, and, if appropriate, diagnose and treat vitamin D deficiency. Also,
due to the inherited risk of multiple sclerosis and the possible preventative
effect of vitamin D supplementation, it may be reasonable for clinicians to
discuss the possible implications of vitamin D deficiency and supple-
mentation for the children of parents with multiple sclerosis.” (http://www.
nationalmssociety.org/). This approach is in progress in several countries
because many neurologists are showing interest in the supplementation of
adolescents and young adults to prevent many cases of MS. In case of
favorable results, it would be possible in the general interest to consider a
monitoring of vitamin D status in the whole population.
In this area, studies are underway, and curiously more than for
many other diseases of the nervous system. Indeed, in 2016, 37 clinical
trials involving multiple sclerosis and vitamin D were listed in the
National Institutes of Health database (https://clinicaltrials.gov), with
seven being still at the stage of patient recruitment. Two major studies,
including one in France, (CHOLINE study) just ended. Their aim was
to determine whether adding vitamin D to the treatment of patients with
interferon-β may have a therapeutic benefit. Thus, it is possible to expect
new results in the near future on both prevention and treatment of this
serious disease.
All studies discussed above indicate that the overall level of evidence for the
involvement of vitamin D in the triggering and development of MS may be
already considered high. From the perspective of prevention, it seems thus
capital to detect any vitamin D deficiency in childhood and if necessary to
begin a supplementation to restore normal circulating levels of this vitamin.
As highlighted in 2011 by Dr. C. Pierrot-Deseilligny, working on MS in
Salpêtrière Hospital in Paris, France, “rather than wait for the results of
phase III trials that still will take several years, it seems wise from a preven-
tive point of view to supplement patients with vitamin D, especially if they
are deficient and have factors tending to worsen that condition.”
5.3 Epilepsy
Epilepsy is a neurological disease known since ancient times and that
remains, despite advances in medicine, the most common neurological
pathology in the world irrespective of age, race, country, or geographic
area. The word “epilepsy” comes from “epilepsia” (επτλ|πσ{α), which means
attack. The disease is complex and multifactorial, involving a genetic back-
ground associated with environmental factors.
The troubles have various causes, mechanisms and events, leading some-
times to talk about epilepsy syndrome. The disease occurs in many ways: by
recurrent and spontaneous seizures known as partial seizures resulting from
brain injury, or as primary generalized seizures involving more widely dis-
tributed mechanisms in the brain. Seizures vary in frequency of less than once
per year to several times per day. The primary generalized seizures are motor
seizures, often impressive, shaking the limb muscles and they may include a
loss of consciousness. This phase is sometimes accompanied with convulsive
movements that could cause the fall of the subject and serious injury.
The seizure is caused by a disruption of the electrical communication
between thousands of neurons becoming hyperexcitable and leading to an
intense electrical discharge in the nervous networks. The wide variety of
the disease symptoms derives from the various brain areas affected by
the electric discharges and their propagation. Thus, when the discharge
starts at the level of the motor cortex, stiffening or rhythmic jerks occur
in different body areas. Other brain areas could be the anatomical origin
of various types of hallucinations (sounds, visions, odors), memory remi-
niscences, or incomprehensible words.
The plurality of manifestations of epilepsy suggests the existence of a
large variety of causes. Indeed, in many countries clinical studies have
shown that epilepsy usually accompanied several cerebrovascular dis-
eases or disorders such as ischemic stroke, trauma, carcinomas, and con-
genital disorders. It can be also present during neurodegenerative
troubles, such as Alzheimer’s disease and vascular dementia. If no cause
has been diagnosed, it is then issued as idiopathic epilepsy, being mainly
present in children and adolescents.
It has been estimated that 3% of the world population suffers from
epilepsy seizures at some moment or another in life.
The average incidence of epilepsy each year in the United States is
estimated at 150,000 or 48 for every 100,000 people. The number of people
with epilepsy (prevalence) ranges from 1.3 million to 2.8 million (or 5 to
8.4 for every 1000 people), but a more accurate estimation is 2.2 million
people or 7.1 for every 1000 people (US Epilepsy Foundation, http://
www.epilepsy.com/learn/epilepsy-statistics).
In Europe, the number of patients with epilepsy has been estimated at
3 million (prevalence of 600 per 100,000 people) (Forsgren et al. 2005).
The World Health Organization has determined that a European doctor
has 10–20 people with epilepsy in his patient base. The total cost incurred
by the disease exceeds 20 billion euros per year for the European continent.
In France, it has been estimated that nearly 400,000 people are suffer-
ing from seizures, with half of them being younger than 20 years, and that
there are about 20,000 new cases per year. With the aging population, an
increase in the proportion of patients can be expected, mainly because of
cerebrovascular and neurodegenerative diseases.
The mortality rate of patients is higher than for the general popula-
tion, but 8%–17% of deaths occur suddenly and remain unexplained.
Several studies have linked this higher mortality to increased heart attacks
during winter and to arrhythmia crises during and between seizures.
Current epilepsy treatments are very specific and aim to block the
alterations in the transmission of nerve impulses from one neuron to
another. The drugs act primarily by blocking synaptic ion channels at the
level of synapses. Unfortunately, nearly 20% of patients do not respond
favorably to these drugs (drug-resistant epilepsy) and may even exhibit a
mortality rate 10 times higher than for the normal population. New treat-
ments are just appearing, with globally better efficiency but inducing sev-
eral more or less important side effects.
As for MS, two types of lipids have been investigated for prevention
or treatment of epilepsy through a supplementation of ω-3 fatty acids
(Section 5.3.1) or vitamin D (Section 5.3.2).

The ω-3 fatty acids (Section 7.1) have quickly attracted the interest of
researchers wishing to limit the magnitude of seizures. Previously, it has
been shown that these fatty acids were able to stabilize plasma membranes
and partially inhibit electrical currents related to sodium and calcium move-
ments in cardiac cells in culture (Xiao et al. 1995). This observation may
explain the well-known antiarrhythmic effect of ω-3 fatty acids on the heart
and could thus be meaningful for the exploration of the causes of seizures
involving cerebral hyperexcitability. This heart effect was moreover
described in animals fed with diets enriched with fish oil and in humans
in some clinical studies after EPA and DHA supplementation (Leray
2015). It is remarkable that some drugs used as anticonvulsant against sei-
zures are also able to inhibit the activity of voltage-dependent sodium chan-
nels. Phenytoin, one of the most prescribed antiepileptic drugs worldwide,
sold under the brand name Dilantin, among others, is also used as both
an antiepileptic and antiarrhythmic.
Except for some short-term experiments, the administration of ω-3 fatty
acids, including linolenic acid, induced usually in animals beneficial effects
on the manifestations of a pharmacological epilepsy (Taha et al. 2010).

In humans, the first experimental study was published in 2002, at the
Weizmann Institute in Rehovot, Israel. Unfortunately, it was realized with
a small number of subjects (Schlanger et al. 2002). Five patients suffering
generalized seizures were hospitalized and treated with several anticon-
vulsant products. Meanwhile, they were ingesting 3.25 g of ω-3 fatty acids
daily (46% DHA, 18% EPA, and 1% linolenic acid) as a spreadable paste.
After a 6-month treatment, the five patients underwent a marked decrease
in the frequency of epilepsy seizures.
Several other published clinical studies have unfortunately provided
only discordant results. These discrepancies may arise from treatment per-
iods being too short (3 months) or from poorly adapted fatty acid doses,
but also from different forms of the disease. The trial published in 2015
by Prof. C. M. DeGiorgio of the University of California–Los Angeles repre-
sents perhaps for the first time a significant hope for a long-term therapy in
patients suffering from a form of epilepsy resistant to conventional drugs
(DeGiorgio et al. 2015). It follows from that publication that a moderate
dose of fish oil (about 1 g of ω-3 fatty acids per day administered for
10 weeks) reduced seizure frequency by approximately 34% compared with
placebo (sunflower oil), with a two times dose of fish oil producing no
effect. This research showed the importance of experimental design and
deserves to be extended to a larger population of patients selected accord-
ing to very specific clinical criteria. As Prof. DeGiorgio pointed out the treat-
ment is efficient, safe, and inexpensive, while improving simultaneously the
patients’ cardiovascular system status. Even more significant results have
been obtained in epileptic children refractory to traditional treatments and
treated daily for only 3 months with 1.2 g of fish oil (240 mg of DHA and
360 mg of EPA) (Reda et al. 2015).
Based on these outcomes, it would be desirable that neurologists take
into account that a possibility of treatment exists and with more data treat-
ment can be offered to all patients suffering from epilepsy. It is hoped that
other studies on wider and more diverse populations in various
countries will confirm these encouraging results; in the United States,
more than 2 million people could benefit and in France, nearly 100,000.
A strong argument for the use of dietary ω-3 fatty acids is their
possible contribution to the antiepileptic effect of the ketogenic diet
(or Atkins diet). Although difficult to tolerate, this diet, rich in lipid
but with low in carbohydrate content, has been successfully used in
the fight against seizures, especially those particularly resistant to drug
treatments. Curiously, it has been shown that the ketogenic diet increased
the blood content of ω-3 fatty acids at the expense of adipose tissue
and liver, probably for a subsequent incorporation into the brain
(Taha et al. 2005). That mechanism may even increase the effectiveness
of the treatment and reduce the complications associated with the diet
(Dahlin et al. 2007).
The work undertaken by Prof. C. M. DeGiorgio focused on the situation
of patients with epilepsy from refractory to current treatments (DeGiorgio
et al. 2015). Indeed, if these patients have two to three times more risk of
premature death than the general population, the situation of 20%–30% of
patients that are refractory to treatment is even more dramatic. The latter are
very often victims of sudden death (up to 17% of deaths), an unpredictable out-
come but likely connected to cardiac abnormalities (Stollberger and Finsterer
2004). Because ω-3 fatty acids are effective in the fight against many cardiovas-
cular diseases, it is not surprising that they may also play a role in the protec-
tion of patients against cardiac complications that accompany epilepsy.
Experiments in animals have already produced encouraging results
(Scorza et al. 2008), and many clinicians hope that patients with epilepsy
refractory to drugs will soon get an easy treatment based on a moderate
and inexpensive intake of natural ω-3 fatty acids. Is it possible to find inter-
national financial support to test this hypothesis on a very large number of
people for many years? More than 3 million patients in Europe and 2 million
in the United States are expecting these advances. The challenge seems so
huge that the Brazilian specialist of these trials, Dr. R. A. Cysneiros, has
alerted researchers worldwide about a possible lack of edible fish as a result

of increasing pollution and climate change.
The limited success of past research and especially the complexity of
protocols in this area probably explain the small number of studies in pro-
gress. Fortunately, height clinical trials are declared completed or recruit-
ing in the international database (www.clinicaltrials.com), including an
ongoing trial with phosphatidylserine-enriched in ω-3 fatty acids in the
Hospices Civils in Lyon, France (Dr. S. Rheims).
In conclusion, clinicians and parents should agree with the epilepsy specialist
Prof. Fulvio A. Scorza, Sao Paulo University, Brazil, that it is reasonable to
ensure that young children, even healthy, maintain their ω-3 fatty acid intake
consistent with the latest recommendations (Section 7.2). He also highlights
that an abundant literature has already shown that eating fish or ingesting oil
capsules enriched with ω-3 fatty acids is not only safe but also may further
increase the effectiveness of pharmacological treatments for epilepsy and
likely reduce mortality risk (Scorza 2015). It is desirable that this message
is forwarded to patients by practitioners, official institutions, and patient
associations known to be very dynamic in this area.
5.3.2 Vitamin D
Since the work of Dr. R. Kruse in 1968, many authors have reported the
presence of bone decalcification (osteomalacia) and fractures accompany-
ing the long-term treatment of epilepsy with various anticonvulsants.
Even if it has not been consistently observed, a link between the disease
and low blood vitamin D levels was very frequently reported.
As with MS (Section 5.2.2), the prevalence or the severity of epilepsy
seem to follow sunshine variations; in general, in relevant subjects such
variations are considered to reflect the vitamin D status.
One of the most important observations was made in London, UK, and
showed that along 1 year the seizure frequency in adults was lower in sum-
mer than in winter (Baxendale 2009). Similarly, in Toronto, Canada, an annual
cycle has been observed in very young children, with a greater frequency of
epileptic spasms in December and January and a lower frequency in April
and May (Cortez et al. 1997). As emphasized by Dr. S. Baxendale, these find-
ings suggest the development of epilepsy treatment using “light boxes,” as
already used for other disorders of nervous origin (Section 6.1.1.2).
As for patients with MS (Section 5.2.2), the epilepsy prevalence in a
population seems to be based on the month of birth of individuals. Thus,
in England and Wales, the systematic perusal of registers of all hospital
including epilepsy (30,080 patients born between 1938 and 1988) has shown
that a greater proportion of patients were born in December or January,

whereas a smaller proportion of patients were born in September (Procopio
et al. 1997). Very similar results were obtained in Denmark by the same
team using a survey of 50,886 patients (Procopio and Marriott 1998).
Seasonal variations have also been demonstrated in patients with epi-
lepsy in studying the incidence of the brain electrical responses to inter-
mittent light stimuli (photoparoxysmal responses) (Danesi 1988). The
records, done in summer, showed much less photoparoxysmal discharges
than in winter, with intermediate figures recorded in spring. This scarcity
of discharges in summer reflected a weaker neuronal excitability.
Curiously, none of these investigators focusing on exploring the influ-
ence of sunshine among patients has evoked a possible relationship with
vitamin D status. Perhaps these clinicians had not inspected the extensive
literature involving vitamin D (often called solar hormone) in various ner-
vous disorders and more specifically in epilepsy (Leray 2015).

Long before these observations, Dr. G. Offermann at the Berlin University
had begun in 1979 to verify in patients with epilepsy the possible close asso-
ciation between the vitamin D status, the state of the skeleton, and drug
treatments (Offermann et al. 1979). That research recommended to supple-
ment sick children with 37–125 μg (1500–5000 IU) per week of vitamin D,
according the time of year. At that time, clinicians postulated that the
vitamin D deficiency, commonly seen in young patients, originated from
the administered drugs, the ketogenic diet (Section 5.3.1), or from external
factors (diet, mobility, obesity).
Since these first investigations carried out in different countries, numer-
ous authors have confirmed the effect of anticonvulsants on the vitamin D
levels, with some being more active (oxcarbezine) than others (valproate)
(Verrotti et al. 2010). The differences are probably related to the more or less
potent effect of these molecules on the enzymes of the vitamin D catabolism
(Hollo et al. 2014).
It was also noted that a combination therapy or a ketogenic diet
(Section 5.3.1) is more detrimental to skeletal health than a monotherapy.
Many clinical studies have shown that a supply of at least 400 IU/day of
vitamin D is necessary to restore an adequate vitamin status in children
(Harijan et al. 2013). Sometimes, a higher supply (1200 IU/day and above)
was required (Snoeijen-Schouwenaars et al. 2015). Control of both vitamin D
and calcium levels in blood is therefore necessary to verify the effectiveness
of that supplementation and to counter the adverse effects of antiepileptic
drugs on skeletal formation.
The vitamin D deficiency induced by the epilepsy therapies does not
seem to be regularly taken into account by clinicians. That situation is
probably due to a lack of clear instructions from medical authorities or
pharmaceutical firms, with the latter being reluctant to promote inexpen-

sive products generating only few profits. Notably, the French Neurology
Society states on its website that many authors propose at least to ensure
an adequate supply of calcium and vitamin D. That academic society sug-
gests also to prescribe a vitamin D supplementation for all patients treated
with phenobarbital, phenytoin, carbamazepine, and valproate. In contrast,
in the United States, the Pediatrics Academy recommends that all children
receive 400 IU/day of vitamin D, but does not specify a precise treatment
for children treated with anticonvulsants.
What about the possible effect of vitamin D on the disease itself? In the
early 1970s, the observation of a hypocalcemia in patients treated for epi-
lepsy had alerted some researchers, and one of them had the idea to check
whether a vitamin D supplementation could correct this state and also
influence the number of seizures. Thus, for the first time in 1974, a clinician,
Dr. C. Christiansen in Glostrup, Denmark, supplemented 23 young
epileptic patients aged from 6 to 27 years for 28 days with 4000 IU/day
(Christiansen et al. 1974). The study showed that all the patients had origin-
ally typical “grand mal” or focal motor attacks and several of them had also
other types of seizure. In addition, all patients were also treated with antic-
onvulsant drugs. It was noted that, despite a persistent hypocalcemia, the
seizure frequency was reduced by 30% compared to a group of patients
receiving a placebo. It is now more than 40 years later since the author
advised that “these results would lend further support to the concept that
prophylactic vitamin D treatment is advisable for epileptics on anticonvul-
sant therapy.” Why did this work remain in the shadows for nearly
40 years? No one knows. Are neurologists more reluctant than other specia-
lists to change their concept? Yet, a Hungarian team of the Neurosciences
National Institute in Budapest took over and confirmed the results
published by Dr. C. Christiansen (Hollo et al. 2012). These researchers
administered adult subjects, epileptic since their youth, an initial dose of
40,000–200,000 IU of vitamin D to correct their initial hypovitaminosis,
and then 2000–2600 IU/day for 3 months. At the end of the experiment,
all subjects had a satisfactory serum vitamin D level (23–45 ng/mL), and
the number of seizures decreased, on average, by 40%. Five patients even
had a decrease of more than 50%. In one of these patients who had a blood
vitamin D level of 4 ng/mL before supplementation and 43.1 ng/mL after,
the number of seizures during the 90-day period before and after treatment
onset decreased from 450 to 30, respectively.
As the authors pointed out for epilepsy, it is surprising that the conse-
quences of a vitamin D deficiency for epilepsy are still unknown. Is it the
result of the conventional treatments, or would it contribute to the disease
development? An early response on the possible effects of vitamin D seems
to be provided by electrophysiological experiments in animals where, as in
humans, the same effects on a drug-induced epilepsy were observed.

Indeed, this vitamin behaves in mice as a true antiepileptic drug; further-
more, it is able to enhance the action of therapeutic substances, such as
valproate and phenytoin, without changing their concentration in the brain
(Borowicz et al. 2007). In Greece, a confirmation of that mechanism seems
also to be provided by an investigation done in newborns. The latter, only
breast-fed, showed clearly that in the presence of epileptic symptoms, doc-
tors must always look for a vitamin D deficiency accompanying an early
rickets, especially if the mother is also deficient (Mantadakis et al. 2012). This
association between vitamin D and epilepsy has been also verified in Turkey
with children aged from 5 to 16 years (Sonmez et al. 2015). Comparing
throughout the year control children with 60 children recently diagnosed
with idiopathic epilepsy but receiving no drug, it has been found that
according to season they had serum vitamin D levels 30%–39% lower
than control children. These studies clearly show a regular combination
of vitamin D deficiency with epilepsy. It seems therefore that a good prac-
tice remains to counteract any deficiency with a well-controlled vitamin
D supplementation.
It is hoped that further research will clarify these aspects of prevention
and treatment of this neurological disease with a vitamin initially known
to help the building of the skeleton. It is obvious that more work is neces-
sary to improve the knowledge of this pathology, affecting at least 3 mil-
lion patients in Europe. It is unfortunate that in 2016, only two clinical
trials on the relationships between vitamin D and epilepsy were declared
worldwide (www.ClinicalTrials.com).
In conclusion, it seems that right now the preventive and therapeutic effects of
vitamin D on epilepsy must be taken seriously, especially when one considers
all the work done in animals and all the clinical, “ecological,” or experimental
studies. As emphasized by Dr. A. Hollo of the National Institute for Medical
Rehabilitation in Budapest, Hungary, low levels of circulating vitamin D
caused by the most conventional treatments of epilepsy and the widespread
deficiency in that vitamin advocate in favor of a systematic supplementation
in patients with epilepsy.
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chapter six
Mental disorders
Mental disorders are also known as psychiatric disorders. There are
different types that induce, depending on the disease, discomfort in
daily life and more or less severe suffering or behavioral disorders. The
WHO defines these disorders as “psychiatric illness” or diseases that
appear primarily as abnormalities of thought, feelings, or behavior, caus-
ing distress or dysfunction. Their manifestations most often appear in
adolescence and early adulthood. Among these diverse pathological
situations are depression, schizophrenia, bipolar disorder, borderline
personality disorder, attention-deficit hyperactivity disorder, and autism
spectrum disorder. The majority of clinical studies use a classification
system regularly updated, recorded in the Diagnostic and Statistical
Manual of Mental Disorders (DSM-IV 1994 revised in 2000), internation-
ally accepted and published by the American Psychiatry Association.
In Europe, a close system, the International Classification of Diseases,
established by WHO, is also used.
The DSM-IV classes all psychiatric disorders on five axes; only some
disorders classified in the first axis are considered here (the major clinical
disorders) because their relationships with nutrition becoming actually bet-
ter known.
According to WHO, mental disorders or psychiatric illnesses in all
their diversity are worldwide the largest cause of disability. The cumula-
tive annual cost of mental disorders in the United States represents about
2.5% of the gross national product.
Throughout Europe, and taking account only hospitalizations, the
WHO estimated in 2011 that the share in expenditures spent on mental
disorders is 20%–25% of the total cost of health services. An evaluation of
the size of the concerned European population and the financial burden
was performed by Wittchen et al. (2011). Each year more than 38% of
the European population suffer from a mental disorder, or approximately
165 million people. Nearly one third of patients currently are receiving
a treatment; and given the extent of future needs, the authors have stated
that these mental disorders could become a major health problem for the
twenty-first century.
In France, the total costs of mental disorders were assessed at about
109 billion euros per year, with the direct health expenditures amounting
to 20% and the rest being attributed to social costs (Chevreul et al. 2013).
123
6.1 Major clinical disorders

Major clinical disorders include depression, bipolar disorder, schizophre-
nia, attention disorders, and those with autism spectrum. Depression and
bipolar disorders are often grouped together under “mood disorders.”
This list is completed by two types of behavior disorders leading to
aggressions or suicide (Section 6.2).
6.1.1 Depressive disorders

Depressive disorders are the most important among the so-called mood
disorders. An estimated 121 million people worldwide currently suffer
from some form of depression. Depression reportedly affects 1 in 10
Americans, but the incidence is actually higher in some states than in
others. Certain ethnicities also report higher depression rates than do
others. In 2014, an estimated 15.7 million adults aged 18 years or older
had at least one major depressive episode in the past year. This number
represented 6.7% of all US adults. Using national survey and administra-
tive claims data, it has been estimated that the incremental economic bur-
den of individuals with major depressive disorder between 2005 and 2010
increased by 21.5% (from US$173.2 billion to US$210.5 billion). That rising
societal burden is primarily due to a combination of the population
growth, an increasing disease prevalence rate, and higher treatment costs
per patient (National Institute for Mental Health). A possible complication
of depressive illness in combination with other risk factors is suicide. It has
been estimated that up to 15% of those who are clinically depressed in the
United States die by suicide. It was also found that suicide rate was high-
est when the economy was weak. Dr. Alex Crosby, an epidemiologist at
the Centers for Disease Control and Prevention, determined that the high-
est rates were during the Great Depression in 1932: 22.1 per 100,000, about
70% higher than in 2014.
European epidemiological studies revealed that nearly 10% of the
population suffer from depression, and one quarter of the population
may have a mental disorder during life. In 2011, it was estimated that
nearly 30 million people in Europe suffered from these troubles; there
were 18.4 million in 2005 (Wittchen et al. 2011). A report of the European
Brain Council evaluated the direct costs to 23% of a total of 113 billion
euros, with the rest of expenses mainly covering sick days and sometimes
the consequences of suicide attempts. For society, the burden is growing
steadily as a result of an aging population becoming more vulnerable
and with multiple diseases. Forecasters indicate that around 2030, depres-
sion could be, in importance, the first disease and the heaviest burden to
be supported by all states. Indeed, world experts say that the cost asso-
ciated with these disorders could quickly bankrupt the national health
Chapter six: Mental disorders 125
systems, knowing that mental health problems are already more severe
than those related to obesity or cardiovascular diseases.
In France, depression is the most common psychiatric illness; nearly
3 million people are affected (INPES 2007). It is the first cause leading to
a support by psychiatric hospitals (20% of adult internees). That pathology
is predominant between 25 and 45 years and from adolescence it is two
times more common in women than in men. Although the average age
of the first depressive episode is between 30 and 35 years, the onset of
the disease is possible at any age.
The symptoms of depression (also called unipolar disorders) are highly
varied; they are characterized most often by feelings of worthlessness, help-
lessness, and hopelessness. The diagnosis is established when an episode
lasts at least 15 days. The patient is sad; has no interest in life, no appetite,
no energy, no sleep; and constantly feels fatigue. These disorders can lead to
suicidal thoughts when the subject is in deep distress. It has been estimated
that in France depression is the leading cause of suicide: almost 70% of peo-
ple who die by suicide suffer from depression, often undiagnosed or
untreated (http://www.france-depression.org).
Recall that research has demonstrated that pregnant women with
depression can pass the condition on to their unborn babies. Thus, MRI
scans have suggested that abnormal amygdala function can be trans-
mitted from mothers to babies before birth. The good news is that this risk
might be reduced by systematic screening of pregnant women for depres-
sion and then initiating effective treatment. This situation emphasized the
importance of therapies devoid of chemical compounds, but rather based
on dietary control.
Epidemiologists and clinicians measure the extent and intensity of
depressive symptoms by using a questionnaire completed by a patient
and then evaluated by a doctor. The scales used are all derived from
the Center for Epidemiologic Studies Depression (CES-D) scale estab-
lished in 1977 in the United States by the Center for Epidemiological
Studies of the National Institute of Mental Health (Radloff 1977)
(Section 7.11).
The goal of current treatments for depression is mainly to reduce
symptoms and their impact on daily life, and especially to prevent
relapses. Although there are effective treatments, it has been estimated
that even under optimal conditions they cannot relieve more than about
one third of patients with major depressive disorders. So, regardless of
the method used in people at risk, the prevention is only effective in
1 in 5 (Opie et al. 2015).
In general, antidepressant drugs are targeting serotoninergic, norepi-
nephrine, and dopaminergic neurons. In case of failure of two or three
successive treatment periods, the chances of success with a new treatment
drop to 13%.
In some cases, the depressive period may extend over several years;
that is, a chronic depression; but if the symptoms are fewer and less
intense, it is a dysthymia.
Given the significantly inadequate results in the fight against depres-
sion, it became necessary to consider a new approach, as well for the pre-
vention as for the treatment of current depressive disorders. Many studies
on laboratory animals and some clinical trials have shown the way by
focusing on the benefits of a Mediterranean diet but also of more specific
factors such as ω-3 fatty acids (Section 6.1.1.1), vitamin D (Section 6.1.1.2),
and vitamin E (Section 6.1.1.3).
6.1.1.1 ω-3 fatty acids

Besides the field of genetics and brain chemical messengers (serotonin, dopa-
mine), how did researchers suspect a possible influence of certain essential
fatty acids?
6.1.1.1.1 Epidemiological investigations Smith (1991) and Hibbeln

and Salem (1995) already hypothesized that throughout the twentieth cen-
tury the increased incidence of depressive disorders and their early onset
could well be due to the increasing consumption of ω-6 fatty acids by the
population. Numerous studies have indeed shown that our diet has been
gradually enriched with these compounds, as a result of increasing con-
sumption of vegetable oils rich in ω-6, but very poor in ω-3 (groundnut,
sunflower) fatty acids. These major changes in the appearance of new
cases of psychiatric diseases are to be compared with the increased inci-
dence of cardiovascular and inflammatory diseases. It is now well known
that these latter troubles are aggravated by a ω-3 fatty acid deficiency and
especially by an imbalance of the ω-6/ω-3 fatty acid ratio. R. S. Smith thus
placed in opposition the proportion of depression in the United States and
that described in Japan to be 10 times lower. This comparison suggested a
parallel with a higher consumption of fish rich in ω-3 fatty acids in Japan.
Using statistical data compiled within nine countries with very different
cultures, J. R. Hibbeln determined that the number of cases of major
depression was inversely related to the average number of fish consumed
by the populations (Hibbeln 1998) (Figure 6.1).
Conversely, based on official statistics from five countries (Argentina,
Australia, Canada, US, and UK), Hibbeln et al. (2004a) verified that the
amount of ingested linoleic acid, the dominant ω-6 fatty acid in the Wes-
tern diet, was positively related to homicide rates. It would be interesting
to generalize these relationships to other people to follow their evolution
in some countries where health statistics are reliable.
This hypothesis seems consistent with the discovery that a vegetarian
diet is frequently associated with a high risk of depressive disorders, with-
out the certitude that these results could be attributed to an excess of ω-6
6
New Zealand
Canada
Depression prevalence (cases per 100 people)
5
Deutschland
France
3
USA Porto Rico
Korea
2
1
Taiwan
Japan
0
10 20 30 40 50 60 70
Fish consumption (kg/year)
Figure 6.1 Prevalence of depression in nine countries based on their fish consump-
tion. (From Hibbeln, J.R., Lancet, 351, 1213, 1998. With permission.)
fatty acids in consumed vegetables. Indeed, it has been shown that the
adoption of such a diet was sometimes occurring after the depressive dis-
order onset (Michalak et al. 2012). It was therefore proposed that their
appearance could encourage patients to adopt a vegetarian diet, but other
psychological factors could also induce both the occurrence of troubles
and a dietary change. With that example, it can be seen that the relation-
ships between diet and mental behavior are very complex. In the future,
lengthy investigations with numerous patients would be required to iden-
tify the various factors that could motivate the subjects to organize their
diet before and during the disease development.
As early as 1983, very high levels of prostanoids deriving from ω-6
fatty acids (prostaglandin E2 [PGE2] thromboxane 2) were observed in
patients with unipolar or bipolar disorders (Lieb et al. 1983). The authors
insisted on a possible causal relationship between PGE2 and depression,
and they also emphasized that prostaglandins of the 2 series could play
a role in mood regulation. They suggested that these lipid mediators, as
well as catecholamines, could be considered by the theories of the depres-
sion. The question was asked by the English team of D. F. Horrobin,
exploring the effect of a tricyclic antidepressant (clomipramine) on the
vascular action of PGE2 (Mtabaji et al. 1977). In the absence of older
documents, this short story shows, despite everything, that it takes a long
time in medicine to develop and defend a hypothesis that is yet supported
by sound scientific data.
In 1996 in the laboratory of Prof. A. J. Sinclair in Victoria, Australia,
there was perhaps the first convincing evidence of the involvement of ω-3
fatty acids in depression symptoms. Using biochemical analyses and speci-
fic neuropsychological tests recognized by the scientific community, this
laboratory team determined that the arachidonic acid/eicosapentaenoic
acid (EPA) ratio measured in the plasma and red blood cells was positively
correlated to the intensity of the clinical symptoms of depression (Adams
et al. 1996). Although a correlation does not necessarily indicate causality,
these results surprised the experts and encouraged them to develop this
new field of clinical research.
Thus, these innovative results prompted the US Department of Health
to publish in 2005 a large report of all work on the effects of ω-3 fatty acids
on mental health (Evidence Reports/Technology Assessments, No. 116,
Agency for Healthcare Research and Quality (US) July 2005, http://
www.ncbi.nlm.nih.gov/books/NBK37689/). After analyzing 79 studies,
the report concluded that, despite some positive results, “much more
research, implementing design and methods improvements, is needed
before we can begin to ascertain the possible utility of (foods or supple-
ments containing) ω-3 fatty acids as primary prevention for psychiatric
disorders or conditions.” The report is clearly aware of the main problem
of new investigations in that field and states that “if future research is
going to produce data that are unequivocally applicable to North Ameri-
cans, it will likely need to enroll either North American populations or
populations exhibiting a high ω-6/ω-3 fatty acid intake ratio similar to
what has been observed in the diet of North Americans.” Since then,
researchers have fully grasped the problem and delivered a considerable
body of evidence that allows for a better understanding of the known
effects of ω-3 fatty acids and hope, in a few years, of great progress for
the clinical improvement of depression disorders. Despite some caution,
seven specialists in that field have published several practical recommen-
dations for the prevention of depression (Opie et al. 2015). These research-
ers have stressed the advantage of some traditional diets, such as those
characterizing the Mediterranean countries, Norway, and Japan, with all
of these diets ensuring a high ω-3 fatty acid supply.
The relationship between consumption of marine fish rich in ω-3 fatty
acids and the incidence of depressive symptoms have been and still is the
foundation of many investigations. Thus, the analysis of fatty acids in
blood and adipose tissue enabled to link high EPA and docosahexaenoic
acid (DHA) concentrations with a low incidence of depression symptoms.
The study of a population in Bordeaux, France, with mean individual age
of 74.6 years, has clearly revealed that among plasma fatty acids, only low
EPA levels characterized the patients with depression symptoms (Féart

et al. 2008). Similar research based on analysis of red blood cells reached
comparable conclusions. Despite this consensus about ω-3 fatty acids, and
particularly EPA, the cause of that relationship remains unclear: Is it of
internal origin? Could it be due to a change in the cellular metabolism?
Or is it of dietary origin? In contrast, Dr. S. Tsuchimine has detected
that the blood levels of ω-3 fatty acids are not likely to be associated
with personality traits in healthy young Japanese subjects (11–19 years)
(Tsuchimine et al. 2016).
Among the most compelling work that merits mention is a study on
Korean subjects showing that the severity of depression symptoms was
inversely related to the ω-3 index (Section 7.1) measured in red blood cells,
as well as to markers of inflammation and oxidative stress (Baek and Park
2013). This study focused on the complex links often mentioned between
inflammation and depression, with the ω-3 fatty acids having a great influ-
ence in the fight against these two important aggressive phenomena. Even
in elderly subjects consuming regularly fish and having high serum ω-3
fatty acid levels, Japanese authors have revealed that depressive symp-
toms were significantly associated with lower serum levels of DHA, ara-
chidonic acid, and folate (vitamin B9) (Horikawa et al. 2016).
By 2007, fundamental results were reported by the recognized specialist
Prof. R. K. McNamara of the University of Cincinnati, Ohio (McNamara
et al. 2007a). Indeed, they showed via postmortem analysis of brain sam-
ples from adult subjects with severe depression that the area called the
orbitofrontal cortex had lower DHA content (−16% in men and −32% in
women) than in control subjects. This brain area is known to be involved
in the regulation of hedonistic and emotional processes associated with
depression disorders. Given the stability of the composition of brain fatty
acids, Prof. McNamara felt that the observed DHA deficiency has yet been
established during the perinatal period and could not therefore be cor-
rected later by the diet.
Nutritional assumption seems preferred considering the great number of
epidemiological studies worldwide that have shown an inverse relationship
between fish consumption and the prevalence of depression. In Europe,
two large studies conducted in Finland with thousands of people have
supported these findings, but curiously with sharper results in women
than in men. The study of many American subjects aged 30–65 years, using
questionnaires on their diet and their depression level, showed that the
intensity of depression symptoms was inversely related to the amount of
ingested ω-3 fatty acids (Beydoun et al. 2013). In Japan, a similar investiga-
tion on people aged 23–63 years came to parallel conclusions (Yoshikawa
et al. 2015). Furthermore, this study revealed a positive relationship
between fish consumption and resilience to depression, an important out-
come because it represents the ability of the individuals to overcome the
stress face to adversity. Using analyses of dietary lipids, others have used
the ω-3/ω-6 fatty acid ratio and come to the same conclusions.
The hypothesis of a possible fight against depression through fish con-
sumption seems strengthened by the latest study initiated by the team of
Prof. D. Zhang, Qingdao University, China. This large meta-analysis, cov-
ering 26 reliable works published between 2001 and 2014 and gathering
together 150,000 subjects, showed that eating fish has a good antidepres-
sant effect, but only in Europeans, with other populations (Americas, Asia,
Oceania) not being significantly affected (Li et al. 2016). The reduced size of
the cohorts studied in each location outside Europe could be at the origin
of this discrepancy. Therefore, it can be concluded that a high fish intake
seems beneficial for the primary prevention of depression. Authors have
thus determined, on average, a 17% reduction in disease risk of people con-
suming the highest amount compared with those who consuming the least
(20% less risk in men and 16% less risk in women).
It is remarkable that when comparing the populations of several coun-
tries, it was observed that the prevalence of depression decreases with
increasing fish consumption. Thus, the Asian populations (Japan, Korea,
and Taiwan) have the lowest rates of major depression and are also those
that consume more fish. These differences could explain the speed with
which depression seems to be spreading in the West for 50 years. Indeed,
the intake of ω-3 fatty acids is estimated to be now two times lower than
it was before World War II. Again, the incidence of depression has greatly
increased over the same period.
It has been also suggested that the high fish intake among Icelandic
people was responsible for their lack of seasonal depression. Similarly,
postpartum depression seems to be less common in women frequently
eating fish or having breast milk with high DHA content.
Remember that this type of study cannot bring irrefutable and definitive
answers, because in addition to the imprecision of consumption surveys,
many genetic, economic, or sociocultural factors could interfere with the
physiological data. Moreover, on a practical level, it was shown that the
culinary preparation of fish also influences the intensity of depression.
Thus, the consumption of breaded fish increased the risk for more severe
depression symptoms (Hoffmire et al. 2012). It has been also stressed that
the influence of the cooking method, such as roasting in an oven or gril-
ling, could be damaging for EPA and DHA contents (Chung et al. 2008).
Given this promising research, the European Union has initiated a major
5-year project (MooDFOOD) in nine countries to explore mainly the relation-
ships between ω-3 fatty acids and depression (www.moodfood-vu.eu).
6.1.1.1.2 Intervention studies Has it been possible to complete these

results by experimental studies to verify the direct effect of ω-3 fatty acids
on depression? Were they administered to patients with depression to
reduce the clinical signs of the disease? Even if the published results remain
equivocal, it is essential to report the most important outcomes.
In 1966, shortly after the detection by P. B. Adams of a relationship
between the blood EPA content and the severity of the disease, the admin-
istration of EPA, DHA, or both was attempted in patients suffering from
depression. A. L. Stoll at Harvard Medical School, Boston, Massachusetts,
demonstrated for the first time in a double-blind study against placebo
that fish oil had a positive effect in significantly reducing the manifesta-
tions of depression outbreaks (Stoll et al. 1999). These exciting results have
led the author to declare that ω-3 fatty acids could be the “missing link”
among the relationships between cardiovascular diseases and depression
(Severus et al. 1999).
That work was taken over in 2002 by B. Nemets at the Ben-Gurion
University of the Negev, Israel, who confirmed that administration of
EPA during 4 weeks strongly decreased depression disorders in more than
half of patients with a major depression (Nemets et al. 2002). These encoura-
ging results were popularized in a book (Servan-Schreiber 2003), where the
author has spread, in France, the idea of a possible benefit of fish oil intake
in restoring the mental balance by formulating the hypothesis of a stabiliza-
tion of cellular membranes in the brain. However, he wrote that “it will take
several years before a sufficient number of studies of this type is achieved.
Indeed, the ω-3 fatty acids are natural products and thus almost impossible
to patent. Therefore, they do not interest the big pharmaceutical companies
that fund most scientific studies of depression.” These conclusions, a bit
pessimistic, obviously could be applied to all areas of medicine where these
lipids could be involved. In contrast, this academic research offers a guar-
antee for their impartiality toward future users.
A careful review of literature on the subject from 2002 to 2011 shows
that authors doubt sometimes the usefulness of treatment with specific
diets (nutraceuticals), despite a growing research effort in this area. If
one takes into account the conclusions of a recent meta-analysis, almost
all clinical studies using ω-3 fatty acids to treat depression symptoms
concluded that this treatment was beneficial in adult patients properly
diagnosed and also in those who had poorly characterized symptoms
(Grosso et al. 2014). Sometimes, the results were more decidedly mixed
and demonstrated a positive effect but only after 12 weeks and after
using the Clinical Global Impression Scale. This test allowed the investi-
gators to assess, on a 7-level scale, a significant improvement of the dis-
ease after a daily supplementation with 1.14 g of EPA and 0.6 g of DHA
(Park et al. 2015).
Concerns also were issued in 2010 by Dr. K. M. Appleton after analyzing
29 supplementation trials against placebo. However, the author recognized
the importance of a ω-3 fatty acid fortification in patients with a severe, but
correctly diagnosed depression. Unfortunately, the heterogeneity of the
analyzed trials made their comparison mathematically difficult. A more

recent meta-analysis of 26 published studies led to the conclusion that ω-3
fatty acid supplementation resulted in a small-to-modest benefit for depres-
sive symptomology (Appleton et al. 2016). Although no differences were
found between a treatment with fatty acids versus antidepressants, the
authors stated that the “evidence is limited and highly heterogeneous,
resulting in findings that are imprecise and potentially biased.” Neverthe-
less, the authors accept that “given the high rates of adverse events asso-
ciated with some antidepressants, n-3PUFAs may offer an alternative
treatment of possible benefit and reduced side effects, but more evidence
regarding both the potential positive and negative effects of n-3PUFAs for
major depressive disorder is required before such a suggestion can be
advocated.”
To clarify the responsible natural agent of the observed effects, the qual-
ity and the amount of fatty acids used as supplements in several meta-
analyses have been rigorously examined. One meta-analysis examined
15 trials published in many countries and highlighted a specific and ben-
eficial effect of EPA on depression. The best positive results were
detected only when this fatty acid represented more than 60% of the
ω-3 fatty acid mixture, the effects being perceived when the intake was
between 0.2 and 2.2 g/day (Sublette et al. 2011). The specificity of EPA
in relation to depression was recently verified by Dr. H. Mozaffari-
Khosravi, University of Tehran, Iran, by comparing the effects of a daily
administration of 1 g of EPA or DHA for 4 months in patients with mild-
to-moderate depression (Mozaffari-Khosravi et al. 2013). In 2010, because
significant research in this area was noted, the American Psychiatric Associa-
tion (Steering Committee on Practice Guidelines) recommended EPA-rich
supplements as adjunctive therapy for major depressive disorders (http://
psychiatryonline.org/guidelines).
Right now, it is well established that the beneficial effects of the con-
sumption of marine fish or fish oil on depression are due to their content
in ω-3 fatty acids, EPA in particular, but not to other components such as
vitamin D, with the latter being active elsewhere (Section 6.1.1.2). Recall
that an essential fatty acid supply may be beneficial not only for mood
but also for the cardiovascular system (Sher et al. 2010).
In the case of perinatal depression (or postpartum depression), the
majority of the work indicates a more or less pronounced tendency of a
direct link between the trouble frequency and the ω-3 fatty acid deficiency.
Work based on a survey of 100 Brazilian women highlighted that the pre-
valence of these troubles was 24% higher when the dietary ω-6/ω-3 fatty
acid ratio exceeded a value of 9 (Da Rocha and Kac 2012). These results
were so important that a Norwegian team checked their validity soon
after the publication by using the fatty acid composition of red blood cells
(Markhus et al. 2013).
The most efficient ω-3 fatty acid is still unknown, although EPA and
DHA are good candidates; however, it seems wise to consider the recently
acquired results by advising fertile or pregnant women to ensure an ade-
quate nutritional intake of these compounds (Section 7.2). If necessary, it is
sufficient to increase the consumption of fatty fish or use dietary supple-
ments. Obviously, this advice is aimed primarily at pregnant women hav-
ing other psychological risk factors.
The relationships between postpartum depression and nutrition is
clearly insufficient when considering the prevalence of mental disorders
in pregnant women (10%–15%) and their impact on the behavioral, cogni-
tive, and psychomotor development of children (Kingston et al. 2012).
More specific findings on the control of depression disorders could be
drawn only with investigations conducted on larger samples and with sui-
table psychometric or biochemical analyses. The selection criteria should
also be subject to a rigorous selection by psychiatry specialists to study
the populations that would best benefit from a supplementation with ω-3
fatty acids. This area interests many research teams because 12 large trials
reported in the WHO International Register of Clinical Trials are recruiting
in several countries (http://apps.who.int/trialsearch/), whereas 96 were
registered in 2016 at http://www.clinicaltrials.gov.
The influence of ω-3 fatty acids on depression is part of the great
MooDFOOD study led by the University of Amsterdam, The Netherlands,
and supported by the European Commission (www.moodfood-vu.eu) in
nine countries. This major multidisciplinary project started in 2014 and
is expected to last 5 years, with the aims to define relationships between
diet, depression, social environment, and obesity.
What is known about the mechanisms involved in the action of ω-3
fatty acids on depression? Much research in animals allowed us to per-
ceive the mechanisms underlying the behavioral troubles induced by
inadequate intakes of EPA and DHA. For example, it was found in rats
that DHA deficiency induced troubles characterized by a dopamine defi-
ciency in cortical areas, with the reduction likely related to a cognitive
deficit. Significant changes were also observed at the level of serotoner-
gic and cholinergic systems. Several neurophysiological studies have
suggested that these changes in the synaptic transmission could result
from a direct action of fatty acids on the expression of genes involved
in neurotransmission processes, membrane plasticity, and neurogenesis.
It has been recently discovered that EPA can increase the release of ser-
otonin from presynaptic neurons, whereas DHA influences directly the
serotonin receptors of the postsynaptic neurons, with these two mechan-
isms also being modulated by vitamin D (Section 6.1.1.2) (Patrick and
Ames 2015). Certainly, these fundamental findings are at the beginning
of a large development in the field of prevention and fight against
depression.
Combined with the previous hypothesis, there is also a growing evi-

dence of an action of the inflammation mediators that interfere in main-
taining or worsening the depression symptoms (Pascoe et al. 2011).
Thus, depressed patients have high levels of specific cellular mediators
such as proinflammatory cytokines (interleukins, interferons). These links
between depression and cytokines have been the subject of a recent clin-
ical application in patients with chronic hepatitis C in which a supplemen-
tation with EPA could prevent depression accompanying the treatment
with interferon-α (Su et al. 2014). Research in animals has confirmed these
relationships.
The assessment of the participation of specific ω-3 fatty acids in the con-
trol of brain oxidative stress may provide additional insight into depression
symptoms associated with inflammatory processes. This approach was
undertaken in a large cooperative study (Boston Pueto Rican Health Study)
that showed an inverse relationship between the ω-3 index measured in ery-
throcytes and the severity of depressive symptoms, but only in participants
with elevated stress biomarkers measured in urine (Bigornia et al. 2016).
These observations suggest that the status of oxidative stress may identify
those who might benefit from ω-3 fatty acid supplementation to improve
depressive symptoms.
Thus, it is certain that ω-3 fatty acids are involved, as well as vitamin D
(Section 6.1.1.2) and vitamin E (Section 6.1.1.3), in the regulatory mechan-
isms generating depression due to their anti-inflammatory function, a func-
tion already well known in the cardiovascular domain (Pascoe et al. 2011).
Clearly, larger clinical studies are needed to determine what the best
preventive treatments are to curb the symptoms of depression, a pathol-
ogy generating major social problems in all populations.
Regarding self-medication, all experts agree to warn people with
depression or other mood disorders not to use ω-3 fatty acid supplemen-
tations without a medical opinion. Such conditions should be analyzed by
a competent specialist, because they can be improved but also worsen and
become worrisome after some time. If necessary, the first intention will be
to find a diet covering properly the ω-3 fatty acid needs, for example, two
or three fish meals per week (Section 7.2).
People with mood disorders and treated could, of course, change their
treatment, but only after medical information. A ω-3 fatty acid intake can-
not replace an antidepressant medication or psychotherapy, but it may
improve their efficiency. A doctor’s consultation is also essential for preg-
nant and lactating women and for people with coagulation problems. For
now, it seems wise to select a ω-3 fatty acid supplementation only in
patients deficient in such compounds, with the deficiency being deter-
mined by the study of their usual diet or especially a blood cell analysis.
Thus, it seems appropriate to extend the estimation of the ω-3 fatty acid
status as it has been proposed with the “ω-3 index” to determine the car-
diovascular risk (Von Schacky 2010).
In general, all past basic research has proved that the consumption of foods rich
in ω-3 fatty acids is beneficial for the prevention of mood disorders. Unfortu-
nately, these recommendations are insufficiently disseminated in specialized
media. For subjects with depressive disorders, a treatment with a mixture of
EPA and DHA (1 g/day) is already recommended by many clinicians. Such
a treatment can be applied isolated or better, with conventional therapies, thus
improving their efficiency. Along with the observance of ω-3 fatty acid intakes,
it is recommended to keep sufficient dietary vitamin D and vitamin E intakes.
Future research should optimize the type of treatment and the useful dose of
these natural products to prevent but also to treat at the onset of the disease.
6.1.1.2 Vitamin D
Besides the effects of vitamin D on cognitive impairment (Section 4.2.3), it
seems increasingly evident that a deficiency in this vitamin is involved in
the development and the severity of depression disorders.
The correlation between depression and the activity of neurotransmit-
ters (serotonin, norepinephrine, and dopamine) is now well established.
Indeed, it is well known that they participate in the regulation of emotional
activity, stress reaction, regulation of sleep cycles, appetite, and many
others functions. It seems therefore logical that vitamin D, such as antide-
pressants, acts on the regulation of the balance of the neurotransmitters
involved in depression. Recent experimental evidence has confirmed this
hypothesis by showing in animals (Jiang et al. 2014) and humans (Kaneko
et al. 2015) that vitamin D stimulates the biosynthesis of cerebral serotonin.
This “solar hormone,” a real “panacea,” might as well be a link in a skin–
brain pathway equivalent to the well-known retina-midbrain-epiphysis
neuroendocrine pathway, according to a hypothesis reported very early
by the famous American specialist of vitamin D target cells Professor
W. E. Stumpf (Stumpf 2012).
6.1.1.2.1 Epidemiological investigations It was only in 1984 that light

therapy in clinical psychiatry was first used for treating seasonal depression.
We owe this discovery, published in 1984, to Dr. E. N. Rosenthal in the United
States. The idea that low serum vitamin D levels could be related to depres-
sion has derived originally from the observation of a high incidence of sea-
sonal affective disorders (winter depression) when sun exposure is reduced
in autumn and winter. An experiment conducted in 1999 by F. M. Gloth in
the United States showed that an administration of vitamin D (100,000
international units [IU]) was more efficient than light therapy to treat
seasonal depression (Gloth et al. 1999). Nonetheless, the relationships

between vitamin D and melatonin are not yet well known, with melatonin
being a hormone produced by the pineal gland, mainly in response to the
absence of light. More investigations would be required to explore the
relationships between light, neurohormones, and vitamin D.
Many researchers were invested in the relationships between vitamin D
and depression, encouraged in that direction by the high incidence (up to
45%) of this pathology in people living in nursing homes, thus frequently
receiving little sun exposure. To get a clear idea of the magnitude of that
disease, check the results of the French PAQUID study, conducted since
1989, on a cohort of about 2800 people over 65 years old living in the Aqui-
taine region. The prevalence of depressive symptoms in these people, iden-
tified from responses to an adapted questionnaire (CES-D scale, Section 7.11),
is about 16%, whereas the prevalence among people over 65 years is
naturally much lower (2%–3%). Moreover, experts agree that detecting
and treating depression is the best prevention of suicide risk in the elderly.
It is possible to find some work on this topic; however, they are uncon-
vincing because they rely generally on a limited number of subjects
with uncontrolled lifestyle or diet. Other studies, performed in more or less
medicalized nursing homes are more satisfactory because they benefit from
better control. The difficulty of comparing results often comes from the type
of populations and the diversity of the psychological tests used in different
countries to assess the gravity of the current depression. Thus, some epide-
miological studies have shown no association between plasma vitamin D
and depression symptoms; nothing actually may indicate the reason
for these negative results. By contrast, the simple analysis of vitamin
D dietary sources together with the clinical observation of depression symp-
toms in important groups (or cohorts) of the elderly has shown a close rela-
tionship between these two parameters. This was the case for a US study
(Bertone-Johnson 2009). The outcomes have clearly shown that subjects
ingesting more than 800 IU/day (20 µg/day) of vitamin D had 21% lower
depression risk compared to subjects ingesting 100 IU/day (2.5 µg/day).
If one considers not only the food intake but also the blood vitamin D
level, a parameter recognized as one of the safest to establish a vitamin status,
several well-conducted studies have shown a close relationship between
depression and vitamin D in adults of any age. An example of this was given
in the study published in the United States as part of the Third National
Health and Nutrition Examination Survey (Ganji et al. 2010). This survey,
conducted on 7970 subjects from 15 to 39 years old, found that those with a
serum vitamin D level above 30 µg/L (78 nmol/L) presented significantly less
depression episodes than those with a level lower than 20 µg/L (52 nmol/L).
Many other epidemiological surveys carried out in different countries
with the elderly achieved similar outcomes; an association between
depression and inadequate serum vitamin D levels was always observed.
In early 2015, three published studies still confirmed this trend: one study
in Japan with 1786 employees from 19 to 69 years old (Mizoue et al. 2015);
one study in Finland with 5371 subjects from 30 to 79 years old (Jääskeläi-
nena et al. 2015), and one study in France with 82 patients with an average
age of 46 years (Belzeaux et al. 2015). The Finnish study concluded that
maintaining a serum vitamin D level higher than 20 µg/L could reduce
the prevalence of depression troubles by 19%. Thus, this effect would have
a favorable impact on the related spending caused by depression in
Finland (1 billion euros for a country of 5.5 million inhabitants). It must
be stressed that the status of vitamin D is still lower than the recommen-
dations of the French Academy of Medicine (Section 7.4).
In France, how much could we save with the application of this
accepted biological standard? Probably about 6 billion euros on an expen-
diture of 30 billion in 1992 caused by only the treatment of depression
(CREDES). Why is this financial aspect not taken into account by the rele-
vant associations, the academic institutions or the Ministry of Health?
Besides these studies, a recent study of a large and diverse Danish popu-
lation, aged 18–64years, did not reveal any link between the vitamin D
status, the self-reported symptoms, and diagnosis of depression or anxi-
ety (Husemoen et al. 2016). The small range of vitamin D concentrations
(17–28 ng/mL) and their low levels (insufficiency zone) might be at the
origin of these conclusions.
In Japan, the results of a study conducted in 2009 should warn researchers
about the period of blood collection within the year (Nanri et al. 2009). Indeed,
the association between low blood vitamin D levels and deep depression was
much more pronounced when the subjects were examined in November com-
pared to subjects having their blood sampled in July. A similar result was
obtained in a study of young American students that observed a smaller num-
ber of depressive subjects in autumn compared to in winter or spring, with
these subjects also having higher vitamin D levels (Kerr et al. 2015).
These last results are consistent with the hypothesis of a protective
effect of vitamin D on depression symptoms known to be seasonal trou-
bles and strongly related to the synthesis of vitamin by exposing the skin
to sunlight (Gloth et al. 1999).
What are the biological mechanisms by which vitamin D level may
predispose to depression? Vitamin D has been shown to modulate seroto-
nin production and glucocorticoid-induced hippocampal cell death.
Furthermore, it has been hypothesized that it plays a role in the produc-
tion of neurotrophins and acetylcholine and in the regulation of specific
calcium channels. Vitamin D may also influence depressive symptoms
via its proposed anti-inflammatory effect.
Despite these findings, many experiments tend to confirm that depres-
sion is not primarily due to an unbalanced diet or to a reduced sun exposure,
with both being possible causes of reduced sources of vitamin D. It is obvious
that supplementation experiments could only demonstrate a clear causal link

between vitamin D and depression after the recognition of a reduction of
symptoms, leading then to consider a simple and natural fight against that
disease. The links between depression and ω-3 fatty acids (Section 6.1.1.1)
or vitamin E (Section 6.1.1.3), now better and better known, should be also
considered in research protocols, so as to reduce the dispersion of results
by controlling the maximum number of physiological parameters.
Given this promising research, in 2014 the European Union initiated
the major 5-year project MooDFOOD in nine countries to explore the rela-
tionships between vitamin D and depression, among other factors (www.
moodfood-vu.eu).
6.1.1.2.2 Intervention studies In 2004, one of the first studies was
published that reported the effects of a 6-month vitamin D supplementa-
tion on its blood level but also on mood and well-being, with the latter
being estimated with parameters such as energy level, sleep, interest, plea-
sure, attention, and weight loss (Vieth et al. 2004). The authors showed
that beneficial and significant effects were already observed with a dose
of 600 IU/day (15 µg/day), but they were even more obvious with a dose
of 4000 IU/day (100 µg/day). It also seemed that a regular intake of
vitamin D is more efficient than the one-time administration of high doses.
A meta-analysis of seven studies, selected by their strict protocol and pub-
lished from 1998 to 2013, showed that the restoration of blood vitamin D levels
between 17 and 33 µg/L improved depression levels significantly (Spedding
2014). A recent trial conducted at Tehran University, Iran, confirmed that a
weekly intake of 50,000 IU (1.25 mg) improved the depression symptoms sub-
stantially in deficient adults after 8 weeks (Sepehrmanesh et al. 2016).
These findings show that the effects of treatment of depression by
vitamin D are similar, in general, to those obtained with conventional anti-
depressant drugs. If these results are confirmed in several other large stu-
dies, the findings summarized above could have quick implications for
public health policy concerning a widespread pathology.
This area of research is currently interesting several research teams
worldwide, because 91 clinical trials were registered in 2016 (http://
www.clinicaltrials.gov).
All of the most recent work concludes that there is a correlation between
vitamin D and depression, however, without being able to define the phy-
siological mechanisms. To support this demonstration, several studies
involving supplementation have shown that, in general, symptoms of
depression or mood disorders are linked to a vitamin D deficiency, with
the latter resulting from a too low dietary intake, an inadequate sunlight
exposure, or both. In the current state of knowledge, experts suggest that
a supplementation with vitamin D may be beneficial for depressed subjects,

especially if they are clearly deficient or if their lifestyle and their place of
residence suggest a potential risk of permanent deficiency. No official med-
ical recommendation has been proposed so far for this type of treatment. As
for ω-3 fatty acids, the monitoring of blood vitamin D levels is basic. A defi-
ciency should be the subject of a medical consultation, followed possibly by
a dietary change, an increasing sun exposure, or both.
6.1.1.3 Vitamin E
In 1962, Dr. F. Post suggested that a cerebrovascular disease was at the
basis of affective disorders as observed in about 12% of the elderly (Post
1962). Thus, many investigators have raised the possibility that the genera-
tion of free radicals, consecutive to the natural oxidation of membrane lipids,
could play a role in the onset of neuropsychiatric disorders such as depres-
sion. These free radicals are produced during inflammatory episodes, during
immune reactions, or during the catabolism of monoamines (dopamine,
adrenaline, and serotonin). This assumption was also raised for ω-3
fatty acids, with the latter being both antidepressant and anti-inflammatory
(Lu et al. 2010). Some research seems to confirm this hypothesis. Thus, an
increased lipid oxidation together with more intense activities of antioxidant
enzymes has been observed in patients with major depressive disorder.
Conversely and more surprisingly, an antidepressant treatment (with a sero-
tonin reuptake inhibitor) is able to decrease lipid oxidation (Bilici et al. 2001).
This close relationship between depression and lipid oxidation seems
to be confirmed by the demonstration that serum vitamin E levels are sig-
nificantly lower in patients with major depression compared to healthy
subjects (Maes et al. 2000). Two years later, doubts have yet been issued
from a Dutch study with a larger number of subjects (262 depressed
and 459 controls), taking into account many factors likely to interfere with
the interpretation of results (Tiemeir et al. 2002). Indeed, in all subjects, the
challenge resided in the monitoring of factors such as depression severity,
disability, smoking, diet, and social level, all factors known to alter blood
antioxidant levels. The authors emphasized the difficulty of attributing a
meaning to the circulating vitamin E levels. Thus, if a lonely person is
unable to do his or her shopping, is he or she depressed because of life-
style or because of an unbalanced diet inducing a vitamin E deficiency?
According to Dr. A. J. Owen, Wollongong University, Australia, the
dietary vitamin E intake does not seem to act directly; he observed that
the severity of depression disorders was linked to low blood α-tocopherol
levels, even with an adequate vitamin supply (Owen et al. 2005). That
hypovitaminosis could therefore result from an increased use of vitamin E,
along with an increased oxidative stress accompanying depression.
Much more research is needed before understanding the nature of the

links between depression and vitamin E.
In conclusion of all these studies and in the absence of well-controlled clinical

trials with large cohorts, any important supplementation of vitamin E may
not be recommended preventively or curatively in the context of depression
disorders. In addition, future trials should take into account the personalized
assessment of an oxidative stress, a difficult task when one knows the number
of the involved molecules. Trials have been already proposed by some private
laboratories. Maintaining a diversified diet consistent with the official recom-
mendations, providing about 15 mg of vitamin E per day up to an old age, is
now the only advice that may be delivered to the population. At the same time,
it is recommended to maintain adequate dietary ω-3 fatty acids and vitamin D
intakes, micronutrients that are likely involved in the depression by increasing
the brain serotonin secretion.
6.1.2 Bipolar disorder and ω-3 fatty acids

Bipolar disorder (formerly manic depression) is characterized by mood dis-
orders defined by repetitive fluctuations between periods of marked excita-
tion (intense excitement or euphoria that may last for weeks or months) and
periods of melancholy (extreme depression with pathological sadness).
Between these two episodes, the subject is again in a calm period returning
to the usual state. Some severe cases may lead to dangerous behavior, even
suicide (8%–10% of deaths by suicide in these patients). Two main types of
bipolar disorder have been described; they are distinguished by the presence
of a distinct period of at least 1 week of intense or irritable mood (mania, type
I) or a period with milder levels of mania, known as hypomania (type II)
where individuals are energetic, excitable, and productive. Many patients
with bipolar disorder exhibit psychotic symptoms that may be confused with
schizophrenia or other mood disorders. During clinical trials, this uncer-
tainty may lead to a dispersion of results and a bias in their interpretation.
Worldwide, bipolar disease affects more than 1% of adults and glob-
ally is part of the 10 most costly and debilitating diseases. In the United
States, the prevalence of the disease is increasing in adults, rising from
905 patients per 100,000 in 1995 to 1679 per 100,000 in 2003. This increase
is even higher among young people under 20 years old.
In 2011, it was estimated that in Europe nearly 3 million people suffered
from the disease; there were 2.4 million in 2005 (Wittchen et al. 2011).
In France, more than 600,000 people of all ages and both sexes could
be affected; it has been estimated that the prevalence is such that 8% of
individuals will present these disorders during their lives. According to
psychiatrists, 50% of depressions diagnosed during consultations are actu-

ally affected by bipolar disorder. If the intensity of troubles may decrease
over time, the disease will persist for long. This pathology has important
physical, social, financial, and professional consequences because many
bipolar patients are unable to work.
Bipolar disorder has been deemed the most expensive behavioral
healthcare diagnosis, costing more than twice as much as depression
per affected individual. In the United States, an estimate of the total cost
of bipolar disorder published more than a decade ago was as high as
US$45 billion/year.
The estimated UK national cost of bipolar disorder was £4.59 billion,
with hospitalization during acute episodes representing the largest com-
ponent of the cost.
In France, studies have estimated that the annual cost of hospitaliza-
tions represents 1.3 billion euros.
Although this pathology is partly genetic, it is also recognized that
environmental factors may be involved. Among these factors, the quality
of dietary lipids has been repeatedly mentioned.

A multicenter comparative study of the bipolar disorder prevalence
according to fish consumption was conducted in the United States by
the team of Dr. J. R. Hibbeln, a recognized specialist on the relationship
between ω-3 fatty acids and psychiatric disorders at the National Institutes
of Health (Bethesda, MD) (Noaghiul and Hibbeln 2003). As for depression,
this work has clearly shown that the prevalence of the disease decreased
according to an exponential decay when fish consumption increased from
5.4 to 100 kg/year. This is the case in Iceland where the prevalence is
about 30 times lower than in Germany. It must be emphasized that below
a consumption of about 23 kg/year, prevalence was increasing rapidly. That
consumption corresponds to about 440 g/week (two large fish servings).
The amount of fish consumed would thus correspond to a minimum of
about 1.2 g/day of EPA plus DHA calculated from salmon, about twice the
amount usually recommended by the medical organizations (0.5 g/day) for
the prevention of cardiovascular disease (Leray 2015).
As for other mood disorders, it is significant that the analysis of speci-
mens of prefrontal cortex sampled during autopsy in patients who have
suffered from bipolar disorder has shown lower DHA concentrations than
in control individuals (McNamara et al. 2007b). This DHA deficiency has
been also observed after analyzes of red blood cells (McNamara et al.
2010) or plasma (Pomponi et al. 2013) in patients compared to control sub-
jects. Unfortunately, the question whether this well-defined deficiency
could be connected to a reduced food intake of ω-3 fatty acids has not been
included in these studies, other studies rather supporting a reduced DHA
biosynthesis (Clayton et al. 2008). From these examples, it seems that

no one yet knows whether this apparent DHA deficiency is the cause or
the consequence of the disease, or whether it could have originated from
the pharmacological treatments. Unfortunately, this lack of knowledge
can only delay any progress in this domain.

What may we learn from the therapeutic attempts of ω-3 fatty acid supplemen-
tation? In 1999, Prof. A. L. Stoll, Harvard University, Boston, Massachusetts,
conducted one of the first nutritional experiments in patients with bipolar
disorder. After 4 months, he observed a significant beneficial effect with a dai-
ly prescription of 6.2 g of EPA and 3.4 g of DHA (fish oil), with patients also
having psychotropic or psychotherapeutic treatments (Stoll et al. 1999).
After this publication, four in five studies, using a single EPA supple-
mentation, resulted in similar conclusions. It seems that a daily intake of
1 g of EPA is sufficient to notice after only 3 months of treatment beneficial
effects in patients taking also conventional drugs (Frangou et al. 2006).
Encouraging results have even been achieved in children aged 6–17 years
with bipolar disorder and treated with an EPA-rich oil. These results are
even more interesting as pediatricians know that the treatment of such
young subjects still poses several problems (Wozniak et al. 2007).
The safety of EPA and the absence of any side effect allow to conceive
an efficient background treatment of bipolar disorder, accompanying any
other therapy chosen by the physician. Despite the lack of precise data,
one can hypothesize that a ω-3 fatty acid supplementation as an adjuvant
allows a more or less rapid reduction of the psychotropic doses, a condi-
tion that should attract the interest of clinicians and patients.
A recent meta-analysis based on five studies comparing a treated
group with a placebo group, all with at least 15 subjects, concluded that
fish oil consumption has a beneficial effect on bipolar symptoms, with
the effect greater for phases of depression than for phases of mania (Sarris
et al. 2012). All these studies have shown that ω-3 fatty acid intake (espe-
cially DHA and EPA) is the most active, with their metabolic precursor
linolenic acid having no effect. The specificity of EPA gives similar results
obtained in subjects treated for depression.
The mechanisms involved in the study of ω-3 fatty acid effects on
bipolar disorder are probably similar to those explored for depression,
with some authors having also discussed a possible action of some lipid
mediators, mainly the endogenous cannabinoids (anandamide, 2-arachi-
donoyl glycerol).
This area of research is currently interesting several research teams
worldwide because about 20 clinical trials in children and adolescents
were registered in 2016 at http://www.clinicaltrials.gov.
The whole results obtained in the field of psychiatric disorders seemed so

convincing that the American Psychiatric Association decided in 2006 to
recommend to patients with psychiatric troubles, especially unipolar and
bipolar disorders, to consume at least 1 g/day of an EPA plus DHA mix-
ture, or to eat at least three fish servings per week. These natural products
display only negligible biological risks and are furthermore beneficial for
patients who have also cardiovascular risks. The cost-effectiveness of such
treatment is also profitable in the current psychiatric practice.
6.1.3 Schizophrenia (psychotic disorders)

In 1896, the German psychiatrist Emil Kraepelin established a pathological
entity he called “early dementia,” consisting of a combination of three situa-
tions: disorganized behavior, negativistic personality, and paranoid demen-
tia (rich, illogical, and incomprehensible delirium). In 1911, the disease was
specified and named “schizophrenia” by the Swiss psychiatrist Eugen Bleu-
ler. This severe psychosis occurs most often in early adulthood, involving
delusions, hallucinations, disorganized thinking and speech, behavioral dis-
orders, cognitive disorders, and various chronic symptoms constituting
sometimes a serious handicap. That pathology should not be confused with
the dissociative identity disorder. All these symptoms usually result in a
loss of contact with the world outside, sometimes with an autistic withdra-
wal. Some patients have simultaneously symptoms of schizophrenia and
bipolar disorder, constituting the “schizoaffective” disorder. The closeness
of the symptoms may obviously reflect a possible transition between the
two diseases, likely explaining the difficulty of the investigations and the
uncertainty of some conclusions from often dispersed results.
In general, the symptoms can be grouped into two categories: positive
symptoms, described as excess or distortion of normal functions (such as hal-
lucinations and delusions) and negative symptoms characterized by a deficit
of normal emotional responses and a loss of speech. The specialist usually
assesses the severity of the disease with the PANSS (Positive And Negative
Syndrome Scale) described in 1987 by Dr. R. S. Kay in the United States.
Schizophrenia is present in all latitudes and in all cultures. However,
the impact of schizophrenia tends to be highest in the Middle East and
East Asia, whereas Australia, Japan, the United States, and most of Europe
have typically a low impact. It ranks among the top 10 causes of disability
in developed countries worldwide. Twice as prevalent as Alzheimer’s dis-
ease, it concerns, depending on the country 0.5%–2% of the population,
but the variance is difficult to track due to differing measuring standards
in many countries. Men are 40% more frequently affected than women,
but with a late form occurring around the age of 40–45 years and less
common in women. The prognosis of the disease is however better in

women because it is less severe and with frequently more positive symp-
toms responsive to neuroleptic treatments. It has been suggested that this
difference according to sex is based on the ability of estrogen to replace vita-
min D during the activation of serotonin synthesis (Patrick and Ames 2015).
The approximate number of people in the United States suffering
from schizophrenia is more than 2.2 million compared with 6–12 million
people in China; 4.3–8.7 million people in India; and 285,000 people
in Australia and in Canada (http://www.nimh.nih.gov/index.shtml).
In the United States, schizophrenia now costs about US$63 billion per year
for direct treatment, societal, and family costs.
In Europe, it was estimated in 2011 that nearly 5 million people suf-
fered with these disorders, compared with 3.7 million in 2005 (Wittchen
et al. 2011). In France, nearly 600,000 people would be affected. Patients
with schizophrenia represent 20% of full-time psychiatric hospitalizations
and 1% of the total health expenditure (data from INSERM). It is impor-
tant to note that life expectancy of these patients is, on average, 10 years
less than that of the general population. Forty percent of the patients
attempt suicide, and 10% manage to terminate normally their life.
What is the origin of this disease? For a long time doctors included her-
edity as a mean to transmit the disease from one generation to the next, but
more recently it has been proved that no specific gene is involved. Indeed,
it is increasingly clear that these patients have a higher tendency to have
rare genetic mutations that involve several genes, in turn disrupting brain
development. The onset of schizophrenia is unfortunately unpredictable;
however, its hereditary character is underlined by the fact that a person
has 10 times more disease risk if a relative (uncle, aunt, grandparent, or
cousin) is already affected. Compelling evidence is provided by the obser-
vation of identical twins because one will have a 50% risk of being affected
by the disease if his or her twin already has it.
In the early 1960s, when neuroleptics were used, an excess of dopa-
mine was formulated. Other neurotransmitter systems have also been
mentioned, such as those based on glutamate, GABA, and serotonin.
Today, it remains difficult to define the true source of the brain dysfunc-
tion generating schizophrenia. Apart from genetic or purely functional
explanations, clinicians have also thought of the neurodevelopmental
and environmental causes. Thus, psychosocial factors still poorly defined,
infections, and malnutrition before or after birth have been invoked.
In 1981, Dr. O. D. Rudin, a supporter of the use of fish oil capsules in
the United States, hypothesized that schizophrenia could be linked to a
ω-3 fatty acid deficiency (Section 6.1.3.1) (Rudin 1981). D. F. Horrobin
explained the effect by the progressive enrichment, for over a century,
of our diet with saturated and ω-6 fatty acids, largely replacing ω-3
fatty acids in membrane phospholipids (Horrobin 1998). Being given the
main source of ω-3 fatty acids (fish and shellfish), their scarcity in the
Western diet is also accompanied by a decrease in the vitamin D supply
(Sections 6.1.3.2 and 7.4). After a large survey in nine countries, Danish
researchers provided further evidence by showing that the prevalence of
schizophrenia is much lower in people eating large amounts of vegetables
and seafood (Christensen and Christensen 1988).
6.1.3.1 ω-3 Fatty acids

6.1.3.1.1 Epidemiological investigations Almost 40 years ago, the first
mention of a possible link between schizophrenia and a disturbance of the
fatty acid metabolism via prostaglandins was introduced by D. F. Horrobin,
an English specialist of the relationships between essential fatty acids and
various diseases (Horrobin 1977). Subsequently and almost without excep-
tion, several studies have shown that ω-3 fatty acids were less abundant in
the plasma (Horrobin et al. 1989), red blood cells (Peet et al. 1995), and even
brain in patients with schizophrenia (Horrobin et al. 1991). Some studies
have validated these results both at the level of red blood cells (Kim et al.
2014) and cerebral cortex (McNamara et al. 2007b).
Despite about 190 studies published since 2000, the origin of this bio-
chemical situation, consequence, or cause of the disease remains unknown.
However, a consensus is emerging to support the hypothesis of an increased
catabolism or an abnormal metabolism of fatty acids in all tissues, including
the nervous system. Nonetheless, some facts remain unexplained as the
observation of a restoration of normal DHA levels in red cell of subjects with
schizophrenia when treated with neuroleptic drugs (Sethom et al. 2010).
In line with previous work (Christensen and Christensen 1988), conclu-
sions of particular interest were drawn from a large epidemiological survey
performed on nearly 33,000 Swedish women aged 30–49 years (Hedelin
et al. 2010). These investigators noticed that eating two fish meals per week
divided by 2 the risk of developing the disease observed in those consum-
ing no fish. In contrast, at a higher fish consumption (more than five times
per week) they observed a higher risk. So far this result remains unex-
plained, but it could be related to the various contaminants present in the
consumed products (heavy metals and pesticides, Section 7.2).
6.1.3.1.2 Intervention studies Well-controlled intervention trials are

unfortunately few, but in almost all cases it has been observed that the
impact of a treatment with ω-3 fatty acids on the disease development usual-
ly involved the appearance of less severe symptoms after a few weeks. One
of the first investigations was that of J. E. Mellor from the University of Shef-
field, Great Britain, showing that a daily intake of 10 g of MaxEPA (fish oil
enriched with DHA and EPA) resulted after 6 weeks in an improvement in
schizophrenia symptoms, an improvement correlated with a significant
increase in the amount of red blood cell ω-3 fatty acids (Mellor et al. 1995).
More recently, an experiment was conducted in India with 28 patients

with an average age of 31 years receiving a conventional pharmacological
treatment and ingesting also each day for 4 months 360 mg of EPA and
240 mg of DHA (Arvindakshan et al. 2003). At the end of the treatment,
the authors found a reduction in all the characteristic symptoms of the dis-
ease, and curiously these changes could be observed yet 4 months after the
supplementation while the original fatty acid composition of red blood cells
was restored. Also, the fatty acid intake was accompanied by vitamin E
(400 IU/day) and vitamin C (500 mg/day).
Early supplementation experiments indicated that an important fish oil
intake reduced the severity of the negative symptoms of the disease and the
dyskinesia (uncoordinated movements), troubles associated with neurolep-
tic treatments (Laugharne et al. 1996). In addition, the hypothesis of a close
link between ω-3 fatty acids and schizophrenia was supported by a preven-
tion trial of psychotic disorders consisting of a daily ingestion of 0.7 g of EPA
and 0.48 g of DHA for 12 weeks (Amminger et al. 2010). At the end of the
experiment, the authors found a reduction in symptoms (positive and nega-
tive) in young subjects. The most surprising outcome from this experiment is
that the beneficial effects were maintained 1 year after the end of the treat-
ment, unlike observations done after a treatment with antipsychotic medica-
tion. A review of the scientific literature has shown that these conclusions
are shared by many authors, all emphasizing the need of an enrichment
of cell membranes with ω-3 fatty acids via dietary intake and for long
enough to enable a change in brain composition (Akter et al. 2012).
An experiment carried out in Iran in subjects aged about 32 years and
sick for 10 years has clearly shown that a daily intake of 1 g of ω-3 fatty
acids for 6 weeks increased the efficiency of conventional antipsychotic
treatments (Jamilian et al. 2014). The authors emphasized the usefulness
of such a treatment in developing countries given the low cost of fish
oil and the absence of adverse side effects.
In patients with a first psychotic episode, an MRI of the brain (hippo-
campus) enabled to verify that EPA induced changes, confirming its neuro-
protective effect. However, it seems that EPA supplementation produced
no effect in patients with a well-established schizophrenia. Conversely, sev-
eral studies emphasized that the treatment is more efficient from the very
beginning of the disease (prodromal phase).
This type of dietary treatment of schizophrenia by ω-3 fatty acids is
therefore an additional tool in the prevention, especially in the treatment
of young people with a clear risk of psychotic disorders.
However, it is unfortunate that the most recent clinical studies have
included too few patients and were conducted for too short a time. Nonethe-
less, the majority of results suggest that a ω-3 fatty acid supplementation
would be especially beneficial, and above all, without side effects (Akter
et al. 2012). This should encourage clinicians to advise their patients to
use ω-3 fatty acids as dietary supplement in addition to their pharmacologi-

cal treatment to control more effectively the deleterious symptoms of schizo-
phrenia. Highlighting a homogeneous category of patients having both
significant negative symptoms and low cellular levels of ω-3 fatty acids must
alert also the clinicians on a possible heterogeneity of patients with schizo-
phrenia (Bentsen et al. 2012). The discovery of the presence of subgroups
in patients with nervous disorders is not new. Right now, the complexity
of these pathologies should encourage clinicians to refine their neuropsycho-
logical methods used for subject recruitment.
Although many encouraging results have been reported in scientific
journals, it is regrettable that the official organizations or associations dedi-
cated to schizophrenia do not promote the opportunities if not to cure, to at
least to alleviate the symptoms of this very debilitating disease. It could be
important to suggest to the general medical press and to the media to seize
the topic, to analyze the scientific findings, and to report the main outcomes.
In this way, many patients could be informed of a simple way to alleviate
their neuropsychological disorders. The investment is moderate; side effects
are few and safe; and the supplementation with ω-3 fatty acids, purified or
as culinary preparations of marine products, are fully compatible with the
conventional antipsychotic treatments.
What may be the mechanisms of the effects of ω-3 fatty acids on psycho-
tic disorders? These effects have been attributed, as in many other cases, to
changes in membrane fluidity, but also to an interaction with dopaminergic
and serotoninergic systems in particular, systems that are conventionally
associated with schizophrenia pathophysiology (Patrick and Ames 2015).
As yet, the unconvincing nature of some results has often been consid-
ered the result of individuals previously treated with one or more neuro-
leptic drugs interfering with the ω-3 fatty acid intake. In addition, patients
with schizophrenia often have a poor diet, sometimes combined with con-
sumption of alcohol, tobacco, or illicit drugs that may influence the results
observed by clinicians. Other better controlled research is needed to
improve our knowledge of the mode of therapeutic action of ω-3 fatty
acids, a natural therapeutic already perceived as a promising way to treat
many other neuropsychiatric diseases. Currently, about 20 major trials in
this area are registered at http://www.clinicaltrials.gov.
Already, it may be considered that in subjects at risk of developing or in devel-

opment of schizophrenia, the results reported above should encourage clinicians
to learn from their patients the frequency of consumption of marine products
rich in EPA and DHA. If in doubt, it may be possible to determine their blood
fatty acid status. If necessary, it is important to advise deficient patients to sup-
plement their diet, so that they meet safely and with no side effects a ω-3 fatty
acid intake close to that recommended by medical authorities (Section 7.2).
6.1.3.2 Vitamin D
In 1978, a link between vitamin D and schizophrenia was proposed for
the first time by R. A. Moskovitz of the Florida University–Gainesville
(Moskovitz 1978). This hypothesis was based on the fact that patients with
this disease were born more often during winter or early spring and that
their mothers had in the third trimester pregnancy vitamin D blood levels
as much as three times higher in August than in February. Thus, these
observations led naturally to suggest that the greater frequency of the mater-
nal vitamin D deficiency in winter, shortly before birth, could be responsible
for an increased risk in young adults of developing schizophrenia.
Unfortunately, this suggestion has found little impact among clini-
cians, and it took 20 years for Prof. J. McGrath, Director of the Queens-
land Center for Schizophrenia Research, Brisbane, Australia, to support
the hypothesis of a close relationship between low vitamin D levels in
the perinatal period and schizophrenia risk (McGrath 1999). Notably, this
scientist contributed significantly to the advancement of our knowledge
by publishing since 1988 more than 230 scientific articles devoted to that
pathology. To support his hypothesis, J. McGrath has grouped all the
data available on the excess of schizophrenia cases among those born
in winter or spring, when the concentration of circulating vitamin D is
at a minimum. Thus, he studied in detail first subjects living in cities com-
pared to those living in the countryside (with more sun exposure, so
more vitamin D) and second, subjects with dark skin who had migrated
in Nordic countries (low sunshine so common hypovitaminosis). In 2012,
a wide survey, conducted at the University of Oxford, UK, by Dr. G. Disanto
on nearly 58,000 English subjects, also came to the conclusion that the
risk of developing schizophrenia is at a minimum for those born in
summer and maximum for those born in winter, peaking in January
(Disanto et al. 2012).
Later, Prof. J. McGrath explored in a Finnish population of more than
9000 people the association between vitamin D supplementation during
the first year of life and the risk of developing schizophrenia in adulthood
(McGrath et al. 2004). This important clinical experiment revealed that a
daily supplementation of at least 2000 IU of vitamin D reduced by 77%
the risk of schizophrenia compared to subjects receiving a lower dose. It
is regrettable that this first trial of a preventive treatment of schizophrenia
has not been confirmed by other clinical teams. More investigations are
necessary to specify in a preventive approach the most critical period
for performing a vitamin D supplementation during brain development.
It seems very likely that the well-known relationships between vitamin D
and nerve growth factor are at the basis of brain damage in case of neonatal
vitamin D deficiency (Garcion et al. 2002). These troubles may therefore
occur throughout life in the form of neuropsychological disorders as those
characterizing schizophrenia, but also multiple sclerosis (Section 5.1.2) and

possibly autistic disorder (Section 6.1.5.2).
Unfortunately, it is uncertain as yet that the mother hypovitaminosis is
predominant in triggering a neuropathological process, as it seems that the
vitamin D status in pregnant women has no effect on the risk of developing
schizophrenia at an age close to 18 years (Sullivan et al. 2013). In contrast, it
may be considered that very low circulating vitamin D levels seem deter-
mined by the month of birth. Indeed, in 2015 Dr. G. Lippi has shown that
subjects born in winter had significantly lower vitamin D levels than those
born during an extended sunshine season (Lippi et al. 2015).
In adult patients with schizophrenia, a vitamin D deficiency has been
repeatedly reported by clinicians, despite the variety and the importance
of the studied human groups. It has been noticed many times that the sever-
ity of symptoms is higher when the level of circulating vitamin D is lower.
To summarize the work published between 2009 and 2013, present-
ing all the strict criteria, it is necessary to keep in mind the recent meta-
analysis of Dr. M. Belvederi Muri, University of Parma, Italy, carried out
on a selection of seven published studies involving 523 patients in total
compared to 7545 controls (Belvederi Muri et al. 2013). All cited authors,
without exception, mentioned a vitamin D deficiency in subjects with
schizophrenia compared with healthy subjects. As a matter of prudence,
it must be emphasized that this deficiency may not be the cause of the
disease, but it may result from an unbalanced food or an insufficient sun-
light exposure, both situations often experienced by patients.
The links between vitamin D and schizophrenia remain unknown, but
some recent research brings new hope for setting specific therapeutic targets
to prevent or even treat a large number of affected subjects. For example, in
2010, the demonstration of a close relationship between geography and
genes associated with vitamin D and some neuropsychiatric diseases such
as schizophrenia has confirmed at the molecular level the link between psy-
chiatric illness and vitamin D (Amato et al. 2010). Moreover, the authors sug-
gested that schizophrenia may result from a dysfunction of the vitamin D
metabolism according to the geographic latitude, thus explaining the greater
number of neuropsychiatric diseases in most northern countries. The impor-
tance of such a correlation suggests that this mechanism could be involved
in other pathologies more or less linked to vitamin D.
More recently, metabolic studies have shown that the links between
vitamin D and schizophrenia may result from an increased synthesis of
the amino acid proline, likely because of neurotransmission disorders
(Clelland et al. 2014). In patients, an exploration of the blood proline levels
has shown that many of them present this metabolism imbalance. A phar-
macological intervention on these mechanisms could be a means to effec-
tively reduce the disease symptoms even in young adults. An increase of
psychiatric disorders such as those characterizing schizophrenia could

also be the result of an inhibition of serotonin synthesis linked to vitamin
D deficiency (Patrick and Ames 2015).
After finding in animals that vitamin D slows the degeneration of the
hippocampus, thus playing a neuroprotective role (Landfield and Cadwal-
lader- Neal 1998), recent anatomical studies using medical imaging (MRI)
have reinforced the already compelling links between vitamin D and schi-
zophrenia (Shivakumar et al. 2015). These studies showed for the first time
that in young subjects with schizophrenia the volume of their hippocampus
was proportional to their vitamin D blood levels, the majority of patients
being in a state of vitamin insufficiency or deficiency. Although a causal
link between both parameters is not established definitively, these observa-
tions suggest strongly that vitamin D deficiency is closely associated with
abnormalities of the hippocampus, in relation to the onset of the character-
istic symptoms of schizophrenia.
Currently, only five clinical trials in this area are registered (http://
www.clinicaltrials.gov).
Much research is still required before deciding the validity of hypothetical

relationships between schizophrenia and vitamin D. However, experts stress
the need to detect as early as possible any vitamin D deficiency and to correct
it as a priority in patients at risk or already diagnosed, although the effective-
ness of such intervention in adults is questionable. The situation is different
for newborns and pregnant women who must be provided nutritional or
supplementation advice to restore, if necessary, a suitable vitamin D level.
It is hoped that a preventive administration of vitamin D in pregnant women
and newborns, as it is now practiced in France on a large scale, will contribute
as it has been observed in Finland to reduce the incidence of some neuropsy-
chiatric conditions, such as schizophrenia, or even neurological diseases, such
as multiple sclerosis (Section 5.2.2).
6.1.4 Attention-deficit hyperactivity disorder

Psychiatric disorders characterized by an attention deficit with or without
hyperactivity disorder, also known as ADHD, are a frequent problem
occurring in childhood and persistent in most cases in adulthood. These
disorders are classified in the broad category of “disorders of autism spec-
trum” that also accounts autism, Asperger’s syndrome, mental retarda-
tion, anxiety, and communication or mood disorders.
Although still poorly understood, ADHD is a genuine neuropsychologi-
cal disorder and not a psychopathological disorder or a neurological disease.
The Diagnostic and Statistical Manual of Mental Disorders (DSM IV-2013)
has classified ADHD in the group of the neurodevelopmental disorders. The

symptoms affect daily operations and often require an appropriate interven-
tion. In this respect, science is evolving rapidly and several treatment options
are available.
The specialists of mental disorders in children and adolescents consider
ADHD as a behavioral disorder characterized mainly by three symptoms:
difficulty in fixing the attention, motor hyperactivity (hyperkinesia), and
high impulsivity (see the National Institute of Mental Health site http://
www.nimh.nih.gov/health/topics/attention-deficit-hyperactivity-disorder-
adhd/index.shtml). In most subjects, attention deficit and hyperactivity
coexist, sometimes inattention or hyperactivity may be predominant, with
that distinction creating three subtypes for the same disorder. Thus, the
manifestations of ADHD vary from one individual to another, the three
symptoms occurring very differently depending on the age or the context
of the subject life. In all cases, symptoms interfere with social, academic, or
professional activities.
It is a chronic disorder that concerns mainly children of preschool age.
The impulsivity often leads to disinhibited or worse aggressive behaviors.
In general, support is considered when these symptoms become a handi-
cap for the child. ADHD is often associated with other mental disorders
(anger, provocation, aggression, obsessive–compulsive disorders, learning
disorders) and without treatment it can lead to many psychological
complications. The ADHD present in child persists in 70% when they
are adult.
In the field of child psychopathology, this disorder is the most common
because its prevalence is 3–5% in western countries, with up to two children
per class being so concerned. In 2013, it was estimated that among the
worldwide population aged 5–19 years, 129 million had ADHD. Estimates
from individual studies have indicated that the global prevalence of ADHD
in adults ranges from 1.1% in Australia to 7.3% in France. However, ADHD
prevalence data may vary widely between studies due to various factors
such as population characteristics; methodological, environmental, and cul-
tural differences; and variability in identification and diagnostic guideline
tools, rather than geographical location per se.
In 2011, the Centers for Disease Control and Prevention reported that
11% of US school children suffer from ADHD. The percentage of children
with an ADHD diagnosis continues to increase, from 7.8% in 2003 to 9.5%
in 2007 and to 11.0% in 2011. The annual societal “cost of illness” for
ADHD is estimated to be between US$36 and $52 billion.
In the French population, there are about 400,000 children aged from
4 to 19 years and up to 7% of adults with ADHD.
The etiology of this disease is poorly known, although biological and
environmental factors are involved undeniably in its emergence. From the
functional point of view, it has been proposed that ADHD is consecutive
to an impairment of catecholamine-based nerve conduction, but with also

a possible intervention of serotonin.
French clinicians are well aware that dietary interventions may some-
times help to prevent a child’s problem in that field. In the United States,
the strict focus on pharmaceutical treatment of ADHD encourages clini-
cians to ignore the influence of dietary factors on children’s behavior.
From the perspective of the possible influence of nutritional fac-
tors, several lipids have been implicated. Among these, ω-3 fatty acids
(Section 6.1.4.1) and vitamin D (Section 6.1.4.2) have resulted in some
clinical explorations of high interest.

Compared with other neuropsychological disorders, ADHD was the subject
of the first hypotheses regarding a possible intervention of essential fatty
acids (Colquhoun and Bunday 1981). It is noteworthy that the authors dis-
cussed their role or those of their metabolites (prostaglandins) a year before
the publication of a fundamental work by R. T. Holman, announcing for the
first time the efficiency of a supplementation with a ω-3 fatty acid (linolenic
acid) in a linolenic acid–deficient person also subject to various neurological
abnormalities (Holman et al. 1982).
6.1.4.1.1 Epidemiological investigations The clinical symptoms of

excessive thirst (polydipsia), eczema, asthma, and other allergies present
in children with ADHD have precociously evoked a situation close to that
observed in children with essential fatty acid deficiency. The similarity of
these symptoms has been confirmed by several clinicians in finding that they
were accompanied by very low blood levels of ω-3 fatty acids. Later, several
analytical studies showed that children with ADHD had lower serum ω-3
fatty acid levels than the control healthy children (Stevens et al. 1995, Burgess
et al. 2000). In addition, a study has shown that reduced levels of plasma ω-3
fatty acids are associated with low scores in psychometric tests focused on
the recognition of facial expressions of emotion (Gow et al. 2013).
Without prejudice to the present mechanisms, some investigations
have shown that, in some children or adults, the severity of symptoms
was accompanied by a greater essential fatty acid deficiency.
An interesting approach to the problem could be to consider the influ-
ence of the nutritional relationships between the mother and her fetus on
the risk of developing that disease, as it has been done successfully for
behavioral disorders in young children (Steenweg-de Graaff et al. 2015).
Fortunately, this large survey (Generation R Study) conducted in Rotter-
dam, The Netherlands, has shown that high DHA values, measured at
midpregnancy, were associated with less behavioral troubles (emotions,
anxiety, mood) in 6-year-old children.
6.1.4.1.2 Intervention studies Based on the knowledge gained from

epidemiological studies, several clinical trials have been undertaken,
including the contribution of ω-3 fatty acids and the assessment of symptoms
of the disease by using appropriate and recognized psychological protocols.
By contrast with the expectations, the published results are unconvincing
because of a too great variability, probably being due to a wide variety of
the administered products, the treatment times, and perhaps the existence
of poorly defined forms of the disease. The biochemical composition of the
administered products seems important as the majority of clinical trials
reporting results interpreted as positive were obtained only after administra-
tion of Environmental Protection Agency (EPA). Moreover, it was discovered
in 2008 that phosphatidylserine, rich in EPA and DHA, was twice as effective
in improving scores of visual attention than triacylglycerols of similar ω-3
fatty acid composition, as present in fish oil (Vaisman et al. 2008).
Recent work demonstrated that the administration of DHA, unlike EPA,
was able to improve after 4 months the symptoms in a subgroup of children
with ADHD aged 7–12 with reading and spelling knowledge difficulties
(Milte et al. 2012). The majority of reviews on this subject also highlight that
children suffering from symptoms related to ADHD could benefit by supple-
mentation with ω-3 fatty acids, especially those exhibiting difficulties with
attention and learning. The relative importance of each long-chain ω-3 fatty
acid remains unclear, as does the possible synergistic role of ω-6 fatty acids.
Currently, it seems that a combined supplement containing ω-3 fatty acids
(EPA plus DHA) and ω-6 fatty acids (linoleic, γ-linolenic, or arachidonic acids)
is most effective. Several clinical trials have revealed a reduction of symptoms
associated with ADHD, at least in a portion of the groups studied, after
administration of a mixture of fish oil and evening primrose (Oenothera) oil,
with this oil being rich in γ-linolenic acid (18:3 ω-6) (Schuchardt et al. 2012).
The dyspraxia symptoms that accompany ADHD tend often to be the first
mitigated. These results are as yet inexplicable given that dietary ω-6 fatty
acids are known to be commonly very (and even too) high.
A recent placebo-controlled trial, conducted in the Department of
Psychiatry, Medical University of Utrecht, The Netherlands, under the
direction of Dr. D. J. Bos, has shown that a daily supplementation with
equal amounts (650 mg) of DHA and EPA for 16 weeks was capable of
improving inattention symptoms in young boys, suffering or not from
ADHD (Bos et al. 2015). Despite the limited results of that research, it is
interesting that ω-3 fatty acids may also increase the benefit of traditional
pharmacological treatments, allowing lower doses of drugs and simulta-
neously reducing their side effects (Barragán et al. 2014).
The variability of the research results may also be influenced by malnu-
trition, low socioeconomic level, differences in learning abilities, and certain
functional deficits afflicting many subjects with ADHD. In fact, clinicians
have noted that benefits of supplementation treatments were higher in
children having lower blood levels of essential fatty acids than in properly
fed children (Frensham et al. 2012).
Even if there is likely no causal link between these nutritional distur-
bances and the disease, all experts agree on their aggravating role. An
imbalance or a deficiency in essential fatty acids in patients could be a factor
modulating the symptoms of the disease, without taking part directly in
their determinism; e.g., it could alter the efficiency of any supplementation.
A recent analysis of 13 publications on this subject, selected from 366
contributions (Cochrane Database Syst Rev. 2012 7: CD007986) remained
unfavorable for ω-3 fatty acid supplementation in children with ADHD.
However, the most recent studies have shown positive results, albeit mod-
est, sometimes in certain patient groups (responders) only, whereas others
remain indifferent (Puri and Martins 2014). Thus, several results are found
similar to those obtained with traditional treatments, likely proving that the
troubles associated with ADHD come from different causes. Despite these
discrepancies, a treatment over the long term with ω-3 fatty acids could
have in some subjects a beneficial effect, especially in the absence of any
side effect and enabling perhaps a better efficiency of other treatments.
The current research interest for ω-3 fatty acids to fight against ADHD
seems obvious because 35 studies in this area were listed in 2016 on the
official website of the National Institutes of Health (NIH) Clinical Trials
(http: //clinicaltrials.gov).
The latest investigations suggest that in the near future, more and more
intense research effort with larger numbers of subjects should lead to the pro-
posal of an efficient nutritional therapy for the greatest number of children
with ADHD. In case of doubt for an adequate intake of essential fatty acids
(Section 7.2), a consultation with a nutrition specialist will enable the estima-
tion of the importance of the deficits and the suggestion of a dietary change
before any supplementation.
6.1.4.2 Vitamin D
Although knowledge of the functions of vitamin D not related to calcium
homeostasis goes back 30 years, its involvement in ADHD pathology is
only beginning to be discussed. Following numerous work on brain
development disorders (Section 2.2), various neuropsychological diseases
such as depression (Section 6.1.1.2), and schizophrenia (Section 6.1.3.2),
clinicians have explored actively the possible links between vitamin D
and ADHD. The search for these relationships was also motivated by
the greater frequency of this pathology among poor, overweight, unmoti-
vated children and those living mainly indoors. These situations are
indeed often accompanied by an unbalanced diet and also by a low sun

exposure, regardless of the location on the planet.
The first study, conducted in Qatar (Weill Cornell Medical College), com-
paring 1331 patients to the same number of control subjects, showed clearly
that children (between 5 and 18 years old) with ADHD have vitamin D blood
levels significantly lower than healthy children (16.6 and 23.5 ng/mL,
respectively) (Bener and Kamal 2014). Thus, the former children were
in a state of vitamin deficiency, whereas the latter children were only
deficient (Section 7.4). That comprehensive study also highlights the
close association between the disease and the sociological and adverse
medical conditions (e.g., low income, little sun exposure, overload
weight). The authors also suggested that a vitamin D supplementation
in early life may reduce the incidence of ADHD in children.
A smaller study (60 patients and 30 control subjects) performed in
Bolu, Turkey, has confirmed that in children aged from 7 to 18 years there
was a clear association between low vitamin D levels and high ADHD
incidence (Goksugur et al. 2014).
As for schizophrenia (Section 6.1.3.2), an association between ADHD
and the month of birth of the subjects was demonstrated. That relation-
ship seems natural if one assumes the influence of a vitamin D deficiency
during pregnancy on child brain development and the risk of subse-
quently developing the disease. This association has been proven through
a recently reported extensive epidemiological survey of approximately
1.75 million people born in New York between 1900 and 2000 (Boland
et al. 2015). Indeed, the statistical analysis has shown that the incidence
of the disease was significantly higher in subjects born from June to
November than in those born from January to May. Thus, these observa-
tions emphasize the importance of a proper sun exposure during the sec-
ond and third trimesters of pregnancy.
Recent work by the team of Dr. M. H. Mossin, University of Southern
Denmark, Odense, suggests a protective effect of prenatal vitamin D after
finding a novel inverse association between neonatal vitamin levels and
ADHD symptoms in toddlers (Mossin et al. 2016). The authors have deter-
mined in a population of 1233 mother–child pairs that infants (mean age
2.7 years) tested with a specific Child Behavior Checklist questionnaire
had an 11% decrease in ADHD scores per 10 nmol/L increase in blood
cord vitamin D. Such tight links between vitamin D and early ADHD
symptoms have not been described before and have therefore attracted
attention.
Further research is necessary to clarify some causal relationships
between the learning difficulties of a child and the mother’s vitamin D sta-
tus, possibly influenced by the month of the birth.
It is regrettable that all these studies have not concurrently paid atten-
tion to essential fatty acid status, thereby determining their possible
contribution to the reported results. In the future, investigators should

focus on this problem and get results quickly after using vitamin D alone
or in combination with ω-3 fatty acids for the treatment of ADHD. Preven-
tive measures could also be practiced in young children.
Although these results are encouraging, only one study on the effects of
vitamin D on the development of autism in children has been listed in 2016
on the official website of the NIH Clinical Trials (http://clinicaltrials.gov).
6.1.5 Autism
Specialists include autism with Asperger’s syndrome in all “pervasive
developmental disorders.” All these disorders are classified in the broad
category of “autism spectrum disorders” that includes also mental retar-
dation, impaired communication, and mood and anxiety troubles (Siksou
2012). Most clinical work does not distinguish between autism and other
related disorders; therefore at present, it is impossible to accurately assign
a result in one or the other of these disorders.
Autism is a complex mental disorder based primarily on a genetic
component. Indeed, among autistics who have an identical twin, this
twin is also autistic in nearly 66% of cases. This disorder also seems to
depend on environmental influences, so it is a multifactorial pathology.
Thus, clinicians have described cases of autism associated with rubella,
valproic acid (antiepileptic) treatment, and exposure to thalidomide dur-
ing pregnancy.
Autism is sometimes considered as a psychosis, with the subject
denying any contact and remaining in his or her inner world. It is char-
acterized by inappropriate social interactions, a restricted directory of activ-
ities and interests, communication problems, language impairment, and
an almost complete ignorance of the environment. Children with Asper-
ger’s syndrome have poor social interactions with stereotyped behaviors,
but they can have also large capacities of perception, attention, and
memory.
It seems that the number of children with autism spectrum disorders
is constantly increasing; a US study has determined that in children born
in 2002, 1 in 68 was affected by the illness against 1 in 150 for those born in
1992 (Centers for Disease Control and Prevention, http://www.cdc.gov/
ncbddd/autism/data.html). The causes and significance of these recent
changes are not yet explained (Kim et al. 2011). Among the possible
causes, the changing of dietary fatty acid supply and also the recent beha-
vior change in relation to sun exposure, with an obvious impact on the sta-
tus of vitamin D (Section 6.1.5.2), may be considered.
Globally, the overall prevalence would be around 1.9% (21.7 million
people); however, a great disparity exists between countries. The lowest
values are registered in several countries of northern Europe, with the

highest being in North Korea.
The newest estimate of autism prevalence among the US children
remained unchanged, at 1 in 68 from 2010 to 2012.
In 2011 it was estimated that approximately 0.6 million people were
suffering from these disorders in Europe (Wittchen et al. 2011).
In France, autism affects about 30,000 children. It grows mainly between
5 and 8 years, with a rate 4 to 5 times higher among boys than girls. Several
autism plans were launched by the French State, the last (and third) covers
the period from 2013 to 2017 (http://circulaire.legifrance.gouv.en/pdf/
2014/07/cir_38551.pdf). Unfortunately, no mention is made to any nutri-
tional intervention in this plan program.
In a child, the existence of autism and the severity of the disorders are
evaluated through a battery of tests suitable for preschool age. The best
known test is the Childhood Autism Rating Scale (CARS), developed in
the United States (Schopler et al. 1980). It uses five behavioral themes
rated from 1 to 4 depending on the extent of the troubles.
The structural causes of autism are still unknown; however, recently
several studies imply changes in the composition of membrane lipids
in nerve tissue of affected individuals and vitamin D status may be
important.

6.1.5.1.1 Epidemiological investigations In autistics, several clinical
signs such as excessive thirst (polydipsia), frequent urine production
(polyuria), dullness, and dry and breaking dander have alerted about a
possible deficiency in essential fatty acids. The first report of a small con-
centration of DHA and EPA in the red blood cells of two subjects with aut-
ism, compared to two healthy subjects, was done in 2000 (Bell et al. 2000).
In addition, two subjects with Asperger’s syndrome were not different
from controls. In studies on the composition of plasma phospholipids,
similar results have been described (Vancassel et al. 2001). Few publica-
tions appeared in the following 10 years, but in 2010, specific work by the
team of Dr. J. G. Bell, University of Stirling, UK, showed that in 45 autistic
children the changes of the fatty acid composition of red blood cells and
plasma indicated an unbalance in the essential fatty acids at the expense
of ω-3 fatty acids (Bell et al. 2010).
In all cases, the part played by the diet, in addition to other intrinsic
metabolic factors, was the object of very little research. A recent Spanish
study performed on 105 children with autism has however reported that
patients had a lower dietary intake of ω-3 fatty acids, compared to typi-
cally developing children (Marí-Bauset et al. 2015). Some authors have for-
mulated the assumption that the frequently found low levels of ω-3 fatty
acids could be related to a slowdown of maternal metabolism, when preg-

nancy occurred in old age or in multiple pregnancies. Prematurity was
also cited as a possible cause of autism, given the late fetal accumulation
of polyunsaturated fatty acids. The role of the maternal intake of essential
fatty acids through breastfeeding seems to be involved if we consider the
results obtained by the team of the American neurologist A. Ascherio,
Harvard University, Boston, Massachusetts (Lyall et al. 2013). This epide-
miological study, one among the most comprehensive, has shown in
fact that in a group of more than 17,700 pregnant women, those with
the lowest dietary intake of ω-3 fatty acids had an increased risk of giving
birth to autistic children. The same was observed in pregnant women
with a very low linoleic acid intake, the major ω-6 fatty acid in the Western
diet.
6.1.5.1.2 Intervention studies In children with autism, several

attempts have been made to discover the curative effects of a ω-fatty acid
supplementation. The trials are few and often conducted on small groups
of individuals of very different ages, likely explaining the variability of
results. Thus, in 2007, improvements in stereotyped behavior and hyper-
activity were obtained by G. P. Amminger, Austria, in supplementing
some boys daily for 6 weeks with 0.7 g of DHA and 0.8 g of EPA (Amminger
et al. 2007). With similar treatments, several research teams have also
observed significant improvements in behavior related to the disease, but
concerning only a part of the explored children.
Moreover, it seems that the benefits of a ω-3 fatty acid supplementa-
tion are no longer observed after a certain age, because no effect could
be detected in autistic subjects beyond 18 years.
If the previously reported work gave some hope for an autism treat-
ment with nutritional supplementation, it must be recognized that until
2010 the review of literature did not allow any definitive conclusions on
the subject. Some studies detected no significant effect except a slight
decrease in hyperactivity in subjects treated with a mixture of EPA and
DHA (Bent et al. 2011).
Hope can still be considered since the publication in 2012 of the results
concerning an interesting Japanese experiment (Yui et al. 2012). The
authors supplemented children who were suffering from Asperger’s syn-
drome daily for 16 weeks with a mixture of arachidonic acid (240 mg) and
DHA (240 mg). Although the size of the experimented groups was small
(seven treated and six placebo), the results clearly showed that the essen-
tial fatty acid supplementation significantly improved the social interac-
tions of the young patients.
Similar results were reported by a Singapore team in 41 young children
with “disorders of the autism spectrum” supplemented each day for 12 weeks
with 1 g of ω-3 fatty acids (192 mg of EPA and 840 mg of DHA) and
arachidonic acid (66 mg) (Ooi et al. 2015). The study of the neuropsychological
results by the experts and the opinions of parents revealed an improvement of
the scores for awakening, recognition, communication, motivation, and
attention. Unfortunately, the authors did not identify with precision the type
of autism disorders from which the children were suffering.
These types of studies need to be extended to broader groups that are
clinically well defined and as homogeneous as possible (age, sex).
In 2016, two large trials in this area were declared in the WHO Inter-
national Clinical Trials register (http://apps.who.int/trialsearch/), and
eight completed studies are reported on the US site (http://www.
clinicaltrials.gov).
In the treatment of autism, as of Asperger’s syndrome, research should be bet-

ter controlled, especially done during longer periods and with more subjects.
It is premature to talk about final recommendations on the role of ω-3 fatty
acids, and perhaps ω-6 fatty acids. However, it seems important that from
the diagnosis of the disease the intake of these nutrients complies in the young
patients with standard values set by medical authorities (Section 7.2).
6.1.5.2 Vitamin D
6.1.5.2.1 Epidemiological investigations The effect of the environment
on the development of autism was considered soon after epidemiologists
noticed a significant prevalence increase in a homogeneous and relatively
large population. In several countries, the prevalence of autism was stable
until 1980, but then it steadily increased. These changes have been well
described around Gothenburg in Sweden where the prevalence was 4 per
10,000 inhabitants in 1980 and 11.5 in 1988, with the increase being globally
estimated at about 3.8% per year (Gilberg and Wing 1999). In England, in a
population residing south of the Thames, a prevalence of 39 per 10,000 people
was observed in 2006, whereas it was only the half 5 years ago in the same
region (Baird et al. 2006).
Many hypotheses have been advanced to explain these worrying
observations. They usually involved special exposures of pregnant
women to environmental factors that could alter the genetic susceptibility
for autism (London 2000). The nature of these factors remained obscure
until 2008 when Dr. J. J. Cannell showed that the main cause could be a
vitamin D deficiency in pregnant women, in very young children, or both
(Cannell 2008).
This suggestion based on various clinical outcomes prompted several
research teams to explore in detail the vitamin D status in autistic subjects.
A review has reported the results of three investigations conducted in
Egypt, United States, and Sweden, with the latter showing clearly that
vitamin D deficiency is very common in patients with autism (Kocovska
et al. 2012). The study in Sweden on Somali women with children having
autism also confirmed that their blood vitamin D level was 30% lower
than that of women who had no autistic children, with the sampling being
made in the spring, a time corresponding to the lowest vitamin D intakes
(Fernell et al. 2010). The same author has recently studied the vitamin D
status in 58 siblings of varied ethnic backgrounds, with one child of each
suffering from spectrum autism disorder (Fernell et al. 2015). Comparing
siblings, it seemed that all the sick children had a blood vitamin D level
lower than that of healthy children.
It is remarkable that the dietary intake of vitamin D was regularly
considered insufficient in children with autism, probably resulting from
a selective behavior toward food (Kocovska et al. 2012). This finding is
important because it is well known that autistic children are reluctant to
go outdoors, thereby reducing the possibility of skin vitamin biosynthesis.
Another interesting situation is that of social groups with low income
explored in the United States (Shamberger 2011). Indeed, this study
showed that in states where an exclusive breastfeeding of infants was
practiced, the prevalence of autism was the highest. Therefore, this obser-
vation proves the need for a supplementation in lactating mothers, espe-
cially in cases where a vitamin D deficiency was demonstrated.
In connection with the importance of the natural biosynthesis of
vitamin D by the skin, a recent review has collected all studies describing
in Nordic countries an increased autism risk among dark skin or veiled
women (Dealberto 2011). All the results are in favor of the hypothesis of
a close association between a maternal vitamin D deficiency and a risk
of autism in unborn children. Moreover, the author emphasized the
importance of monitoring the vitamin D status in pregnant women, espe-
cially among dark skin or veiled immigrants. The problem was expanded
through a large survey in the United States made by Dr. W. B. Grant, an
expert in this field at the University of San Francisco, California (Grant
and Cannell 2013). This author has found that the prevalence of autism
disease in children aged 6–17 years was inversely related to the winter-
time solar ultraviolet B radiation in various US states, as well as for people
with white or black skin.
As for multiple sclerosis (Section 5.2.2), epilepsy (Section 5.3.2), and
schizophrenia (Section 6.1.3.2), the prevalence of autism in a population
seems to be influenced by the month of birth of patients. That effect is
further evidence of a relationship with the capacity of the skin to synthe-
size vitamin D under the influence of solar radiation. Thus, after analyzing
a large number of publications from 11 countries, Dr. W. B. Grant noticed
that the period corresponding to the birth of a higher proportion of chil-
dren with autism is the spring or the summer for middle latitudes and
the winter for high latitudes, with these observations corresponding to

gestation periods with a minimum of sunshine (Grant and Soles 2009).
This effect was found again by the study of Dr. E. Fernell, but only among
those born in Sweden or other countries, with the exception of countries in
Africa and the Middle East (Fernell et al. 2015). These findings reinforce
the hypothesis of the autism development linked to vitamin D deficiency,
specifically to its seasonal variations.
In addition, the prevalence of the disease increases with the latitude of
the place of patient birth, with that place conditioning consequently the
time to sun exposure of subjects and therefore the amplitude of the seaso-
nal variations of the blood vitamin D level. In France, despite a substantial
sunshine, this amplitude is important and is not hidden by low dietary
vitamin D intakes. As in many European countries, it is possible to con-
clude that as a result of the scarcity of foods fortified with vitamin D
and supplied to consumers, the observed deficiency state arises as a con-
sequence of a lack of political will to encourage a supplementation prac-
tice (Ovesen et al. 2003).
The beneficial effects of vitamin D on autism-related disorders are
probably due, as for other neurological or psychiatric disorders, to its
interaction with dopaminergic and serotoninergic systems in particular,
all associated with behavior disturbances (Patrick and Ames 2015).
6.1.5.2.2 Intervention studies What is known about the options of

autism treatment with vitamin D? One recently published trial fills the
gap. An Egyptian team has reported that the administration of vitamin D
(300 IU/kg/day) for 3 months to autistic children deficient in vitamin D
significantly improved disorders in about 80% of subjects (Saad et al. 2016).
At the end of treatment, the blood vitamin D levels had recovered an accep-
table level in all subjects who received the treatment.
Up to now, only one team in Portland, Oregon, had reported promis-
ing results concerning a preventive treatment during pregnancy and early
childhood (Stubbs et al. 2016). The study was performed prescribing
vitamin D at a dose of 5000 IU/day during pregnancy to 20 mothers hav-
ing already children with autism. The newborn siblings, at high risk for
the recurrence of autism, were also prescribed vitamin D (1000 IU/day
to the age of 3 years) and followed for 3 years. The final outcome was
5% developed autism in contrast to the recurrence rate of about 20% in
the literature for that children population. Notably, this is the first pro-
spective study of the hypothesis of using vitamin D in an attempt to pre-
vent the recurrence of autism in a high-risk group of newborn siblings.
Although difficult to conduct, more research with larger numbers and a
control group are necessary to enable precise recommendations.
A literature review has recently identified a large number of observa-
tional studies, but very few intervention trials, investigating the
relationships between vitamin D and autism (Mazahery et al. 2016). The

authors concluded that despite inconsistent results, there are clear indica-
tions that early exposure to inadequate vitamin D may contribute to the
etiology of autism. Thus, vitamin D deficiency is highly prevalent in popu-
lations with autism, and intervention with vitamin D might be beneficial
in reducing the symptoms. Therefore, there is an urgent need for rando-
mized controlled trials of vitamin D in populations genetically predis-
posed to autism as well as in adults suffering from the disease.
It is to be hoped that the increasingly common practice of vitamin D
supplementation in lactating women and newborns, combined with a
recommendation of extended breastfeeding, will help to decrease autism
prevalence in the population. In 2016, four studies evaluating the effect
of vitamin D on clinical outcome in autistic children were reported recruit-
ing or completed on the US site (http://www.clinicaltrials.gov), and two
studies were declared on the WHO International Register of clinical trials
(http://apps.who.int/trialsearch/).
Parents are strongly recommended to encourage their children participate

in outdoor activities to obtain the maximum benefit of skin synthesis of
vitamin D, while avoiding excessive sun exposure. For many authors,
the observed increase in recent years of the number of subjects with autism
in all countries is due to a change in children's lifestyles, with decreased
sunshine exposure following the increase of activities practiced indoors (tel-
evision, computers). In addition, it is imperative to recommend pregnant
women to monitor their blood vitamin D levels to reduce the risk of devel-
oping autism in their children. These children should also benefit if neces-
sary from a prolonged vitamin D supplementation.
6.2 Other personality and behavior disorders

It is accepted that subjects with attention-deficit disorder may have also,
sooner or later, behavioral problems characterized by impulsiveness often
accompanied by aggression and violence (“conduct disorder”). The sub-
jects do not recognize the rights of others; their communication is
restricted to physical or verbal aggression and often the subjects become
cruel and destructive, or perform acts of thievery. In young children,
when these disorders appear, they are socially disruptive and may persist
among adults who become predisposed to injure others (homicide and
imprisonment) or themselves (suicide attempts).
The estimate of the extent of personality and behavior disorders
described in this chapter is most often performed using a scale called
Hopkins Symptom Checklist 90 (SCL-90) (Derogatis et al. 1973). The test
as a questionnaire is designed primarily to assess in patients over 13 years

various psychological and psychiatric problems during pharmacological
treatments. It comprises 90 questions, rated 0 or 1, divided into nine themes:
somatization, obsessive–compulsive disorder, interpersonal sensitivity,
depression, anxiety, hostility, phobia, paranoid ideation, and psychoticism.
The sum of the scores for each theme gives a graph enabling to establish a
personal profile and to follow its evolution throughout treatment.
Another very commonly used scale, Brown-Goodwin Assessment
(BGA), was established in 1979 to help military enrollment (Brown et al.
1979). The scale is established by a professional on the basis of a direct
interview of candidates or patients. Eleven themes are analyzed and rated
from 0 to 4 according to the seriousness of the facts. These themes are
anger, fight, aggression, behavior at school, civic discipline, antisocial
behavior without intervention of police, antisocial behavior with police
intervention, military discipline, military discipline with judicial system,
damage to objects, and verbal aggression.
6.2.1 Aggressive behavior

Psychologists explain aggression as a desire for domination with malice
leading to ensure the subject that his or her own power will be recog-
nized and that could drift toward sadism. Psychiatrists propose to find
at the base a concept of frustration, a theory of Freudian inspiration,
but the reality of a socially learned behavior cannot be eliminated. There
is nothing to oppose these two theories. Aggressive behavior may be
characterized by verbal attacks, physical attacks, or both. Aggressiveness
generates most often a violence that, in children as in adults, may start
with intimidation and harassment and then progress to more serious
forms such as theft, sexual assault, hold-up, and even murder. In adults,
it is now considered that an aggression that does not meet a real threat is
a sign of mental disorder, a comorbidity accompanying frequently schi-
zophrenia or alcoholism.
Psychologists have established that aggression stems from a form of
rejection of other people and also of oneself and of refusal to accept rea-
lity. The hostility facing others remains complex to understand because it
manifests variously; therefore, its assessment requires several psychologi-
cal tests adapted to the specific conditions of each country (Section 7.12).
For about 30 years, much research in this field has highlighted several
biological factors related to impulsiveness and violent behaviors. Among
these determinants, clinicians have found that abnormally low levels of a
serotonin derivative, 5-hydroxyindoleacetic acid, were present in violent
military (Brown et al. 1979), impulsive criminals (Linnolila et al. 1983),
and even arsonists (Virkkunen et al. 1987a). Similar results were obtained
from persons categorized as violent and with suicidal behavior (Asberg

et al. 1976).
Following this research, investigations were extended to lipids influen-
cing likely brain functions by disrupting serotonin metabolism. Among
these lipids, ω-3 fatty acids (Section 6.2.1.1) and vitamin D (Section 6.2.1.2),
already involved in various other neuropsychological disorders, have been
the subject of most research efforts. Cholesterol also has been investigated
regarding violence (Section 6.2.1.3).

It is accepted in everyday life by the medical profession that an angry or
hostile behavior greatly increases the risk of developing heart troubles that
can be fatal. Conversely, a treatment leading to reduce hostility tends to
limit the risks of heart attack (cardiac ischemia) (Williams and Littman
1996). With the established relationships between ω-3 fatty acids and car-
diovascular diseases (Leray 2015), it seems obvious to explore whether
these dietary lipids may also improve impulsivity and the hostility state
even without any cardiovascular impairment.
6.2.1.1.1 Epidemiological investigations Early research in this area

has demonstrated the presence of very low levels of plasma ω-3 fatty acids
in violent and impulsive individuals. Dr. M. E. Virkkunen, University of
Helsinki, Finland, was the first to show that usually violent men and crim-
inals (murderers, arsonists) had very low blood levels of ω-3 fatty acids,
mainly DHA, whereas ω-6 fatty acids were more concentrated than in nor-
mal subjects (Virkkunen et al. 1987b). So, an impaired blood composition
focusing on essential fatty acids is revealed because it has been reported in
subjects with ADHD (Section 6.1.4.1). This similarity demonstrates the
existing relationships between attention-deficit disorder with hyperactivity
and behavior troubles oriented toward aggression, with the latter likely
belonging to ADHD-associated disorders. Indeed, we know that among
these associated impairments, oppositional disorder with provocation
and conduct disorder with aggressiveness may be present in 25%–66%
of cases, especially if the ADHD treatment was late (Szatmari et al. 1989).
These biological characteristics were found also in young violent
offenders (Corrigan et al. 1994) and among boys aged 6–12 years, regu-
larly angry with sleep and learning problems (Stevens et al. 1996).
Low levels of ω-3 and even some ω-6 fatty acids have also been observed
in the blood of regular cocaine consumers with aggressive behavior
(Buydens-Branchey et al. 2003a). More recently, it has been shown that
the plasma EPA concentration was the biochemical indicator the most
highly correlated (negatively) with aggression and impulsivity in young
subjects, but only in addicts to alcohol, cannabis, or cocaine, even if in
remission (Beier et al. 2014). This relationship was found to not originate
from an inadequate EPA dietary intake.
The knowledge of the relationships between the ω-3 fatty acid status and
drug addiction is just getting started. Indeed, experiments in animals have
emphasized the role of these lipids in the abuse of some substances control-
ling serotonergic and dopaminergic systems. The first exploration of that
complex problem was reported in 2003 by Dr. J. R. Hibbeln, an American
expert on these issues. He showed in 32 patients consuming cocaine that
the lower the plasma level of the ω-3 (and ω-6) fatty acids, the more elevated
was the risk of relapse in the short term (Buydens-Branchey et al. 2003b). The
authors insisted that low levels of these fatty acids at the beginning of
the treatment were the best predictor of a future relapse. Unfortunately, no
direct causal link has been discovered between the consumption of seafood
(fish, mollusc, shellfish) and drug use, such as cannabis or cocaine. It is
amazing that no large-scale clinical study has been undertaken on this
subject, especially because this hypothesis was also raised for smoking
(Zaparoli and Galduróz 2012) and alcoholism (Le-Niculescu et al. 2011).
It is obviously desirable that research should be a starting point for
explorations extended in all addiction areas. Moreover, potential treat-
ments with essential fatty acids are known to be well tolerated and inex-
pensive, in contrast with the expenses currently incurred in the fight
against these behavioral disorders.
To explore the involvement of neurotransmitters and fatty acids in the
brain function, Dr. J. R. Hibbeln studied men guilty of domestic violence
(Hibbeln et al. 2004b). He demonstrated an inverse relationship between
plasma DHA levels and the concentrations of corticotropin-releasing fac-
tor, an hypothalamic hormone known to be involved in the responses to
stress as violent and defensive behaviors.
Because there could be interference of ω-6 fatty acids in the physiolo-
gical process underlying an aggressive behavior, a cooperative study of
Australian researchers recently published the values of the “ω-3 index”
(Section 7.1) of red blood cells measured in 136 adult prisoners with
aggression troubles and attention deficit (Meyer et al. 2015). The results
have shown that all the scores on the parameters defining the subject
behavior were negatively correlated with the ω-3 index values. Despite
great variability, it is clear from that study than those having the lowest
ω-3 index were the most aggressive and had the most severe attention dis-
orders. The interest of this work is to have taken into account the ω-6 fatty
acid levels, knowing that their abundance in the tissue influences the ω-3
fatty acid requirements.
Further research was conducted by Dr. A. Zaalberg, Altrecht Institute
of Psychiatry, Den Dolder, The Netherlands, on 51patients interned after
physical aggression (Zaalberg 2015). The fatty acid composition of red
blood cells was determined, and neuropsychological tests were performed
to estimate the intensity of the psychopathological symptoms by using the

General Health Questionnaire (GHQ-28) (Pariente and Smith 1990) and
especially aggressiveness by using the Social Dysfunction and Aggression
Scale (SDAS) and the Aggression questionnaire (Meesters et al. 1996)
(Section 7.12). The authors reached the conclusion that there was a close
association between DHA levels and total ω-3 fatty acid concentrations,
the ω-3 index, and aggressiveness (Figure 6.2). Besides the small amounts
of ω-3 fatty acids, the authors also measured very low vitamin D levels,
at least for the majority of the subjects studied. Among the 51 subjects,
32 had insufficient concentrations and only 8 had values above the
national standard (28.5 ng/mL [75 nmol/L]). However, no correlation
could be detected between vitamin D levels and the intensity of aggressive
events.
That rigorous work combining fatty acids and vitamin D underlines
the need to take into account several biochemical parameters in biological
samples. Obviously, the characterization of the effects strictly related to a
specific substance could be established only with the help of supplemen-
tation experiments, with any synergy between several substances being
obviously not ruled out.
A confirmation of the involvement of ω-3 fatty acids in human aggres-
sive behavior may also be obtained by exploring among populations, or in
a given population, a possible association between these behavioral disor-
ders and fish consumption, the main source of ω-3 fatty acids.
The first major “ecological” study of the relationships between fish
consumption and mortality by homicide (not suicide) in 26 countries
was reported by J. R. Hilbbeln in 2000 at the 4th Congress of the
50
40
SDAS test scores
30
20
10
2 3 4 5 6 7 8
Omega-3 index
Figure 6.2 Relationship between SDAS scores and ω-3 index. (From Zaalberg, A.,
Nutrition, neurotoxicants & aggressive behaviour, PhD Diss., Nijmegen, 2015.)
International Society for the Study of Fatty Acids and Lipids (Hibbeln
2001). Although estimating the number of homicides is an expression of
violence in extreme situations, it remains a simple and precise method.
The author noted for the year 1995 homicide rates in the WHO statistics
and fish consumption in those of FAO. He dismissed the United States
from his list of countries because at that time the homicide rate was very
high (20 per 10,000), likely influenced by the ease of buying arms and by
the violence displayed in media. Taking into account the extreme values,
the homicide rates between countries ranged from nearly 10 times and fish
consumption about 15 times. Hibbeln has determined a decreasing loga-
rithmic relationship highly significant between these two parameters.
Furthermore, he estimated that below a consumption threshold of 10–20
kg of fish per year, the homicide rate increased very quickly. That correla-
tion is therefore consistent with the previous results based on blood bio-
chemical parameters. That communication was released to the media
(New York Times) 5 years later (April 16, 2006) as an article titled, “Does
eating salmon lowers the murder rate?” It was widely discussed in the
US media and perhaps it contributed to the awareness of the population
focusing on the interest of increasing the consumption of seafood pro-
ducts, while decreasing that of oils and any product rich in ω-6 fatty acids.
This hypothesis was also ascertained 3 years later by J. R. Hibbeln by
using statistics from five countries. These recommendations may be also
delivered to the French population because all official surveys have shown
that ω-3 fatty acid intakes are largely insufficient because they represent
only one half of the dietary reference intakes advised by medical authori-
ties (Leray 2015).
Following these first quite spectacular results that were well reflected in
the media, several epidemiological studies attempted to explore more
broadly the association between dietary intake of ω-3 fatty acids and violent
behaviors. A great survey was conducted in the United States with 3581
individuals of both sexes enrolled in three cities (Birmingham, Chicago,
and Minneapolis), within the context of the CARDIA study (Iribarren et al.
2004). Analysis of the fish consumption and the estimation of the hostile
behavior of subjects aged 18–30 years showed a highly significant relation-
ship between an increase in DHA intake and a decrease in the violence level.
Although the authors could not perform blood tests, the results strengthened
the hypothesis of a reduced hostility in individuals consuming relatively high
amounts of marine fish.
6.2.1.1.2 Intervention studies Naturally, all these studies are not a

definitive proof of a beneficial effect on hostile behavior exclusively due
to a diet rich in marine fish; indeed, the study of ω-3 fatty acid supplemen-
tations is the most effective way to clarify and deepen the subject.
The first experimental study was done in Japan with 41 students for a
period of 3 months before a stressful exam (Hamazaki et al. 1996). It
turned out that students ingesting daily 3 g of fish oil (1.5 g of DHA
and 0.2 g of EPA) maintained a stable behavior throughout the trial,
whereas control subjects ingesting soybean oil became much more hostile
at the end of the study. Later, the author was able to confirm that a similar
treatment was also effective in employees of approximately 50 years old
subjected to stressful situations such as videos of real crimes and accidents
caused by guilty negligence (Hamazaki et al. 2001).
Obviously, we have to be careful before drawing general and final con-
clusions because these studies have shown that the education level could
also influence the results; thus, a higher education level would induce more
significant answers after ingesting DHA.
With this experiment, one can measure the interest of a natural pre-
ventive treatment with fish oil during stress periods, such as those experi-
enced before competition or examination. By this means, the decrease in
aggressiveness, therefore anxiety, can be surely a pleasant training for
psychologically difficult periods, certainly more efficient than many usually
used pharmacological treatments.
In 2008, Prof. T. Hamazaki, University of Toyama, Japan, has reviewed
several previous work related to the influence of ω-3 fatty acids on various
manifestations of aggression (opposition, violence, anger, and aggression)
or its opposite friendliness (Hamazaki and Hamazaki 2008). Of the 14 listed
studies, 13 confirmed to varying degrees the outcomes set out above, with
only one reporting no modification.
Children have been also the target of this research theme, probably
due to the finding of increasing adaptation difficulties with manifestations
of violence, both in society and in academics. It must be noticed that the
reason for aggressive behaviors is the cause of almost half of the pediatric
psychiatry consultations. These troubles result in learning difficulties that
naturally lead to employment problems, social isolation, violence, and
even crime or suicide.
Physiologically, the period of adolescence is one of the times when the
prefrontal cortex undergoes maturation involving a growth of neuronal
dendrites and an increase in the white matter volume. Furthermore, the
executive functions involving attention, emotion, and impulse control
are localized in the prefrontal brain area.
It can be considered that the study done by Dr. M. Itomura, Toyama
Medical University, Japan, is the first attempt to highlight a reduction in
aggressive behavior in young children between 9 and 12 years old (Itomura
et al. 2005). In this work, a group of 90 children were fed for 3 months with
food (bread, sausage, pasta) supplemented with fish oil so as to provide a
daily intake of 0.51 g of DHA and 0.12 g of EPA; the control group was sup-
plemented with vegetable oil. The author reported beneficial results for
impulsiveness, but only in young girls. However, the test results were not
correlated with the concentrations of blood ω-3 fatty acids. Unfortunately,
the difference in response between boys and girls still remains inexplicable,
but it reminds us to remain wary of results according to sex in studies on
the lipid effects.
In the United States, a similar study at The University of
Pennsylvania, Philadelphia, on children from 8 to 16 years old reached
positive conclusions, but for both sexes (Raine et al. 2015). The origin of
that difference lies likely in a greater treatment time (6 months instead
of 3months) and a more important ω-3 fatty acid intake (1 g instead of
0.6 g/day). The author reported that the beneficial effect on behavior
was maintained 6 months after the end of treatment.
A recent study conducted in Australia (Mater Health Services,
South Brisbane) investigated the effect of a daily supplementation of
4 g of fish oil in children 7–14 years old, selected for their particularly
aggressive behavior. Despite the use of many neuropsychological tests,
this study failed to highlight a behavior change after 6 weeks, except for
a decrease of hyperactivity (Dean et al. 2014). As the author suggested,
the treatment time may have been too short for obtaining significant
results.
In young adults in good health and without aggressive behavior, a daily
supplementation for 12 weeks with fish oil (672 mg of DHA and 100 mg
of EPA) decreased impulsivity and aggressiveness, both measured using a
battery of specific neuropsychological tests (Long and Benton 2013).
Prison seems to be the ideal environment to highlight a possible effect
of dietary lipids on antisocial behavior and violence. Two trials were
undertaken and provided substantially similar results. The first experience
of supplementation with ω-3 and ω-6 fatty acids performed as a double-
blind against control trial was undertaken in an English prison to reduce
disciplinary incidents (Gesch et al. 2002). The test subjects ingested a cap-
sule containing 80 mg of EPA, 44 mg of DHA, and 1.4 g of ω-6 fatty acids
daily, with the control subjects ingesting a capsule containing only vege-
table oil. All received a multivitamin capsule. The authors determined that
disciplinary complaints (especially for serious incidents) were reduced by
35.1% after 2 weeks and 26.3% after a 5-month treatment, thus seeming to
validate the effect of the fatty acid supplementation on the antisocial beha-
vior of incarcerated subjects.
A very similar test was done in The Netherlands on 220 prisoners with
the mean age being 21 years (Zaalberg et al. 2010). The daily double-blind
supplementation in half of inmates randomly selected consisted mainly of
0.4 g of EPA and 0.4 g of DHA together with 0.6 g of linoleic acid and
0.1 g of γ-linolenic acid; the other half of the subjects received a placebo.
The authors have found a significant decrease of incidents between incar-
cerated subjects and the prison institutional staff, even neglecting the
incidents under the influence of alcohol or illegal drugs. In contrast, neurop-

sychological tests did not reveal any difference between the placebo and the
test group. These results are surprising, but they suggest that it would be
necessary to extend these trials to different categories of supervised offen-
ders to improve at little extra expense their living conditions and those of
prison staff.
From these studies, it is unfortunately difficult to attribute the profit of
treatments only to ω-3 fatty acids because the used preparations contained
also ω-6 fatty acids, vitamins, and other trace elements. It is possible that
the restoration of other biological parameters were involved in the EPA
and DHA effects. In addition, the groups of subjects studied had some-
times more or less defined disorders.
It seems desirable that psychiatric clinics, as prisons, could be the
place for experimentation involved in improving the welfare of detained
patients or inmates and possibly decreasing the aggression toward others
or themselves. Unfortunately, no establishment has currently embarked
on this path. Clinical trials should also be programmed to test the indivi-
dual effects of EPA or DHA at various doses and independently of other
substances. The possible profits of these inexpensive tests could lead
rapidly to an important economic and social progress.
It seems increasingly clear that research on human behavior can-
not be carried out like those on drugs used to fight, as an example,
against hypertension. One or even several biological indicators may
not be enough, but owing to animal studies several ways involving
fish oil in regulating human aggression are clearly emerging. As with
cardiovascular diseases or cancers, the data already acquired allow to
hypothesize that many cases of violence are caused by the excessive
dietary importance of vegetable oils rich in linoleic acid. It is therefore
necessary that the relationships between dietary lipids and the aggres-
sion mechanisms could be quickly identified. Thus, clinicians will be
able to propose simple preventive treatments against violent beha-
viors that are affecting our societies in remaining a heavy financial
burden for all countries. As mentioned by Dr. J. R. Hibbeln, could it be
wise to return to millennia practices of Christian churches and Chinese
sages who very early associated fish with calm and peaceful beha-
viors? (Hibbeln 2007).
In 2016, only six trials in this area were declared in the United States
(http://www.clinicaltrials.gov).
6.2.1.2 Vitamin D
The relationships between vitamin D and aggressive behavior have been
very rarely explored. This temporary statement is not comprehensible if one
recalls many results proving an unequivocal association between vitamin D
and often-violent situations such as schizophrenia (Section 6.1.3.2) and

attention-deficit disorder with hyperactivity (Section 6.1.4.2).
A recent work reported earlier about ω-3 fatty acid effect (Sec-
tion 6.2.1.1) has also shown that in 51 patients interned as a result of phy-
sical attacks, 32 had insufficient vitamin D levels, whereas only eight had
levels above the national standard (Zaalberg 2015). However, no correla-
tion has been found between vitamin D levels and the intensity of aggres-
sive behavior as measured by several neuropsychological tests. A similar
vitamin D status has been also reported for long-term inmates in Phoenix,
Arizona, where 90% of the correctional population had serum vitamin D
levels lower than 20 ng/mL (Jacobs and Mullany 2015).
An attempt to explore this type of neuropsychological relationships was
made when studying a population of 1095 Iranian teenagers (Ataie-Jafari
et al. 2015). The authors have detected that 40% of subjects were vitamin D
deficient (concentration <10 ng/mL), 39% were insufficient (concentration
between 10 and 30 ng/mL), and only 21% had normal values (concentration
>30 ng/mL). The clues of psychiatric distress (anger, anxiety, insomnia, fear,
and depression) were closely related to the serum vitamin concentrations.
The intensity of disorders was almost twice as elevated in deficient subjects
compared with those who were not deficient. However, the violent beha-
viors were not influenced by the vitamin D status. Note that the assessment
of violence was established in using only individual self-reported state-
ments on the frequency of physical assaults and several psychiatric dis-
tress situations. The large number of subjects interviewed for that research
cannot compensate for the simplicity of the retained tests. Unfortunately,
no data on dietary or circulating essential fatty acids have been produced.
It is hoped that further studies will explore this area of violence not
well known in prison by using blood analysis of vitamin D and also of
ω-3 fatty acids, with the latter being already widely suspected to influence
the generation of violent behaviors. Supplementation trials should update
these investigations to restore if necessary appropriate lipid intakes, an
unavoidable action facilitated by standardized diets and adequate sun
exposure.
To date, no clinical trial concerning this specific area has been declared
in the international registers.
It is obviously premature to conclude that there is a causal link between

psychiatric distress and vitamin D, but the analysis of social data allow
to consider a possible influence of the diet, as for sun exposure. In the cur-
rent state of knowledge and medical practice, the authors of all work in that
field may recommend only a better control of vitamin D deficiency mainly
in adolescents.
6.2.1.3 Cholesterol
6.2.1.3.1 Epidemiological investigations Several early work sug-
gested that a low blood cholesterol concentration could be associated with
a decreased incidence of cardiovascular diseases, but also with the pre-
sence of violent behavior often followed by death.
In 1979, the psychiatrist specialist of these questions Dr. M. Virkkunen,
Helsinki University, Finland, showed that subjects with antisocial beha-
viors had usually low cholesterol levels. Later, he explained that among
adolescents with attention deficit and hyperactivity disorders, those with
an aggressive behavior had lower cholesterol levels than other children
(Virkkunen and Penttinen 1984).
The problem therefore seems complex and shows that several nutri-
tional or environmental factors may interfere with neuropsychological
parameters. A clarification of behavioral parameters seems also necessary
because different types of hostility have been linked or not with serum
cholesterol (Hillbrand et al. 1995).
To illustrate this field, the recent publication by the team of Prof.
M. Virkkunen (Repo-Tiihonen et al. 2002) brings some answers. That work
demonstrated that in a group of 250 criminal offenders, the subjects with
a cholesterolemia below the median value and classified as violent (guilty
of armed robbery or murder) were seven times more likely to die before
the median age of death in the cohort studied. In contrast, those classified
nonviolent (arsonists, thieves, fraudsters, and drunken drivers) had a risk
to die of unnatural causes eight times higher than other criminals. The
mean total cholesterol level of these offenders with antisocial personality
disorders was lower than that of the general Finnish male population.
Considering the social history of offenders, the authors hypothesized that
the circulating cholesterol could be a biological marker in children with
antisocial behaviors, with a prognosis value for a further development
of criminal behavior.
It would be interesting to establish the possible influence on this type
of behavior for the past 20 years of the replacement of cholesterol-rich
breast milk by cholesterol-poor infant formula (containing only vegetable
lipids). That progressive change in infant feeding might be able to influ-
ence the cholesterol status in adolescents and even adults (Horta and
Victora 2013).
A large health study was done in Sweden comparing the police records
and blood cholesterol levels in 100 criminals among nearly 80,000 people
followed for about 30 years. That survey has thus shown that when cho-
lesterolemia decreased, the proportion of criminals in the population
increased (Golomb et al. 2000). So, for a cholesterolemia between 2.51
and 2.79 g/L, there was 0.85 violent criminal per 1000 individuals; from
2.26 to 2.50 g/L, the ratio became 1.55 and below 2.26 g/L it reached 2.0.
The authors emphasized that there was no significant causal link

between cholesterol and violence, but they noted that cholesterolemia
was determined long before the appearance of criminal offenses. It must
be recalled that these cholesterol levels are well above the currently
recommended levels (1.50–2.00 g/L). Among patients with schizophrenia,
no significant relationship could be detected between cholesterol and
violence (Steinert et al. 1999).
The study of populations in good mental health may also help to
detect the possible predispositions to violence for a precise range of cho-
lesterolemia (Pozzi et al. 2003). This has been done with a large survey
of more than 2000 Italian young men aged 19–31 years. That study
revealed an association between cholesterol and impulsivity, although less
obvious than in subjects suffering from psychiatric disorders but still
verifiable in individuals with the lowest cholesterol levels (<1.40 g/L).
6.2.1.3.2 Intervention studies Intervention studies are infrequent

and difficult to interpret. During a long-term trial, 149 people were selected
in a normal population and were subjected to a new diet with less lipids but
rich in complex carbohydrates to improve their cholesterol levels (Weidner
et al. 1992). After a 5-year treatment, the authors found low blood cholesterol
levels accompanied by an improvement of the emotional state and a
decrease of the subject aggressiveness. Note that before intervention, they
did not suffer from psychiatric diseases and that no blood sampling or
nutritional survey had been carried out. It seems therefore prudent to elim-
inate any influence of cholesterol during important dietary changes that
could alter other biochemical indicators. Thus, in the absence of direct sup-
plementation with cholesterol, ethically impossible to perform, it seems dif-
ficult to conclude that cholesterol plays a role in aggressiveness with only
the help of epidemiological studies.
To reduce the incidence of cardiovascular diseases, the increasing use
of statins to fight against elevated cholesterol levels has prompted clini-
cians to search for the possible influence of these drugs on all causes of
mortality. Could this type of pharmacological intervention help us in
understanding that complex problem?
In 1990, Prof. M. F. Muldoon, University of Pittsburgh, Pennsylvania,
showed that a cholesterol-lowering diet or a statin treatment decreased, as
expected, the mortality from acute myocardial infarction (−15%) but
increased the nonillness mortality (accidents, violence, and suicide) (Mul-
doon et al. 1990). Ten years later, the same author realized an analytical
review of 19 similar studies and found a lack of relationship between
reducing cholesterol and nonillness mortality. Nevertheless, a trend
toward increased deaths from violence (and suicide) was observed in trials
of dietary interventions and nonstatin drugs (Muldoon et al. 2001). Despite
some reservations, these results suggest an association between the
circulating cholesterol concentration and certain behavioral predispositions

oriented to violence and followed by accidents. Similar conclusions were
obtained from cholesterol supplementation experiments in Cynomolgus
monkeys (Kaplan et al. 1996).
Much work is still required before clear links between cholesterol and
aggressiveness can be established. Thus, it seems unavoidable now to pay
attention to dietary essential fatty acids or vitamin D. Yet, it seems very
important to determine the minimum threshold of blood cholesterol to
avoid any impact on social behavior. Such research should help to reas-
sure people who raise questions on the merits of the anticholesterol treat-
ments based mainly on statins.
As with other neuropsychological disorders, the development of
aggressive behavior under the assumed effect of low cholesterol concen-
trations is probably related to the decreased activity of serotonergic neu-
rons. This effect is likely a consequence of a slowed transmission or a
decreased activity of specific receptors. Professor B. Wallner, University
of Vienna, Austria, has suggested that a reduction of the cerebral choles-
terol biosynthesis induced by food scarcity could be able, in prehistoric
humans, to start a beneficial aggressiveness for foraging and hunting
(Wallner and Machatschke 2009).
6.2.2 Suicidal behavior

Suicide is an exacerbated expression of a feeling of violence turned toward
oneself. In 1897, Émile Durkheim, the French sociologist and anthropolo-
gist, considered to be one of the founders of modern sociology, defined
suicide as “the end of life resulting directly or indirectly from a positive
or negative act of the victim who knows he is going to kill himself.” Will-
ful, deliberate, or not, the act to end one’s own life is achieved with violent
(e.g., hanging, drowning, firearm, cold weapon) or nonviolent (e.g., poi-
soning, suffocation, drug overdose) methods, the psychiatric importance
of which has not been extensively studied. Moreover, the methods of sui-
cide vary across countries and cultures, with firearms being preferred in
the United States, hanging in Eastern Europe, and poisoning by pesticides
in China. In the majority (about 90%) of the cases analyzed by specialists in
Western countries, and in contrast with China, the suicide attempt or the
suicide itself is related to a mental disorder such as depression, bipolar dis-
order, or schizophrenia. It is often an act of desperation consecutive to alco-
hol or illicit drug use, drug-seeking behavior being frequently considered as
suicidal equivalents. Suicide is rarely motivated by religious or moral con-
siderations. The diversity of situations complicates the understanding of the
act itself and contributes certainly to increase the dispersion of biochemical
and neuropsychological analyses used by investigators.
From a semantic point of view, there is the suicidal act, grouping sui-
cide and suicide attempt, and also the suicidal thoughts, including all
thoughts or beliefs of a person about the end of his or her life.
It is accepted that about 90% of persons dying by suicide previously
suffered from a mental disorder, with mood disorders being the most
common of the associated diseases. The psychiatric studies have shown
that 25%–50% of patients with a bipolar disorder complete at least
one suicide attempt and 15%–20% die. The second risk condition is
depression, often associated with alcoholism and addiction. Note that
10%–13% of patients with schizophrenia die by suicide, often referred
to as psychotic or delirious suicide.
Worldwide, the WHO has estimated that about 1 million people com-
mit suicide each year, thus more than the total deaths caused by wars and
homicides.
In the United States, the annual age-adjusted suicide rate is 12.9 per
100,000 individuals; this rate corresponds to an average of 117 suicides
per day. Men die by suicide 3.5 times more often than women. In 2014,
the highest US suicide rate (14.7) was among whites and the second high-
est rate (10.9) was among American Indians and Alaska natives. Lower
rates were found among Hispanics (6.3), Asians and Pacific Islanders
(5.9), and blacks (5.5). It has been estimated that the numbers could be
higher (data from the American Foundation for Suicide Prevention).
In Europe (27 countries), the average rate of death by suicide is esti-
mated at 10.2 per 100,000 people. Suicide is thus a serious public health pro-
blem even in France where it is responsible for about 11,000 deaths per year
(16 per 100,000 inhabitants). This rate makes France one of the five countries
of the European Union with the highest suicidal mortality. In addition, the
French Health Ministry has estimated that attempts are probably more than
15 times greater than death by suicide. It is the leading cause of death for
subjects aged 25–34 years. Higher rates are even noticed in some coun-
tries, with the highest being in Russia and Lithuania (>30 per 100,000
inhabitants), Finland (28 per 100,000 inhabitants), and Japan (26 per
100,000 inhabitants). Men have, except in China, higher suicide rates than
women.
Worldwide, it has been established that the importance of suicides in
premature mortality has more than doubled in the past 30 years. It is
therefore understandable that the search of risk factors of suicide is the
subject of a major effort by psychiatrists.
Although at present, no scientific evidence allows to predict a suicide
gesture, clinicians may use more than 30 tests to evaluate risk assessments,
with one of the oldest and most used being the SSI (Scale of Suicide
Ideation) (Beck et al. 1979). Undoubtedly, this plurality is the reflection
of the difficulty encountered by every professional in the evaluation of a
suicidal potential in a patient.

Very early, suicidal behavior has been associated with low levels of the
serotonin metabolite 5-hydoxyindolacetic acid (5-HIAA) in cerebrospinal
fluid, with this status being due to lower serotonin amounts in the central
nervous system (Roy et al. 1987).
In addition, serotonin is known to be involved in various psychiatric
disorders such as stress, anxiety, phobia, and depression; it is the target
of some drugs used to treat these diseases. Low 5-HIAA levels were
also associated with reduced levels of ω-3 fatty acids, in particular DHA
(Hibbeln et al. 1998). Such levels were much lower in the very impulsive
subjects with suicidal thoughts than in nonimpulsive or in control subjects
(Cremniter et al. 1999).
An original observation was done in the Ghent University Hospital,
Belgium, concerning a close synchronism between the seasonal variations
of the blood ω-3 and ω-6 fatty acids, serotonergic markers, and the rate of
violent suicides (De Vriese et al. 2004).
All these observations are consistent with the hypothesis that insuf-
ficient amounts of brain EPA and DHA may increase the susceptibility
to impulsiveness and violence and therefore to violent suicide. Indeed,
Dr. R. K. McNamara has found that DHA levels in postmortem samples
of prefrontal cortex taken from suicide victims were lower than in control
samples (McNamara et al. 2013).
In 1990, shortly before comparable studies on depression, a vast survey
on the lifestyle in 265,000 Japanese followed for 17 years has shown that
the daily consumption of one fish serving was associated with a 20% lower
risk of suicide compared to subjects consuming less fish (Hirayama 1990).
Later, a similar relationship was found in a population of 3000 individuals
from Kuopio in the east-central Finland, where the subjects with the least
suicidal thoughts consumed at least two fish servings per week (Tanskanen
et al. 2001). In several countries concerned by their high suicide rate, these
large epidemiological studies have formed the starting point of a lot of
research.
The Japanese population, known for its high suicide rate, but also for its
important fish consumption, has been the subject of a large epidemiological
study that followed for 5 years 47,351 men and 54,156 women aged from
40 to 69 years (Poudel-Tandukar et al. 2011). A relatively high risk of death
by suicide was observed in women only consuming very few fish. There-
fore, the elevated national average of the ω-3 fatty acid intake is likely the
cause of these unconvincing results, but the authors also refer to the diver-
sity of social, nutritional, and psychiatric situations in the population. Equi-
vocal results have also been reported in the United States after an extensive
survey of the dietary habits and the number of suicides for 4 years in more
than 205,000 subjects (Tsai et al. 2014).
At the European level, it is very difficult to establish any relationship

between ω-3 fatty acids and suicide rates, with the official statistics and the
surveys concerning nutrition in different countries being incomplete. In
contrast, it is possible to take into account the overall amounts of the diet-
ary polyunsaturated fatty acids (PUFAs) in 14 countries (Eilander et al.
2015). These values, published between 2004 and 2012, correspond mainly
to the ingested linoleic acid (ω-6), the ω-3 fatty acids being 10–30 times
lower. The official suicide statistics in Europe are accessible from the
European Health for All database established for WHO (http://data.euro.
who.int/hfadb/). From all the reliable and recent data on 14 countries, it
is possible to show a positive correlation between the levels of PUFAs (as
percentage of the total energy intake) and suicide rates (Figure 6.3). This
25
Hu
20
Fr
Fi
Pol
15
Suicide rate
No
Sw
Da
Ge
10
Ned
UK
Sp
5 It
Por
Gr
0
3.5 4.5 5.5 6.5 7.5 8.5 9.5
PUFA (as % of total energy)
Figure 6.3 Relationship between suicide rates and the importance of dietary ω-6
fatty acids for people from 14 European countries (R = 0.55, α < 0.05). Suicide rates
(WHO source) are expressed per 100,000 inhabitants and the proportion of PUFA
in percentage of the total energy intake (Eilander et al. 2015). Ge, Germany;
De, Denmark; Sp, Spain; Fi, Finland; Fr, France; Gr, Greece; Ne, The Netherlands;
Hu, Hungary; It, Italy; No, Norway; Pol, Poland; Por, Portugal; Sw, Sweden; UK:
United Kingdom.
relationship highlights again the influence of the imbalance between the

intake of ω-6 and ω-3 fatty acids in Western populations. All experts agree
that the imbalance results from a too high intake of vegetable oils contain-
ing only ω-6 fatty acids (sunflower, peanut, or grape seed oil) at the
expense of oils rich in ω-3 fatty acids (canola, walnut, flax oil, fish lipids).
It would be important across Europe to collect reliable data on the
amounts of the consumed ω-3 fatty acids, or better the dietary
ω-6/ω-3 fatty acid ratio, to clarify their real influence on the suicidal beha-
vior of populations. The situation in Greece (low suicide rates and high
dietary PUFAs proportion) could thus be explained by the relative
importance of the ω-3 fatty acids among all the dietary fatty acids.
These large surveys have their limits as a low accuracy being not
necessarily compensated by the size of the cohorts studied. It is further
increasingly clear that in a large-scale study, the origin of the ω-3 fatty
acids and their consumed amounts are very difficult to appreciate. So,
as in the other described studies, it is evidently more reliable to record
internal biological parameters, reflecting more faithfully the typical diet
of the investigated subjects.
To overcome these drawbacks, a Chinese study compared the fatty acid
composition of erythrocytes in 100 subjects hospitalized for suicide attempts
and in the same number of control subjects hospitalized after an accident.
The authors observed a highly significant association between a low cellular
EPA concentration and a high risk of suicide (Huan et al. 2004). Investigators
at the Columbia University, New York, followed for 2 years 33 depressed
subjects with high suicide risk (Sublette et al. 2006). After the observation
of seven attempts of suicide, they found that the suicide risk was clo-
sely linked to low DHA levels in blood (Table 6.1) or to high levels of
the ω-6/ω-3 fatty acid ratio. The authors did not hesitate to proclaim that
blood DHA concentrations could predict future risks of suicide in
depressed patients.
Table 6.1 Time course change of survival probability

after suicide attempts based on the blood DHA level
Time to first Low DHA High DHA

attempts (days) (n = 17) (n = 16)
0 100 100
200 86 100
400 86 100
600 71.3 100
800 51.5 93.4
Source: Sublette, M.E., et al. Am. J. Psychiatry, 163, 1100–

1102, 2006.
A study done in the Galway National University, Ireland, compared

40 patients urgently admitted for suicide attempt with 40 control subjects
having no psychiatric history (Garland et al. 2007). The authors confirmed
that the diseased subjects differed significantly from controls, with the for-
mer having 47% lower EPA and 27.4% lower DHA and with cholesterol
being 14% lower in plasma lipids.
Recently, a study of 27 patients with bipolar disorder showed that
the 17 subjects with suicidal history had blood EPA levels slightly lower
and arachidonic acid (20:4 ω-6) levels significantly lower than in the 10
subjects having no disorders (Evans et al. 2012). The analysis of fatty acid
profiles enabled to conclude that the balance between the fatty acid pre-
cursor linolenic acid and its metabolites EPA and DHA was closely asso-
ciated with the parameters measuring personality and suicidal
intentions. Recently, a biochemical study of several metabolites (metabo-
lomics study) demonstrated in bipolar subjects a similar relationship
between fatty acid metabolism and psychiatric disorders (Evans et al.
2014). The precise analysis of these phenomena should make possible
to consider later the opportunities for nutritional or pharmacological
interventions in subjects at risk.
In response to a significantly increased number of suicides in soldiers,
the US authorities undertook a major study to prevent the risk of suicide dur-
ing or after operations. The blood ω-3 fatty acid composition in 800 soldiers
whose death was by suicide was compared to that measured in 800 military
in good mental health (Lewis et al. 2011). The investigators discovered that
soldiers in front from 2002 to 2008 with the lowest DHA levels had a risk
of suicide increased by 62% compared to soldiers with the highest fatty acid
levels. The significance of these findings has motivated the US Army Medical
Service to launch a major research program on this subject. The officials have
already recommended a change in the military food rations in approaching
closer to the essential fatty acid composition of the Mediterranean diet
(Hibbeln and Gow 2014). The interest of military members in that prevention
may surely grow as a group of doctors from the US Army has decided as
part of a search for a “nutritional armor” to raise in an ethical way the ω-3
fatty acid status of military personnel.
If these results are confirmed by further studies, they could have
implications for neurobiology of suicide and the ways psychiatrists will
implement to reduce the risk of suicide, or at least the risk of a renewal
of a previous attempt.
So far, no studies of prevention or treatment by using supplementation
with ω-3 fatty acids have explored its possible effects on suicide frequency.
In all investigations, including those referred to as foresight, there are sev-
eral possible confounding factors (social status, favorable lifestyle, higher
living standards, income) that may be associated with fish consumption,
these factors being now increasingly taken into account.
Only one clinical study on the impact of ω-3 fatty acids on the resili-
ence capacities of US veterans is listed on the NIH Clinical Trials website
(http://clinicaltrials.gov).
6.2.2.2 Vitamin D
As mentioned at the beginning of section 6.2.2, the risk of a suicidal beha-
vior increases dramatically in individuals with a mood disorder, even
minor, combined with bipolar disorder or schizophrenia. In adolescents
and young adults, it has been determined that nearly 80% of individuals
who made at least one suicide attempt were suffering from one or several
psychiatric disorders (Wunderlich et al. 1997).
Many studies have shown a close association between vitamin D and
aggressive behavior (Section 6.2.1.2), but also several psychiatric disorders
such as depression (Section 6.1.1.2), schizophrenia (Section 6.1.3.2), ADHD
(Section 6.1.4.2), or autism (Section 6.1.5.2). It seems thus logical to add the
suicidal behavior to this list (Tariq et al. 2011).
Until now, little work had been devoted to the possible correlations
between the vitamin D status and the suicide risk. Therefore, a large sur-
vey was conducted in the United States by comparing blood vitamin D
levels in soldiers who committed a fatal suicide with those of healthy
military (Umhau et al. 2013). It seemed first that soldiers were very fre-
quently vitamin D deficient, a probable consequence of their lifestyle due
to their clothing; and second, the most deficient (<15 ng/mL) subjects
had a high suicide risk. Because no relationship has been found between
suicide and depression, the authors suggested that the aggressiveness
linked to vitamin D deficiency in that population of soldiers could very
naturally lead to the fatal act in connection with a reduction of the brain
serotonergic activity (Lindqvist et al. 2010).
In Sweden, the presence of very low vitamin D levels (approxi-
mately 18 ng/mL) was observed among individuals who have
attempted suicide but not followed by death, with that average vitamin
level being 25% lower than in nonsuicidal depressed and 28% lower
than in healthy controls (Grudet et al. 2014). In addition, 58% of suicidal
subjects had a deficiency because their plasma vitamin D level was
lower than the accepted threshold in most countries. The interesting
nature of that work was to measure simultaneously several inflamma-
tion indicators. Thus, the authors have found that the vitamin D
deficiency of suicidal subjects was accompanied by increased levels
of proinflammatory cytokines (interleukin-6 and –1β). The known links
between inflammatory processes and vitamin D (Zhang et al. 2012)
will certainly boost the research, already very active in the field of
suicidal behavior, at least in patients at risk suffering also from
depression.
Given the metabolic link between vitamin D biosynthesis and sun-

shine, any seasonal variation of suicides offers a major way for the study
of involved causes, allowing to consider preventative measures.
While the causes of suicide and the methods used to achieve it are
very diverse, an annual frequency cycle has been observed with a peak at
the end of spring and early summer and that in many European, American,
or Asian countries (Christodoulou et al. 2012). When the precise circum-
stances of the suicide are known, the investigators have noticed that the
cycle was more pronounced if the death was caused by violent methods
(e.g., hanging, firearm).
Despite the apparent reality of the seasonal variations in suicides,
there are conflicting studies raising the question of a possible interference
of sex, age, suicide method, or other elusive sociological or biological para-
meters. Some epidemiologists have even evoked an antidepressant action
of the sun in May–June strengthening the motivation to perform an act
previously buried in the subconscious.
A broader survey of lifestyle along with vitamin D and serotonin
assays could improve our knowledge on the physiological mechanisms
underlying these biological cycles.
As with many psychiatric disorders mentioned above, a synchrony
was observed between birth season and suicide frequency. After the first
studies on small groups (Lester et al. 1970), the phenomenon was particu-
larly analyzed in England, Wales, and Scotland on a large cohort of about
52,000 suicides listed for 21 years (Salib and Cortina-Borja 2010). In these
countries, a 15% increase of the suicide risk for men and 27% for women
was recorded for people born in April–May compared to those born in
October–November. A recent study in Finland, including 1902 cases of
suicide in patients with schizophrenia or other psychotic disorders
reached similar conclusions (Karhumaa et al. 2013). This apparent predis-
position to suicide in schizophrenic people born in the spring raises the
problem of a possible role of vitamin D deficiency, likely due to a limited
sun exposure during the second and third trimesters.
A causal link between this maternal deficiency and the onset of a sui-
cidal behavior in adults has been considered by various authors, but it is
still hypothetical as for other psychiatric or neurological disorders. Larger
studies, and in several countries located in various latitudes, are needed
before giving credit to that influence. Thus, prevention campaigns could
help reduce suicidal risks, considering the potentiality of a long-term pre-
ventive treatment with vitamin D to decrease mortality after several psy-
chiatric disorders.
6.2.2.3 Cholesterol
For the first time, in 1966, information was published on possible relation-
ships between cholesterol and suicide (Hoch-Ligeti 1966). An exploration
of the adrenal glands of subjects that died by suicide has revealed that
their cholesterol content was about 60% higher than in subjects who died
in accidents and not very different from that measured in subjects with
hypertension. By contrast, along abundant research attempting to eluci-
date the relationships between cholesterol and cardiovascular disease,
clinicians have noted an increased suicidal risk in groups of individuals
having low blood cholesterol concentrations.
These first results were verified 24 years later in a large study invol-
ving 25,000 men followed for nearly 5 years, with half having a dietary
plan or a treatment (without statin) to lower cholesterolemia (Muldoon
et al. 1990). The authors observed a significant death increase not related
to illness (accident, suicide, or violence) in subjects subjected to cholesterol
lowering, but a lower mortality in subjects with coronary heart disease.
As for aggressive behavior (Section 6.2.1.3), the concern about these
conclusions was noticed by the medical world that fostered several research
studies to decide whether the new statin treatments fighting against
hypercholesterolemia could induce a suicidal behavior, despite their inter-
est and efficiency for cardiovascular diseases.
The first investigation in this field was already done in Sweden with
more than 54,000 subjects followed for 20 years (Lindberg et al. 1992).
Authors had verified that the lower the cholesterol level, the higher the mor-
tality by suicide, but in men only. Thus, the relative suicide risk in the group
of subjects having an average of 2 g/L of total cholesterol was nearly
four times the risk measured in the group with an average of 2.9 g/L.
The same year, an American study confirmed approximately these results
after monitoring 351,000 men for 12 years (Neaton et al. 1992). Apart from
a few exceptions, all subsequent studies have reached similar conclusions
(Colin 2003). Very recently, a broad analysis of 65 studies published since
1994 and involving observations on more than 510,000 participants
showed that those with the lowest cholesterol levels were significantly
associated with a nearly two times suicide risk compared to those with
high blood cholesterol levels (Wu et al. 2015).
Alarmed by these outcomes, some clinicians asked early on for a mor-
atorium on the use of statins, the most widely used drugs to lower choles-
terolemia (Smith and Pekkanen 1992). Fortunately, Prof. Dr. F. Muldoon,
University of Pittsburgh, Pennsylvania, published in 2001 a review of 19
studies and concluded that there was currently no evidence of an effect
of statins on mortality by suicide, whereas the other treatments (diet, var-
ious medications) should be avoided if possible (Muldoon et al. 2001).
All these results have been disputed, especially in the case of experi-
ments for therapeutic purposes where the proposed diets contained lipids
with different fatty acid compositions. In 1995, an analysis of the literature
by J. R. Hibbeln had already highlighted the interference of the ω-6/ω-3
fatty acid ratio in the experiments (Hibbeln and Salem 1995). In fact, a
lowering of cholesterolemia by a dietary change often leads to replace

saturated fats by excessive amounts of vegetable oils, rich in ω-6 fatty
acids. These changes clearly contribute to lower the relative contribution
of ω-3 fatty acids, an alteration known to increase the depression risk
(Section 6.1.1.1), and therefore suicide (Section 6.2.2.1).
This example illustrates the complex interconnections between dietary
lipids, physiology, and the behavior of individuals, beneficial modifica-
tions for a system being able to hamper one or several others.
The direct relationships between cholesterol and suicide attempts were
clinically explored several times. A study of people hospitalized with bipo-
lar disorder has shown that those who attempted suicide had a 20% lower
cholesterol level compared to those who have made no attempt
(Vuksan-Cusa et al. 2009). Interestingly, when hypocholesterolemia is of
familial origin, due to a mutation of a specific lipoprotein, the affected sub-
jects have a very high risk of violent death by suicide (Edgar et al. 2007).
A study done in Prague, Czech Republic, has clarified that cholesterol
levels measured in women hospitalized after suicide attempt were signif-
icant lower compared to controls when violent means only had been used
(stabbing, firearm, hanging, drowning, falling). Subjects using nonviolent
means (drugs) were comparable to controls (Vevera et al. 2003). Despite
the absence of dietary data, the present results clearly show that subjects
attempting suicide are not a homogeneous group. The means used
for their suicide attempt enable the distinction of at least two types of
subjects, likely related to a change in brain serotonergic activity (Mann
1989).
Another discovery highlighted the complexity of the family behavior
combining violence and suicide, parents and children. Indeed, it has
been shown that among a group of people who attempted suicide by vio-
lent means, those having a cholesterol level below the median of the
group had been more frequently exposed to violence in their childhood
(6–14 years) than individuals with a cholesterol level above the median
(Asellus et al. 2014). Thus, it seems that the circulating cholesterol level
may change the “cycle of violence” often described in violent adults who
have experienced violent periods in their childhood. It is likely that if
that cycle really exists, it seems more significant in individuals with
low cholesterol levels. Unfortunately, there is no record in children to
assess the influence of their cholesterolemia on their future behavior;
conversely, it is the same for a possible effect of violent behaviors in
childhood on cholesterol metabolism.
Although the links between cholesterol and suicidal behavior are now
accepted by the scientific community, the mechanisms involved remain
poorly defined. Most hypotheses suggest, however, the intervention of a
reduced serotonergic activity, likely a consequence of a lack of cholesterol
at the level of synapses. The increased impulsivity could find its origin
from other mechanisms, such as a regulation by steroids or by some neu-

rotrophic factors (Cantarelli et al. 2014).
To date, only two studies on the links between cholesterol and suici-
dal behavior are listed in the US Government site for clinic trails (https://
clinicaltrials.gov/).
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chapter seven
Annexes
7.1 Essential fatty acids
The ω-3 fatty acids are biochemically different from their counterparts, the
ω-6 fatty acids, by the position of their first double bond, situated between
the third and the fourth carbon atom instead of being between the sixth
and the seventh carbon atom. According to that nomenclature, the carbon
numbering starts from the terminal methyl group (opposite to the acid
function), hence their name ω-3 (or n-3) and ω-6 (or n-6). Only plants have
the ability to convert linoleic acid ([LA] 18:2 ω-6) (Figure 7.1), the precur-
sor of the ω-6 fatty acid series, into α-linolenic acid ([ALA] 18:3 ω-3)
(Figure 7.2), the precursor of all the ω-3 fatty acid series.
Animals (including humans) do not have the capacity to synthesize
these two fatty acids (considered as essential) and their supply can be done
only from food. In humans as in animals, the same enzymes along the seven
metabolic steps are involved in the biosynthesis of long-chain ω-3 fatty
acids, as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or of
long-chain ω-6 fatty acids, as arachidonic acid (AA), with each family being
not convertible into one other (Table 7.1). This property results in competi-
tion for the biosynthesis of the products from LA and ALA, as well as
to their metabolic derivatives (prostaglandins and various oxygenated or
hydroxy derivatives). Thus, an excess of LA may reduce the production
of EPA and DHA from ALA, the latter of which is present in very low
amounts in animal tissues.
The ω-3 fatty acid content of biological samples (red blood cells, whole
blood, plasma) is now often estimated by calculating the “ω-3 index.”
The value of this index, calculated as the sum of EPA plus DHA in percen-
tage of the total fatty acids in the sample, provides an indication of the ω-3
fatty acid status for the whole body. High blood EPA plus DHA levels
(>8%) are found in people from regions near the Sea of Japan, in Scandi-
navia, and in areas with indigenous populations or populations not fully
adapted to westernized food habits. Very low blood levels (<4%) were
observed in people of North America, Central and South Americas, Europe,
the Middle East, Southeast Asia, and Africa.
It is generally estimated that an ω-3 index of 8% or more is an ideal goal
for general good health. If the value of the index is 4% or less, it is recom-
mended to change food habits by consuming more marine animals (fish,
molluscs, shellfish) or by ingesting food supplements rich in long-chain
197
O
6 7
1
OH
Figure 7.1 Linoleic acid (18:2 ω-6, LA).
O
1 3 4
OH
Figure 7.2 Linolenic acid (18:3 ω-3, ALA).
ω-3 fatty acids (EPA, DHA, or both). In that case, the generally admitted
practice is to use a pharmaceutical-quality product supplying 500–1000
mg of EPA and DHA per day. To optimize the dietary ω-3 fatty acid intake,
it is necessary to look at a precise table of food fatty acid composition. A
convenient table containing 8000 different foods with their ω-3 and ω-6 fatty
acid composition and the value of their ω-3 index may be consulted on a
dedicated website (www.fattyacidshub.com/tools-for-fatty-acids/omega-
3-omega-6-ratio-calculator/). From a practical point of view, Prof. Bill
Lands has established the “Omega 3-6 Balance Scores” for nearly 5000
foods, providing a simple way to highlight the essential fatty acid state in
a diet and allowing to plan more accurately better balanced meals (www.
efaeducation.org/Omega3-6BalanceApp.html).
7.2 Dietary allowance of essential fatty acids

The tables (Tables 7.2–7.4) below summarize the opinion of the French Food
Safety Agency (AFSSA) concerning the updating of the recommended diet-
ary allowances for fatty acids (saisine no. 2006-SA-0359, 1 March 2010).
Similar data may be found in various official or medical sources from sev-
eral countries.
7.2.1 Main DHA and EPA sources as sea products

Despite heavy metals and pesticides pollution, fish remain the most conve-
nient and most abundant source of long-chain ω-3 fatty acids. In terms of
risk, in 2014 two US agencies (Food and Drug Administration, Environ-
mental Protection Agency) recommended for pregnant women or those
planning to become pregnant to not eat more than three servings of fish
per week to limit the exposure of the fetus to mercury. Sweden recom-
mended limiting the consumption to once per month. The UK authorities
Chapter seven: Annexes 199
Table 7.1 Biosynthetic pathways of ω-6 and ω-3 fatty acids

(enzymes responsible are in italics). The first digit indicates the number of carbon
atoms, the second the number of double bonds
Metabolic
step ω-6 Fatty acid Enzyme ω-3 Fatty acid
18:2 ω-6 (LA) 18:3 ω-3 (ALA)

Linoleic acid Linolenic acid
1 Δ6 desaturase
18:3 ω-6 18:4 ω-3
γ-Linolenic acid Stearidonic acid
2 elongase
20:3 ω-6 20:4 ω-3
Dihomo-γ-linolenic acid Eicosatetraenoic acid
3 Δ5 desaturase
20:4 ω-6(AA) 20:5 ω-3 (EPA)
Arachidonic acid Eicosapentaenoic acid
4 elongase
22:4 ω-6 22:5 ω-3
Docosatetraenoic acid Docosapentaenoic acid
5 elongase
24:4 ω-6 24:5 ω-3
Tetracosatetraenoic acid Tetracosapentaenoic acid
6 Δ6 desaturase
24:5 ω-6 24:6 ω-3
Tetracosapentaenoic acid Tetracosahexaenoic acid
7 beta-oxidation
22:5 ω-6 22:6 ω-3 (DHA)
Docosapentaenoic acid Docosahexaenoic acid
Table 7.2 Recommended dietary intakes of polyunsaturated

fatty acids (as % of the total energy intake or mg) for pregnant women and
nursing mothers, consuming respectively 2050 and 2250 kcal (or 8583 and
9420 kJ) with 35%–40% of energy intake as lipids
Linoleic Linolenic Arachidonic Docosahexaenoic

acid acid acid acid
18:2 ω-6 18:3 ω-3 20:4 ω-6 22:6 ω-3 EPA+DHA,
(LA), % (ALA), % (AA) (DHA), mg mg
Pregnant 4 1 – 250 500

women
Nursing 4 1 – 250 500
mothers
Table 7.3 Recommended dietary intakes of polyunsaturated fatty acids for

newborn or infant (in % of total energy intake or % of total fatty acids, TFA)

acid acid acid acid
18:2 ω-6 18:3 ω-3 20:4 ω-6 22:6 ω-3
(LA), % (ALA), % (AA), % (DHA) EPA+DHA
Newborn 2.7 0.45 0.5 0.32 TFA EPA<DHA

or infant
Table 7.4 Recommended dietary intakes of polyunsaturated fatty acids for infants
aged of more than 6 months, children, and adolescents
(in % of total energy intake or mg)

acid acid acid acid EPA
18:2 ω-6 18:3 ω-3 20:4 ω-6 22:6 ω-3 +DHA,
(LA), % (ALA), % (AA) (DHA), mg mg
Infants aged 0-1 2.7 0.45 – 70 –

Infants aged 1-3 2.7 0.45 – 70 –
Infants aged 3-9 4 1 – 125 250
Infants aged 10-18 4 1 – 250 500
recommend pregnant women avoid eating certain marine fish (tuna, shark,
marlin, swordfish, bar). In 2004 in France, the AFSSA recommended that
pregnant and lactating women, and children aged up to 30 months, con-
sume no more than 60–150 g/week of these wild predatory fish.
New studies on mercury contamination of fish consumed in Europe are
alerting consumers about safe versus unsafe fish consumption (see below).
To regularly eat fish is thus not without risk to health.
Among fatty fish, some contain more DHA and EPA that others and
are therefore particularly interesting for a balanced diet.
Fish may be grouped into three categories:
• Fatty fish with high ω-3 amounts (>1.5 g/100 g): salmon, mackerel,
herring
• Fatty fish with medium ω-3 amounts (0.5–1.5 g/100 g): trout,
sardine, tuna
• Lean fish with low ω-3 amounts (<0.5 g/100 g): sole, cod, carp, eel
Table 7.5 shows that even a modest consumption of marine fatty fish, or
even farmed salmon or trout, is able to cover the ω-3 fatty acid requirements
Table 7.5 EPA and DHA content (g/100 g, in descending

order) of various fish, shellfish and molluscs and weight of
a portion providing 500 mg of these fatty acids
EPA+DHA Fish weight

Fish (g/100 g) (g per 500 mg EPA+DHA)
Farmed salmon 3.1 16

Mackerel 2.3 22
Salmon 1.96 26
Herring 1.57 32
Sardine 0.98 51
White tuna 0.86 58
Farmed trout 0.74 68
Shrimp 0.55 90
Mussel 0.44 114
Oyster 0.39 128
Octopus 0.31 161
Sole 0.25 200
Cod 0.18 278
of an adult. A 150- to 200-g portion of some of these fish (right column),

consumed two times per week, covers the requirements of an adult for
EPA and DHA (about 500 mg/day).
7.2.2 Foods for infants and young children

Since 1996, an amendment to the European Union Directive on infant
formulas allowed the marketing of milk enriched with polyunsaturated
fatty acids, specifying the limits to be respected, but without setting a
minimum threshold for DHA (and AA). For specialists, an enrichment
corresponding to the amounts found in breast milk seems the most appro-
priate. Many foods (milk) supplemented with polyunsaturated fatty acids
for infants or children are already marketed in various countries. Some of
them are detailed below:
• Bon départ from Nestlé contains 10 mg of DHA and 56 mg of LA in
100 mL of preparation.
• Enfamil A + from Mead Johnson contains 11.5 mg of DHA in a 100-mL
preparation.
• Candia source d’Omega-3 from Candia is a milk containing 1.7 g of
lipids with 23 mg of EPA and 33 mg of DHA per 100 mL.
• Calisma 2 from Gallia contains 8.3 mg of DHA and the product
“croissance” 12 mg of DHA in 100 mL of preparation.
For other products, consumers must check the manufacturers’ indications

on the fatty acid composition and especially the presence of DHA and
EPA in favoring formulas containing low amounts of ω-6 fatty acids.
7.2.3 Food supplements rich in EPA, DHA, or both

Because the recommended dietary allowance for ω-3 fatty acids is about
500 mg/day, usually in the form of a mixture of EPA and DHA, a supple-
mentation may be provided by the daily intake of these fatty acids in
capsules (0.5 or 1 g). They contain esterified derivatives of free fatty acids
(usually as ethyl esters) or better fish or shellfish (krill) oil (triacylglycerols).
These oils are generally declared to be low in heavy metals and pesticides.
They are also enriched in vitamin E to ensure a better conservation (usually
about 10 mg per capsule). These oils are extracted from cold water fish
(anchovies, sardine, cod, salmon, hoki), from Antarctic water shellfish
(krill), and even from marine mammals (seals). They are used after purifica-
tion, usually by molecular distillation to remove heavy metals and pesti-
cides. Their ω-3 fatty acid concentration ranges from 30% to >90%. Krill
oil is characterized by its very low level of organic pollutants and heavy
metals, thereby justifying the intense development of its production.
Now, the ω-3 fatty acids on the market are mainly extracted from fish
and to a lesser extent from shellfish and algae. It is expected that the grow-
ing worldwide demand for DHA and EPA will push manufacturers to
offer new products derived from seaweed and possibly from genetically
modified plants.
Among oils from marine animals and algae present on the market,
one can find the following brands:
• Arctic Omega-3 seal oil with 500 mg of Arctic seal oil containing 120 mg
of ω-3 fatty acids, including 36 mg of EPA, 51 mg of DHA, and 31 mg
of 22:5 ω-3
• DHA Neuromins-Solgar with 500 mg of oil containing 100 mg
of DHA from seaweed
• Fitoform DHA omega-3 vegetal, 1-g capsule containing 12 mg of
EPA, 152 mg of DHA, and 12 mg of LA
• CNG Salmon oil, 1 g of oil containing 180 mg of EPA and 120 mg of
DHA
• NKO Krill, 300 mg of Antarctic shrimp oil, mainly phospholipids
containing 39 mg of EPA and 16.5 mg of DHA (Oemine brand: a cap-
sule of 500 mg NKO krill oil contains 75 mg of EPA, 45 mg of DHA,
and 0.75 mg of astaxanthin)
• Marin EPA Platinum (Nutrogenics), capsule of purified oil contain-
ing 764 mg of EPA, 236 mg of DHA, and 300 international units (IU)
of vitamin D
• Omacor soft caps, 1 g of ω-3 fatty acid ethyl esters with 460 mg of
EPA and 380 mg of DHA
• Omega-Brite, 500 mg of 90% ω-3 fatty acids with EPA (350 mg) and
DHA (50 mg)
• Omegavie DHA 1050 TG/EE (Polaris nutritional lipids), capsule
containing 7%–17% EPA and 50% DHA
• Triglistab, 1010-mg capsule containing 700 mg of ω-3 fatty acid ethyl
esters
• Ultimate Omega, 1 g of anchovy and sardine oil containing 640 mg
of ω-3 fatty acids as EPA (325 mg) and DHA (225 mg)
• Unocardio (WHC-Nutrogenics), capsule containing 460 mg of EPA
and 380 mg of DHA
• Xtend-Life Omega/DHA Fish Oil (hoki oil), 1-g capsule with 120 mg
of EPA, 280 mg of DHA, and 50 mg of 22:5 ω-3.
• Ysomega, 1 g of fish oil containing 320 mg of EPA and 200 mg of DHA
• ZenixX (IXX Pharma), 1-g capsule containing 60%–75% of DHA and
15% EPA ethyl esters
The reader may explore a comprehensive list of fish oil products with
all the testing results established by the International Fish Oil Standards
program (www.nutrasource.ca/ifos/product-reports/default.aspx).
For problems of fish mercury contamination, see the 2010 report of the
joint Food and Agriculture Organization of the United Nations/World Health
Organization (WHO) expert consultation on the risks and benefits of fish
consumption (http://www.fao.org/docrep/014/ba0136e/ba0136e00.pdf)
and the 2015 EFSA’s official publication (http://onlinelibrary.wiley.com/
doi/10.2903/j.efsa.2015.3982/pdf) (report of the Scientific Committee
“Statement on the benefits of fish/seafood consumption compared to the
risks of methylmercury in fish/seafood”).
Unexpected solutions could result from studies performed in animals in
2012 by the team of Dr. C. Stanton, University of Cork, Ireland, showing
that the ingestion of certain strains of Bifidobacterium could increase the
brain DHA content. After a possible verification in humans, this effect could
act synergistically with a moderate food supplementation of ω-3 fatty acids.
7.3 Vitamin A and carotenoids

7.3.1 Vitamin A
Vitamin A (Figure 7.3) is a generic term for several lipidic compounds related
to retinol and having the same biological activity, such as retinol esters,
retinal, and retinoic acid. They all belong to the group of retinoids. They
are formed from a carotenoid by splitting the middle of the carbon chain.
OH
Figure 7.3 Vitamin A (all-trans-retinol).
In animals, they offer two vitamin activities: photoreception (retinol, retinal)

and cell growth regulation (retinoic acid).
For humans, natural sources of vitamin A are retinoids included in
consumed animal products (meat, eggs, dairy products) and formed from
some carotenoids (provitamin A) of plant origin.
The amounts of vitamin A are expressed in micrograms of retinol
equivalent (RE), with that unit enabling the conversion of all sources of
vitamin A in a single expression. Thus, it is recognized that 1 RE is equiva-
lent to 1 μg of retinol, 1.78 μg of retinyl palmitate, and 6 μg of β-carotene.
WHO has recommended humans have a dietary allowance of 600 μg
RE. In France, for adults, AFSSA has set daily vitamin A intake to 800 μg
RE. A partial deficiency status has been highlighted in many countries.
Indeed, the WHO estimates that several millions of children are deficient
worldwide. This situation leads nearly 500,000 children to blindness each
year in developing countries, mainly South Asia and Africa. It can be also
considered that the French population is currently in a deficiency state
because it was established that about 72% of a population between 50 and
68 years have a vitamin A intake lower than that recommended. To establish
a reliable vitamin A intake, it is recommended to have a diet that includes
various fruits and vegetables. These vegetables will be consumed preferably
cooked in the presence of a little oil to facilitate carotenoid absorption. The
consumption of liver (10,000 RE/100 g) and cheese (200–400 RE/100 g) is
also recommended for direct supply of retinol. It is possible to carry out a
daily supplementation of about 1 mg of vitamin A, not to exceed 3 mg/day
(Leray 2015, Lipids: Nutrition and Health, CRC Press, Boca Raton, FL).
7.3.2 Carotenoids
β-Carotene is the best known carotenoid (Figure 7.4). It gives some fruits
and vegetables an orange-red color, but it is always present hidden by the
green chlorophyll in plants. Like all carotenoids, it protects cells against
free radicals formed by the action of light energy.
It is used as a food coloring (E160a) and also as provitamin A in
vitamin supplements.
The following carotenoids are not provitamin A: lutein (Figure 7.5) and
zeaxanthin. Lutein is a carotenoid of the xanthophyll group. It is present
Figure 7.4 β-Carotene.
OH
HO
Figure 7.5 Lutein.
in some foods of vegetal origin and characterizes the retinal macula.

Zeaxanthin is a cis isomer of lutein (both hydroxyl groups in the same
plane). Three stereoisomers are present in human serum and in retina, the
most abundant being meso-zeaxanthin (3R,3′S-zeaxanthin). Lutein (E161b)
and zeaxanthin (E161h) are permitted as food additives.
The main dietary sources of lutein are vegetables with green leaves, in
descending order (from 15 to 1 mg/100 g), cabbage, watercress, spinach,
chard, small peas, broccoli, and lettuce. Fruits such as oranges and pea-
ches are also significant sources of zeaxanthin.
It has been determined that dietary fortification with macular carote-
noids (10 mg of lutein, 2 mg of zeaxanthin, and 10 mg of meso-zeaxanthin)
can have meaningful effects on visual function.
In France, the AFSSA considers that there is no scientific evidence to
justify a lutein or zeaxanthin supplementation in healthy humans with a
varied diet. However, it is possible to use a supplement of 6 mg/day of
lutein, alone or combined with zeaxanthin. Some health professionals
also recommend to their patients such a supplementation. Higher doses
(10–20 mg) are prescribed for the prevention of cataract and age-related
macular degeneration (AMD) in individuals at risk (Leray 2015).
7.4 Vitamin D
This vitamin is represented by several molecules derived from sterols
(cholesterol in animals and ergosterol in plants) by solar ultraviolet irra-
diation (UV-B) and by enzymatic hydroxylation. The most abundant form
is the cholecalciferol (vitamin D3, Figure 7.6), which can be considered a
HO
Figure 7.6 Vitamin D3 (cholecalciferol).
provitamin D. It is metabolized when required in the liver into a circulat-

ing form, 25-hydroxycholecalciferol (calcidiol), and then in the kidney into
the active form of the vitamin, 1,25-hydroxycholecalciferol (calcitriol).
Considering its biosynthesis pathway and its mode of action, that vitamin
is now frequently taken as a hormone. It is sometimes called “solar
hormone.”
The amounts of vitamin D are expressed in milligrams (or in nano-
grams) of cholecalciferol. The IU may also be used, with 40 IU being equiva-
lent to 1 μg of vitamin D. Blood concentrations are expressed in nanograms
per milliliter or nanomoles per liter (1 ng/mL = 2.6 nmol/L).
Initially discovered as part of the regulation of calcium and phosphate
metabolism, vitamin D is now recognized as having a crucial role in meta-
bolic disorders, diabetes, cardiovascular diseases, cancers, immune system,
and brain function (Leray 2015).
Vitamin D is a lipid present in some foods, such as fatty fish (herring,
sardine, tuna, salmon, and mackerel), milk, and eggs, but its supply is
mainly via synthesis in the skin under the effect of sun exposure. Indeed,
it has been shown that fish consumption in accordance with the recom-
mended amounts is able to increase the blood vitamin D level, but it cannot
alone optimize its status.
UV irradiation of ergosterol, contained in vegetable oils and fungi,
produces ergocalciferol (vitamin D2). Its biological activities with respect
to vitamin D3 have not yet been precisely determined; for some they are
three times lower, whereas for the others the two forms are equivalent.
Ergocalciferol is poorly represented in the diet, but it is often provided
by pharmaceutical preparations used as vitamin D supplement.
As recalled Dr. J.-C. Souberbielle, Hospital Necker-Enfants-Malades,
Paris, France: “from 43% to 50% of the adult French population (‘healthy’)
have a vitamin D concentration less than 20 ng/mL (deficiency state) and
more than 80% have a concentration below 30 ng/mL (insufficient state

between 20 and 30 ng/mL). These percentages are even higher in subjects
aged over 70–80 living at home and among teenagers in apparent good
health, and increase further in patients with various pathologies.”
It is estimated that more than 1 billion people worldwide are vitamin D
deficient, with the intake in Western countries often being less than 9 μg/day.
Deficiency states are more common in women than in men, with preg-
nancy representing a situation at risk. This situation can be aggravated
by obesity, age, season, a highly pigmented skin, or a full body covering.
There is a possibility that the patients treated with statins may not have
enough cholesterol because it is effectively the primary substrate for
vitamin D production.
It is possible to assess the risk of vitamin D deficiency by using a ques-
tionnaire to determine the contribution of sun exposure and that of the
food (Diagno® vitamin D, www.nutritionpreventiveisio.fr).
The prevention of the vitamin D deficiency in Europe is a subject of
such a priority that the European Commission has decided to support a
large multidisciplinary research project, the ODIN project, in 19 countries
to prevent that deficiency and improve the public health through nutrition
(http://www.odin-vitd.eu). This 4-year project should provide reliable
results by the end of 2018.
New recommendations for daily intakes of vitamin D were put
forward by health authorities in various countries. Thus, the daily require-
ments of vitamin D are at least as follows:
• From 0 to 1 year old: 10 μg (400 IU) per day

• From 1 year to 70 years old (including pregnant women): 15 μg
(600 IU) per day
• After 70 years old: 20 μg (800 IU) per day
Many experts have claimed that this is still far too low to address chronic
insufficiency of the vitamin that comes with modern life wherein people
spend much of their time indoors and use sunscreen when they are
outdoors.
The European Food Safety Authority (EFSA) for the first time (March
2016) issued vitamin D intake recommendations for European adults,
pregnant women, children, and infants. After consideration of factors such
as sun exposure, the panel set an adequate intake level of 15 µg/day from
food sources for adults and children to achieve a serum level of 19 ng/mL
(50 nmol/L). For infants aged 7–11 months, a supply of 10 µg/day was
established.
In July 2016, the Public Health of England (Scientific Advisory
Committee on Nutrition) advised that without taking into account sun-
light exposure, adults and children in the United Kingdom over the age
of 1 year should get 10 μg of vitamin D every day. People who have a

higher risk of vitamin D deficiency are being advised to take a supplement
year-round. As a precaution, babies aged less than 1 year should have a
daily 8.5–10 μg vitamin D supplement, whereas children aged 1–4 years
should have a daily 10 μg of vitamin D supplement year-round.
The French government authorities decided early on that it was neces-
sary to fight against vitamin D deficiency in children, deciding a prophy-
laxis was mandatory for all infants from 0 to 18 months; then in winter,
in children up to 5 years old (ministerial circulars, February 21, 1963
and January 6, 1971). The prophylaxis is recommended in children and
adolescents when the life conditions provide an insufficient sunlight expo-
sure or a diet low in vitamin D.
According to the French Academy of Medicine, the currently recom-
mended daily intakes are not enough; they should be doubled to reach
30 μg per adult. Since 2012, the academy recommends that the vitamin
status of an individual must be defined by the calcidiol serum level, with
the latter being higher than 30 ng/mL (75 nmol/L) without exceeding
200 nmol/L. Any vitamin D deficiency should be corrected only by an oral
supplementation and should not lead subjects to extend their sun exposure.
The supplementation will be in the form of a regular intake of vitamin D,
corresponding to approximately 800 IU from 1 to 8 years old, 1000 IU from
9 to 50 years old, 1500 IU from 51 to 70 years old, and more than 1500 IU
after the age 70 years. Practically, that supply is done each month or every
2 months (e.g., with 100,000 IU per ampoule).
Because most vitamin D experts agree that an intake lower than
10,000 IU/day is safe in healthy adults, the US Endocrine Society has
recommended 1500–2000 IU/day as the minimum dose.
In France, short sunlight exposure may cover the vitamin D needs:
about 15 min of exposure (hands, forearms, and face), two to three times
a week between 9 am and 16 pm from spring to autumn. Notably, vitamin D
synthesis cannot be carried out through a window or in the presence of
sunscreen.
Natural sources of vitamin D:
• Canned Cod Liver: 100-g supply 54 μg of vitamin D (250 μg for 100 g

of cod liver oil).
• Salmon: pink salmon has two times more vitamin D (15 μg/100 g)
than wild Atlantic salmon (8 μg/100 g), with the latter having
slightly more vitamin D when produced by farming (7 μg/100 g).
Trout is a little less rich in vitamin D (11 μg/100 g).
• Herring: 100 g is sufficient to supply almost half the daily require-
ments. The cooking mode influences the level of vitamin D: 100 g
of marinated herring supplies 12–22 μg of vitamin D, when oven
cooked or broiled a piece of 100 g supplies 16 μg.
• Fried mackerel, grilled or canned sardines: 100 g provides about

12 μg of vitamin D.
• Canned tuna: 100 g of natural white tuna (albacore) contains about
5 μg of vitamin D; 100 g of tuna in oil contains 3 μg.
• Egg yolk: a 100-g raw egg yolk provides 3 μg of vitamin D, but
2 μg/100 g for cooked egg yolk.
• Cow milk: 250 mL of whole milk provide 3 μg of vitamin D, equiva-
lent to 20% of the recommended daily intake in children and adults.
• Veal liver: 100 g provide about 2.5 μg of vitamin D, nearly one quar-
ter of the recommended daily intake. Beef liver is a little less rich
(about 1.2 μg).
It is now possible to find on the French market dairy products fortified

with vitamin D (milk, yogurt). There are also vegetable oils supplemented
with vitamin D (Isio 4 Lesieur with 0.5 mg/L).
7.5 Vitamin E
Vitamin E is a generic term that encompasses eight molecules with closely
related structures (vitamers). They may be distributed in two groups:
four tocopherols or vitamin E with a saturated side chain (Figure 7.7)
and four tocotrienols or vitamin E with an unsaturated side chain
(Figure 7.8). All these compounds are specific to the plant world and
essential to humans who have to get them from their food (Leray 2015).
α-Tocopherol is the most common form and is often used to define
chemically and physiologically the “vitamin E.”
R2 O
HO
R1
R1 R2
CH3 CH3 α-Tocopherol

CH3 H β-Tocopherol
H CH3 γ-Tocopherol
H H δ-Tocopherol
Figure 7.7 Tocopherols.

R2 O
HO
R1
R1 R2
CH3 CH3 α-Tocotrienol

CH3 H β-Tocotrienol
H CH3 γ-Tocotrienol
H H δ-Tocotrienol
Figure 7.8 Tocotrienols.
All compounds forming the vitamin E complex are, to varying

degrees, powerful antioxidants, protecting cellular and circulating lipids.
The amounts of vitamin E are expressed in milligram equivalents of
α-tocopherol; the other vitamers are usually estimated by applying a speci-
fic coefficient (0.56 for β-tocopherol, 0.16 γ-tocopherol, 0.5 for δ-tocopherol,
and 0.16 for α-tocotrienol).
The IU is not frequently used, with 1 IU corresponding to 0.67 mg of
natural α-tocopherol (RRR-α-tocopherol) or 0.91 of synthetic α-tocopherol
(all-rac-α-tocopherol).
In the United States, the recommended daily allowance is 15 mg of
α-tocopherol in adults for both men and women. A serum α-tocopherol
concentration of ≥30 µmol/L is considered as a desirable target for health
benefits, with manifest clinical symptoms of vitamin deficiency being
reported below 8 µmol/L. It has been estimated that in the United Kingdom
and the United States more than 75% of the population do not meet the
recommended daily intake.
The EFSA recommends a daily intake of 5 mg vitamin E (α-tocopherol
equivalent) in the very young child (7–11 months) and an intake from 6 to
9 mg in children (1–10 years). In adolescents (>10 years) and adults, the
EFSA recommends an intake of 11 mg in women and 13 mg in men. For
people of more than 75 years, the recommended intake should be higher
(up to 50 mg/day). In pregnant or nursing women, the EFSA considers that
it is not necessary to increase the vitamin E dietary intake.
Plant products are the main source of vitamin E in humans, with
the richest being oils from seeds and grains (maximum for wheat germ
oil, 2600 mg/L). The distribution of the different vitamin E vitamers varies
with the source: wheat, corn, soybean, and peanut contain mostly tocopher-
ols, whereas palm oil, rice, oat, and barley contain mostly tocotrienols. The
vitamin E content of fruits and vegetables is very low. Thus, the vitamin E
status may be improved in encouraging the consumption of vitamin

E-rich food sources (e.g., vegetables, dairy products, eggs), an adequate
fortification of food products (e.g., vegetable oils), and a supplementation.
7.6 Cholesterol
Cholesterol (Figure 7.9), as phytosterols or sterols, belongs to the large
group of steroids. All derive from squalene, after formation of a core with
four cycles, the sterane core. Cholesterol may be the source of many other
compounds, such as steroid hormones, bile acids, and vitamin D.
Cholesterol is the major sterol in animals where it participates in build-
ing cell membranes to which it brings a certain rigidity. It is particularly
concentrated in the nervous system, adrenal glands, liver, and gallstones.
It was isolated for the first time in 1770 by F. Poulletier de la Salle in gall-
stones and found in animal fats in 1815 by M. E. Chevreul, who named
it “cholesterine” (from the Greek khole = bile and stereos = solid). With
few exceptions, cholesterol is absent from plants.
It is estimated that the body of an adult man contains about 100 g
of cholesterol and that his daily needs are about 1 g. Ten percent to 20%
of that supply comes from food, with the rest being produced endogenously
(mainly in the liver and intestines). Cholesterol metabolism varies among
individuals and probably depends on their age. Disruption of its biosynth-
esis is the cause of hypercholesterolemia, whether hereditary or acquired.
The regulation of cholesterol biosynthesis occurs mainly in the liver from
acetyl-coenzyme A (CoA) through several enzymatic steps and more parti-
cularly through the key enzyme in that metabolism, hydroxymethylglutar-
yl-CoA reductase. This enzyme is also the target of statins, a family of drugs
used to fight against elevated circulating cholesterol. When excessive cho-
lesterol amounts are absorbed from the intestine, its synthesis in the liver
is less efficient. It follows that, in the majority of subjects, any dietary inter-
vention will have little impact on blood cholesterol levels.
H H
HO
Figure 7.9 Cholesterol.

There is no official recommendation for a daily cholesterol intake.

Although a positive link between dietary cholesterol and a risk of cardio-
vascular disease is suspected, an important intake reduction does not
seem desirable because it would be necessarily accompanied by a large
change in eating habits. It seems however reasonable from a dietary point
of view not to exceed an intake of 300 mg of cholesterol per day. It is recog-
nized that the plasma concentration of total cholesterol in healthy adults
should be between 1.8 and 2.5 g/L (between 4.6 and 6.3 mmol/L). Among
the commonly consumed foods, only five deserve a special attention: three
offals (brain, kidney, and liver), eggs, and butter. Because of their high
cholesterol content, it is recommended that they be moderately consumed
(Leray 2015).
7.7 Phospholipids
Phospholipids are mostly glycerophospholipids; therefore, they contain
one molecule of glycerol esterified with two fatty acids, most frequently
different from each other, and a “head group.” This polar head group
gives an originality to phospholipids; thus, for the most important, it
is a phosphocholine for phosphatidylcholine, a phosphoserine for phos-
phatidylserine, and a phosphoethanolamine for phosphatidylethanola-
mine. They are the main lipid constituents of cellular membranes and
are therefore present in all meats, but they also are in the form of fat
depots in milk and egg yolk. Plants also contain these phospholipids,
but their content remains low (up to 0.2%), greatly reducing their nutri-
tional value except when consumed in the form of supplements prepared
from seeds. Their interest lies in their polar head and their fatty acid con-
tent (Leray 2015).
7.7.1 Phosphatidylcholine
Phosphatidylcholine (Figure 7.10) is the most abundant phospholipid in
animal and plant tissues (almost 50% of total phospholipids). It contains
about 14% by weight choline. The most often encountered fatty acid is
palmitic acid (16:0) in the sn-1 position (R1) and oleic acid (18:1 ω-9) or
LA (18:2 ω-6) in the sn-2 position (R2).
The historical term “lecithin” (from the Greek lecithos, egg yolk) is
often used for this phospholipid. It was named by the French chemist
N. T. Gobley in 1845 after its discovery in the egg yolk. By extension, the
term lecithin is used in food industry to denote a mixture rich in phospho-
lipids (at least 60%); therefore in phosphatidylcholine, its content in neutral
lipids (or simple lipids), being less than 40%. This lecithin is extracted
from various animal (egg yolk) or vegetable (soybean or others) sources.
O O
P
R1 O O – O CH3
O +
N
R2 O H CH3
CH3
Figure 7.10 Phosphatidylcholine (R1 and R2 are the fatty acid carbon chains).
O
O O
H
P OH
R1 O O O
HO NH2
O H
R2
Figure 7.11 Phosphatidylserine (R1 and R2 are the fatty acid carbon chains).
Crude soybean oil is the vegetable oil with the highest lecithin concentra-
tion (1%–3%).
Choline is the most specific component of phosphatidylcholine and
must be supplied to the body at a suitable level (400 mg daily for adults,
EFSA source). A dietary supplementation in phosphatidylcholine is
recommended in various pathological situations, but the role of choline
has not been well discriminated from that of the remainder of the
molecule.
7.7.2 Phosphatidylserine
Phosphatidylserine (Figure 7.11) is a minor constituent of cell membranes,
but the nervous system, especially the white matter, contains large
amounts of this phospholipid (up to 18%). One of its features is to have
a very unsaturated fatty acid (often DHA) in sn-2 (R2). It can be consid-
ered a bioactive lipid, because it is involved in several physiological
mechanisms, such as activation of protein kinase C and initiation of blood
coagulation.
7.8 Apolipoprotein E
The apolipoprotein E (ApoE) forms a class of apolipoproteins found in the
blood at the level of chylomicrons and mainly at the level of the very-
low-density lipoproteins. They are able to bind specifically to receptors
located primarily on the hepatocyte surface. These proteins are essential
for the transport and the metabolism of the constituents of triglyceride-rich
lipoproteins. They are, for example, essential for the cholesterol supply of
nerve cells (internalization phenomenon). The genetic heterogeneity of
ApoE was highlighted early. In humans, the coding gene for these proteins
is located on chromosome 19.
Three alleles (isoforms) have been described: ApoE2, ApoE3, and ApoE4,
thus determining six genotypes. With a frequency of 55%, the E3/E3 geno-
type is the most common in France; it is not linked to any known pathology.
The E4 allele is recognized as the main genetic risk factor for the non-
familial form of Alzheimer’s disease, especially if the subjects have two
copies of that allele (E4/E4). Indeed, the risk of developing the disease
for the carriers having the heterozygous form E3/E4 is 3.2 times higher than
that of E3/E3, with the homozygote carriers (E4/E4) having a 11.6 times
higher risk. It has also been suggested that the ApoE4 allele limits the trans-
port of DHA in the brain, probably at the level of the blood–brain barrier.
Thus, it would reduce the tissue metabolism of DHA and could cause very
damaging local deficiency.
7.9 Evaluation of cognitive performances

The estimation of brain function is done in various ways, but in leaving
aside the personality assessment, only the cognitive performances and
the tests used to evaluate the efficiency of the various types of memory
or the intellectual level are summarized here.
7.9.1 Different types of memory

Memory is, with learning, one of the higher features enabling humans to
acquire and retain information deemed necessary for later use, thereby
enabling the development of new skills gradually throughout life. There-
fore, memory may be considered as the result of learning: it is the record
of our contacts with the world that are saved in our neural network. In fact,
despite great progress, memory remains at the center of much controversy
for neuropsychologists. The identification and the systematic classification
of the various types of memory, both in humans and animals, rely heavily
on the observations of specific memory impairments after a lesion of a
defined brain structure. Historically, the starting point of the classification

of the different types of memory was based on the description in 1957 of a
patient, by Scoville and Milner. The man, aged 27 years, had normal
intelligence, but a bilateral and total ablation of the anterior areas in the
median temporal lobes. The aim of that surgical operation was to remove
severe epilepsy crises. Postoperatively, the patient developed total antero-
grade amnesia (inability to permanently keep new information) and a
retrograde amnesia, covering a 1- to 10-year period before the operation.
His other cognitive abilities (social, verbal, emotional) were preserved;
the patient retained a capacity to acquire and retain some information
under certain circumstances.
The description of the preserved and lost memory capacities in this
patient has been the source of modern memory classifications. Conven-
tionally, function is divided mainly into two categories:
1. Working or short-term memory, which seemed preserved in the

patient
2. Long-term memory, itself divided into two subclasses
2a. Declarative memory (or explicit memory), the conscious, inten-
tional recollection of information. It depends on the integrity of
the median temporal lobe.
2b. Nondeclarative memory (or implicit memory), the unconscious,
unintentional form of memory (procedural memory).
7.9.1.1 Working or short-term memory: Baddeley model

The working memory concept was proposed in 1974 by Baddeley and
Hitch. Working memory is a form of short-term memory essential for all
the cognitive activities. It is based on the temporary storage of a limited
amount of information, enabling associations with other events. It requires
all the immediate attention of the subject, and it was found to be involved
in the performance of many cognitive tasks, remaining in relation to the
long-term memory systems.
Recently, the trend is to separate working memory and short-term
memory. The latter allows for information to be remembered for up to
1 minute and can restore it within that period. This memory is used, for
example, when it is necessary to restore in a definite order a series of ele-
ments (such as figures) that were previously given. Generally, it is possible
to hold between five and nine elements (one keeps usually seven, some-
times called “magic number”).
Working memory has been separated from the short-term memory
owing to the development of new analytical techniques. It allows for cog-
nitive treatments on previously stored items. It could be involved in rea-
soning processes such as reading, writing, and calculating. It could also
play a role, for example, when it is necessary to list in descending order a

series of numbers previously set in an ascending order. This type of
memory would be widely used by an interpreter in the exercise of a simul-
taneous translation.
7.9.1.2 Long-term memory

Modern conceptions of memory refer usually to long-term memory and
break it down into two main subclasses: declarative memory and a nonde-
clarative memory, primarily on the criterion of a conscious or not conscious
recall of information, respectively. This classification is based on the psy-
chological characteristics of the information to be stored and on the
brain structures for which integrity is required for managing this informa-
tion (encoding, storage, retrieval). Long-term memory is used to store sig-
nificant events experienced throughout the life, but also to remember
the meaning of words and manual skills. Its capacity seems unlimited;
it may last a few minutes, days, months, or years, or even a lifetime. Unfor-
tunately, its reliability tends to decrease with age.
2a. Declarative memory (explicit or relational or recognition mem-

ory) refers to what is commonly considered the “memory” in
the everyday life, and it corresponds to “to know that.” It relates
to the acquisition of specific autobiographical facts or general
rules learned by repetition (learning by heart), such as grammar
rules and multiplication tables. Then, these data consciously
emerge expressing this memory through language; hence, the
term declarative.
Neuropsychologists often use the term explicit memory. It has
been subdivided into two categories: episodic memory that stores
specific personal experiences and semantic memory that stores
factual information.
• Episodic memory concerns autobiographical memories and
allows explicitly to recall personal events stored in the hippo-
campus. It is in that brain area, a part of the limbic system,
that different aspects influencing our behavior are managed:
fear, aggression, and pleasure. It was shown that the hippo-
campus of London taxi drivers is overdeveloped related
to their ability to connect places between them owing to a
mental mapping. Recent investigations state that memories
are stored for a few days in the hippocampus and then trans-
ferred slowly, during a few weeks, toward cortical areas
specialized for the “older” memories. Episodic memory
enables us to remember the past (e.g., meal of the day before,
name of an old friend, or a historical date) and to plan for
the next day. It is that form of memory that helps us to
“travel mentally in space and time.” A disorder of the episo-

dic memory is observed in the Korsakoff’s syndrome and
during bitemporal amnesia.
• Semantic memory is the memory of knowledge and learned
facts, such as those acquired during schooling (depending on
the parahippocampal region). This memory allows, through a
wide association network, to form the world’s knowledge in
a broader sense. It forms a database owned by everybody and
that is quickly available, as in the memory of the meaning of
words, capital names, traditional customs, object functions,
color, or even the smells of objects. The semantic memory is used
daily (e.g., highway code, grammar and conjugation rules). The
disorders of this memory are associated with deficits in higher
cognitive functions such as the language, the ability to recog-
nize a face or perceive the shape of an object (gnosis), and the
coordination of gestural activity (praxis). This is the memory
affected very early in patients with Alzheimer’s disease. The
exact location of semantic memory in the brain, the conditions
of its formation, and its links with the episodic memory continue
to be debated.
2b. Nondeclarative memory (implicit or procedural memory) is a
heterogeneous set of capabilities dependent of multiple brain sys-
tems; it corresponds to “to know how.” Unlike declarative mem-
ory, it is inaccessible to consciousness. Neuropsychologists often
use the term implicit memory. It is used during the motor, percep-
tual, or cognitive learning requiring repeated training, and it is
mainly the memory of habits and skills, such as cycling. It is also
subdivided into several subgroups, but the most important form
is the form concerning the procedural memory. The latter, also
known as automation memory, concerns the learning of many
skill types. It operates at an automatic level and can be expressed
in a normal manner without requiring the integrity of hippocam-
pal structures, but it is dependent on the striatum. For example,
the act of driving a car requires some automation related to pro-
cedural memory, allowing the driver not to be aware constantly
of the necessary gestures. This memory is especially requested
by athletes and artists.
7.9.2 Evaluation of memory capacity by MMSE

The Mini-Mental State Examination (MMSE, or Folstein test), commonly
used in neurology, evaluates quickly memory problems reported by a
subject. It allows to quickly give a physician or psychologist an idea of
the condition of a patient with suspected dementia. The MMSE is a
global cognitive evaluation tool and is used to establish various aspects

of the cognitive state of patients, but not enough for a definitive diagno-
sis. It is only a tool to direct toward other investigations. Thus, it explores
a person’s sense of time and space, attention to details, ability to calcu-
late, language skills, and constructional praxis. The results can be inter-
preted based on normative values, taking into account the age and
education of the subject.
Below is an example of various tests, but there are variations depend-
ing on neurology centers.
Orientation test
1. What is the year?

2. What is the season?
3. What is the month?
4. What is the day?
5. What is the day of the week?
6. Where are we now?
7. In what state?
8. In what city?
9. What is the hospital's name?
10. What floor (or place, cabinet, etc.)?
Learning test
The examiner names three unrelated objects (e.g., flower, door, car)
clearly and slowly and then the patient is asked to name all three of them
and to remember them. The patient’s response is used for scoring:
11. flower
12. door
13. car
Attention test and calculation

The examiner asks the patient to count backward from 100 by sevens
(ask for five subtractions).
14. 100 − 7 = 93
15. 93 − 7 = 86
16. 86 − 7 = 79
17. 79 − 7 = 72
18. 72 − 7 = 65
As an alternative, ask to spell the word “WORLD” backwards? —>

DLROW (one point per letter given in the correct order.)
Recall test
What were the three names of objects presented below?
19. flower
20. door
21. car
Test of language
22. Show a pencil: “What is the name of this object?”

23. Show a watch: “What is the name of this object?”
24. “Repeat after me: No if, and or but.”
25. “Take the paper in your right hand.” (The examiner gives the
patient a piece of blank paper.)
26. “Fold it in half”
27. “Put it on the floor”
28. Show on a sheet of paper on which is written in large letters CLOSE
EYES and say “Please read this and do what it says.”
29. Give a sheet of paper and ask the following: “Make up and write a
sentence about anything.” (This sentence must contain a noun and
a verb.)
Test of constructive praxis
30. Give the subject a piece of paper with a geometric design (two pen-
tagons, 10 angles, but two must intersect) and request, “Please copy
this picture.”
Total score (from 0 to 30, one correct answer per point). Below 27 points, it
can be considered that there is a deficit that may or may not progress to
dementia. According to a recommendation of the French High Authority
for Health, a score less than or equal to 24 points enables to evoke an altered
state of consciousness and gives an indication to the diagnosis of dementia.
7.9.3 Test of executive functions

Executive functions, sometimes called “cognitive control” or “supervisory
attentional system,” are necessary for monitoring and execution of com-
plex, new, and not automatic tasks. They allow the subject to set goals
and to forecast a strategy to achieve them. These functions have been
defined in various ways, but traditionally they are related to planning
and execution behavior, abstract reasoning and judgments. From a prac-
tical point of view these higher level functions correspond to the efficiency
that an individual displays to use his knowledge necessary to lead his
everyday life. Although nonexclusive, the structures of the frontal lobes

are considered as fundamental to the smooth running of these functions.
Suitable techniques enable to appreciate one important aspect of executive
functions and cognitive flexibility. The latter may be defined as the ability
of an individual to adapt to new situations or new rules.
If a neurodegenerative disease is suspected, the neuropsychological
examination should help to assess the extent and severity of the cognitive
impairment by practicing a test of executive functions. Among the tests
used in that field, the Trail Making Test (TMT) is the most used. Devel-
oped in 1944 by the US Army, the TMT has been very successful with clin-
ical psychologists, due to its simplicity and speed. It is a motor and visual
screening test involving attention and reaction speed.
The TMT has two parts:
• Part A is to connect with a pencil, as fast as possible and in ascend-
ing order, the series of numbers ranging from 1 to 25 semirandomly
distributed on a sheet of paper. This part A is particularly indicative
of the cognitive processing speed.
• Part B is to juggle between two alternating series: a series of figures
and a series of letters. Thirteen circles containing the numbers from
1 to 13 and 12 circles with the letters A to L are distributed semiran-
domly on a paper sheet. The subject must connect as quickly as
possible numbers and letters in their respective order, alternating
each time between a number and a letter. This part B is useful to
examine the executive functioning itself. Errors are recorded and
also the time it takes the patient to perform the task.
Numerous studies have reported the existence of considerably reduced
performances in various dementia syndromes such as Alzheimer’s disease
and even in cases of mild cognitive decline.
For screening Alzheimer’s disease, the patient’s opinion may be taken
into account, but it may be distorted due to memory problems. The eva-
luation by a clinician is more objective, but it may be supplemented
by questioning the immediate entourage, allowing an appreciation of
the subject behavior in the activities of daily living. As emphasized by
all the Alzheimer’s associations, the entourage can efficiently contribute
to the detection of the first signs of the disease. That approach helps the
specialist to practice, if necessary, a medical evaluation, a brain imaging
investigation, or neuropsychological tests. The latter particularly notes
the changes in habits and everyday repeated incidents.
The following indices are particularly noted:
• Difficulties recording information

• Changes in mood and behavior
• Language problems
• Disorientation in time and space

• Judgment and reasoning losses
• Difficulty in managing money
The main purpose of the cognitive assessment by the clinician is the screen-
ing and the estimation of the severity of the trouble and its evolution. The
forms of the disease where deterioration seems evident (MMSE < 20) are
explored with more accurate and sensitive neuropsychological tools.
A large number of tests are currently available; 18 tests using a computer
were already listed in 2008 (Wild et al. 2008, Status of computerized cogni-
tive testing in aging: a systematic review. Alzheimer’s Dement. 4:428–437).
The assessment of cognitive functions is often done with the Alzheimer’s
Disease Assessment Scale-cognitive (ADAS-cog) and may be performed in
45 min. This test was developed in the United States by Ros in 1984. Its score
ranges from 0 to 70. It is thus possible to estimate the average degradation of
the cognitive performances for the mild and moderate stages of the disease
by a loss of 6–8 points per year against 2–4 MMSE points per year. Below,
a summary of the various steps performed during this test is given. In an
interview, a series of questions is asked about classmates and friends.
Depending on the interview, the following are noted:
• Intelligibility of the spoken language.
• Comprehension.
• Lack of words.
• Reminder words (from a list of 10).
• Designate the fingers one by one in a given order.
• Set a date and time.
• Execution of orders, e.g., make a fist, double-tap with two fingers on
each of your shoulders, keeping your eyes closed.
• Praxis: Fold a sheet of paper, put it in an envelope, stick the envel-
ope, write the address, and apply a stamp.
• Constructive praxis: Copy simple geometric figures.
• Word recognition: 12 words among 24 words presented to the patient.
• Instructions reminder: Evaluation of the patient’s ability to retain the
instructions of the previous test.
This test can be completed by the assessment of noncognitive functions for

depression, anxiety, autonomic dysfunction, behavior disorders, initiative
in daily activities, psychotic symptoms, motor activity, restlessness, and
night confusion.
7.9.4 Global deterioration scale

This scale, also called the scale of Reisberg, allows healthcare profes-
sionals to measure the progression of Alzheimer’s disease. It sets out
seven stages of deterioration of neuropsychological abilities during the

disease development:
1. No cognitive impairment: no difficulty in daily life

2. Very mild cognitive deficit: forgets names and locations of objects;
may have some difficulty finding words
3. Mild cognitive impairment: difficulty to find way in an unfamiliar
place; difficulty in functioning at work
4. Moderate cognitive impairment: difficulty performing complex tasks
(e.g., finance, purchasing, planning a meal)
5. Relatively severe cognitive impairment: needs help choosing clothes,
needs to be reminded to go to the toilet
6. Severe cognitive impairment: loses sense of experiences and recent
events from life; needs help with bathing or is afraid to bathe; needs
increasingly help to go to the toilet or is incontinent
7. Very severe cognitive deficit: use a very limited vocabulary that will
be reduced to only some words; loses the ability to walk and sit;
needs help to eat
8. A state of dementia is often considered to be characterized from the
stage 4.
7.9.5 Peabody picture vocabulary test

This test was designed to provide a quick estimate of language skills and the
ability to pursue an education. It was developed in 1959 by L. M. Dunn. The
examiner presents to the subject a series of images grouped by four on a
page. These images are numbered. The word describing one of images is
pronounced and the subject is asked to tell (or show) the correspond-
ing number. The final score can be expressed as a percentage, mental age,
or IQ.
7.9.6 Wechsler intelligence test

This test was created by D. Wechsler for children aged 6–17 years; it has
been also adapted for adults. The most used version is that of 1996. It is
the most-used psychometric test in the world and is used even for kids in
major difficulties. It comprises two groups of questions in two general
areas: verbal scales and performance scales. Verbal scales measure general
knowledge, language, reasoning, and memory capabilities. Performance
scales measure the abilities to solve orientation problems in space and
analysis. This scale seems to offer certain advantages over the McCarthy
Scales of Children’s Abilities and also the Stanford–Binet Intelligence Scales.
The test is performed by an examiner using a comprehensive set of
educational materials for a period of about 1 h. Results are usually
processed in IQ. Scores above 130 characterize excellent; between 120 and
130 very high; and between 110 and 120 normal, but intelligent. From 90
to 110, the subject is medium and from 85 to 90 average.
7.9.7 Bayley motor test

The scale of development according to N. Bayley was established in 1969 to
appreciate in children 0–3 years old the evolution of motor movements,
cognition (with language), and behavior. The test runs according to age
in the form of games for 15–60 min. The scores are calculated taking
into account the questionnaires prepared by the parents and others in the
immediate environment (childcare worker, supervisor). These scores are
then compared to values established in many children of the same age
having a development considered as a reference.
The motor movements are estimated by assessing the degree of
control of the body, muscle coordination, manipulation of objects (agility
of the hands and fingers), postural imitation, and recognition of objects by
the sense of touch.
Mental development is evaluated in the areas of perception, memory,
problem-solving, verbal communication, and number appreciation. The
behavior is evaluated with tests of attention, orientation, awakening,
emotion regulation, and quality of movements.
7.10 Kaufman children intelligence test

The Kaufman Test, known as the K-ABC, was established and calibrated
in 1983 in the United States and 10 years later in France. Its author is a
professor of psychology at Yale University, New Haven, Connecticut.
This test is frequently used in academic or clinical psychology to estimate
the intellectual level of children between 2.5 and 12.5 years old. It aims to
measure intelligence and knowledge, while focusing more on the mental
processes that on content. Basically, that test tries to determine how
the child solves problems and his or her ability to do so by relying as little
as possible on language, information, and skills.
The Kaufman Test includes several different scales of intelligence.
In general, only some of them are used in one test.
• The sequential processing scale measures the ability of a child to solve
problems dealing mentally with the stimuli within a series. For
example, to reproduce a sequence of different hand positions, or a
repetition in the order of a sequence of numbers given verbally by
the experimenter.
• The simultaneous processing scale assesses the ability to solve pro-
blems requiring the organization and the integration of many
stimuli, in parallel or simultaneously. For example, name or describe

an incomplete stylized drawing after its presentation; assemble sev-
eral identical triangles to reproduce an abstract model; memorize
the location of randomly placed images on a page.
• The scale of knowledge enables to evaluate a wealth of knowledge and
skills acquired at school or through some awakening to the environ-
ment. For example, vocabulary; characters and known places; and
arithmetic, reading, and understanding. One benefit of the K-ABC
test is the possibility to use it with children suffering hearing disabil-
ities, speech disorder, and language disorders, while visually
impaired children are penalized.
7.11 Estimation of depression

In the area of the depression, the first scale in 20 points was established
in 1977 in the United States by L. S. Radloff. It is still used today by
researchers. Practically, other more simple scales may be used, including
a scale developed by the Danish psychiatrist Per Bech for WHO, under the
form of the Major Depression Inventory (MDI) questionnaire. This test is
also known as the Center for Epidemiologic Studies Depression (CES-D)
scale (http://www.therapiebreve.be/plus/tests/depression-mdi). That
scale allows a self-assessment of the severity of a mood disorder, but it
can be established in the presence of a specialist or remotely, by phone
or even by mail. It enables the exploration of the nine symptoms identi-
fied as diagnostic criteria of a major depressive episode described in the
Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).
This 12-point questionnaire is given below:
1. Have you felt low in spirits or sad?

2. Have you lost interest in your daily activities?
3. Have you felt lacking in energy and strength?
4. Have you felt less self-confident?
5. Have you had a bad conscience or feelings of guilt?
6. Have you felt that life wasn’t worth living?
7. Have you had difficulty in concentrating? (e.g., for watching TV,
reading newspaper)
8. Have you felt very restless?
9. Have you felt subdued or slowed down?
10. Have you had trouble sleeping at night?
11. Have you suffered from reduced appetite?
12. Have you suffered from increased appetite?
Each point is the subject of a choice of an occurrence frequency: at no time,

some of the time, slightly less than half the time, slightly more than half
the time, most of the time, or all the time. The score calculation is weighted
for each question according to the choice of the frequency.
Many other derivatives questionnaires derived from that of Radloff
may be found on websites, but in all cases their use should be only taken
as an alert for the examiner. Confirmation by a specialist consultation is
always necessary.
7.12 Evaluation of aggressiveness and violence

The aggressive state has been studied for a long time in both children and
adults. This is a relatively stable personality characteristic, because it has
been shown that an aggressive state evidenced in children is very predic-
tive of disorders and even delinquency in adolescence, often followed in
adults by criminal behavior. Among the many methods of evaluation,
the Social Dysfunction and Aggression Scale (SDAS) is frequently used.
The questionnaire is divided into 10 parts, with each part being
the subject of a question and a note: 0 = absent, 1 = equivocal, 2 = poor,
3 = moderate, 4 = severe.
The assessments noted by the specialist include the following:
1. Irritability (estimates the reduced ability to cope with situations

considered as provocative by the patient, anger, impatience, and
the reduced ability to control responses)
2. Negative and uncooperative behavior (estimates the reduced abil-
ity to cooperate or to conform to a group)
3. Irritable or dysphoric mood (covers a type of unpleasant feeling
where the patient is moody, testy, and fed up)
4. Socially disruptive and provocative behavior (estimates how the
patient behaves in a provocative manner toward others, including
sexually provocative behavior)
5. Nondirected verbal or vocal aggressiveness (verbal aggressiveness
or noises assumed to represent aggression directed toward others
or things in general)
6. Directed verbal or vocal aggressiveness (covers aggressiveness
directed toward defined persons)
7. Physical violence toward things
8. Physical violence toward staff
9. Physical violence toward others that staff
10. Self-mutilation
Another also widely used method is the Aggression Questionnaire estab-

lished by C. Meesters in 1996. The protocol described by this author
is given below. The questionnaire is divided into four parts: physical
aggression, verbal aggression, anger, and hostility. The subject must note
his or her answers on a scale from 1 (yes, that is true) to 5 (no, that is
wrong). The final note is between 29 and 145.
Physical aggression
1. Once in a while I can’t control the urge to strike another person

2. Given enough provocation, I may hit another person
3. If somebody hits me, I hit back
4. I get into fights a little more than the average person
5. If I have to resort to violence to protect my rights, I will
6. There are people who pushed me so far that we came to blows
7. I can think of no good reason for ever hitting a person
8. I have threatened people I know
9. I have become so mad that I have broken things
Verbal aggression
10. I tell my friends openly when I disagree with them

11. I often find myself disagreeing with people
12. When people annoy me, I may tell them what I think of them
13. I can’t help getting into arguments when people disagree with me
14. My friends say that I am somewhat argumentative
Anger
15. I flare up quickly but get over it quickly

16. When frustrated, I let my irritation show
17. I sometimes feel like a powder keg ready to explode
18. I am an even-tempered person
19. Some of my friends think I am a hothead
20. Sometimes I fly off the handle for no good reason
21. I have trouble controlling my temper
Hostility
22. I am sometimes eaten up with jealousy

23. At times I feel l have gotten a raw deal out of life
24. Other people always seem to get the breaks
25. I wonder why sometimes I feel so bitter about things
26. I know that my “friends” talk about me behind my back
27. I am suspicious of overly friendly strangers
28. I sometimes feel that people are laughing at me behind my back
29. When people are nice, I wonder what they want
Index
A prevalence of, 60
prodromal stage, 60
Acetylcholine, 36 risk of, 54
Acetyl-coenzyme A (CoA), 211 screening tests for, 220–221
Acitretin, 69 vitamin A and, 68–70
Acute myocardial infarction, 173 vitamin D and, 70–77
Addiction, 164–165 vitamin E and, 77–81
ADHD. See Attention-deficit hyperactivity ω-3 fatty acids and, 62–68
disorder (ADHD) Alzheimer’s Disease Assessment Scale-
Adolescents cognitive (ADAS-cog), 61, 221
aggressive behavior in, 168 Amyloid deposits, 47
vitamin D and, 40 Antidepressants, 125, 127
Adrenal glands, 182 Antioxidants, 63–64, 78–79, 139
Adrenaline, 139 Apolipoprotein E (ApoE4) isoform, 35,
Age-related cognitive decline, 45–59 54–55, 61, 81, 214
carotenoids and, 58–59 Aquaculture, 4
symptoms of, 45–46 Arachidonic acid (AA), 9–14, 128, 197
vitamin A and, 57–58 recommended dietary intake, 199–200
ω-3 fatty acids and, 47–57 AREDS2. See Age-Related Eye Disease
Age-Related Eye Disease Study 2 (AREDS2), Study 2 (AREDS2)
55, 59 Aristotle, 1
Aggression Questionnaire, 225–226 Atherosclerosis, 81
Aggressive behavior, 163–174 Atkins diet, 113
cholesterol and, 172–174 Attention, 46
epidemiological investigations on, Attention-deficit hyperactivity disorder
164–167 (ADHD), 150–156
evaluation of, 225–226 epidemiological investigations on, 152
intervention studies on, 167–170 intervention studies on, 153–154
overview of, 163–164 overview of, 150–152
vitamin D and, 170–171, 180 prevalence of, 151
ω-3 fatty acids and, 164–170 symptoms of, 151
Alzheimer’s disease, 35, 45, 47, 59–84 vitamin D and, 154–156
carotenoids and, 70 ω-3 fatty acids and, 152–154, 164
cholesterol and, 81–84 Autism, 19, 39, 149, 156–162
costs of, 60–61 epidemiological investigations on,
diagnosis of, 61 157–161
genetics and, 61–62 geographical distribution of, 161
measuring progression of, 221–222 intervention studies on, 158–159,
phosphatidylcholine and, 36 161–162
227
228 Index
overview of, 156–157 Calcium, 116, 206

prevalence of, 156–157 Caldwell, D. F., 2
vitamin D and, 159–162 Calf liver, 36
ω-3 fatty acids and, 157–159 Cambrian explosion, 1
Automation memory, 217 Cambridge Neurological Test Assessment
Battery, 30
Cannabis, 165
B CARDIA study, 167
Baddeley model, 215–216 Cardiovascular disease, 51, 173, 182, 212
B-amyloid proteins, 81–82, 83 Carotenoids, 204–205
Bartholin, Thomas, 1 Alzheimer’s disease and, 70
Bartholin glands, 1 cognitive decline and, 58–59
Basal ganglia, 27 CARS. See Childhood Autism Rating
Bayley Motor Test, 20, 223 Scale (CARS)
B-carotene, 204–205 Catecholamines, 127
B-complex vitamins, 66–67 Center for Epidemiologic Studies
Behavior disorders, 162–163 Depression (CES-D) scale, 125
aggressive behavior, 163–174 Cerebrovascular disease, 139
suicidal behavior, 174–184 Charcot, Jean-Martin, 101
Bipedalism, 3 Chevreul, Michel Eugene, 1
Bipolar disorder, 127 Childhood Autism Rating Scale (CARS), 157
costs of, 141 Children
epidemiological investigations on, 141–142 foods for, 201–202
intervention studies on, 142 vitamin D recommendations for, 208
prevalence of, 140–141 Cholecalciferol (vitamin D3), 40, 205–206
ω-3 fatty acids and, 140–143 Cholesterol, 211–212
Birth month, 19, 39, 114–115, 155, aggressive behavior and, 172–174
160–161, 181 Alzheimer’s disease and, 81–84
Blood-brain barrier, 46, 84 suicidal behavior and, 181–184
Bone decalcification, 114 vitamin D production and, 207
Brain Choline, 36
maturation of human, 27 Chronic depression, 126
research on, 1–3 CoA. See Acetyl-coenzyme A (CoA)
Brain development, 7–22 Cocaine, 164, 165
critical period of, 8–9 Cod liver oil, 11, 106, 208
duration of, 27 Cognitive assessment, 47, 53, 217–221
nutrition and, 7 Cognitive decline, 45–84; See also
vitamin D and, 19–21 Alzheimer’s disease; Dementia
vitamin E and, 21–22 age-related, 45–59
ω-3 fatty acids and, 7–19 carotenoids and, 58–59
Brain lipids, 1–3 vitamin A and, 57–58
Brain plasticity, 46, 57 ω-3 fatty acids and, 47–57
Brain volume, 3, 46 vitamin D and, 73–74
Brain weight, 9 Cognitive development, 27–40
Breastfeeding, 7, 9–15 breastfeeding and, 10–11
Breast milk, 8, 10, 16–17, 172 DHA and, 10–13
Brown-Goodwin Assessment (BGA), 163 fatty acids and, 18, 36–39
intervention studies on, 32–35
tests of, 28–29
C
vitamin D and, 19, 39–40
Calcidiol, 206 vitamin E and, 22
Calcitriol, 206 ω-3 fatty acids and, 27–36
Index 229
Cognitive performance, evaluation of, Parkinson’s disease and, 97, 99

214–224 in pregnancy, 10–14, 18
Corn oil, 11, 80 schizophrenia and, 144–147
Corticotropin-releasing factor, 165 vitamin D, 74–77, 99, 105–106, 108–110,
Couerbe, Jean-Pierre, 1 116, 161–162
Crawford, Michael, 3 vitamin E, 79–80, 100–101
Critical periods, 22 ω-3 fatty acids, 32–35, 48–57, 97, 104–105,
Cycle of violence, 183 130–135, 144–147, 158–159,
Cytokines, 134, 180 167–170, 197–198, 202–203
Docosahexaenoic acid (DHA), 1, 2, 3, 197
ADHD and, 152–154
D aggressive behavior and, 164, 166,
168–170
Declarative memory, 36, 46, 216–217
Alzheimer’s disease and, 64–68
Dementia, 35, 45, 47, 59–84
autism and, 157–159
carotenoids and, 70
bipolar disorder and, 141–142
cholesterol and, 81–84
brain development and, 7–19
costs of, 60–61
cognitive development and, 31
diagnosis of, 48–49, 61
deficiency, 8–9, 129
phosphatidylcholine and, 36
depressive disorders and, 128–129, 133
prevalence of, 60
in fish, 201
types of, 59
Parkinson’s disease and, 97
vitamin A and, 68–70
RDA for, 17–18
vitamin D and, 70–77
recommended dietary intake, 199–200
vitamin E and, 77–81
schizophrenia and, 144–147
ω-3 fatty acids and, 62–68
sources of, 198–201
Depressive disorders, 124–140
suicidal behavior and, 176, 179
costs of, 124–125
supplementation, 33–35, 54–57
estimation of, 224–225
Domestic violence, 165
prevalence of, 124, 125, 127
DOMIno study, 10–11, 13
symptoms of, 125
Dopamine, 99, 133, 135, 139, 144, 165
treatment of, 125, 134–135
Drug addiction, ω-3 fatty acids and,
164–165
Dysthymia, 126
DHA. See Docosahexaenoic acid (DHA)
Diabetes, 67 E
Diagno, 207
Diagnostic and Statistical Manual of Mental EDEN study, 13
Disorders (DSM-IV), 123, 150–151 Eggs, 36, 209
Dietary approach, to treatment, 4–5 Eicosapentaenoic acid (EPA), 2–3, 7–8,
Dietary supplementation 31, 197
ADHD and, 152–154 ADHD and, 152–154
aggressive behavior and, 167–170 aggressive behavior and, 164–165,
Alzheimer’s disease and, 64–68 169–170
autism and, 158–159, 161–162 Alzheimer’s disease and, 64–66
bipolar disorder and, 142 autism and, 157–159
B vitamins, 66–67 bipolar disorder and, 142
carotenoids, 205 depressive disorders and, 128, 131–134
cognitive development and, 32–35 in fish, 201
depressive disorders and, 130–135 Parkinson’s disease and, 97
fish oil, 18 recommended dietary intake, 199–200
multiple sclerosis and, 104–105 schizophrenia and, 144–147
230 Index
sources of, 198–201 Fish oil, 8, 10, 11, 18, 202–203

suicidal behavior and, 176, 179 aggressive behavior and, 168–169
Elderly bipolar disorder and, 142
cognitive decline in, 45–59 cognitive decline and, 54–57
memory disorders in, 46 cognitive development and, 33–34
ω-3 fatty acids and, 48 depressive disorders and, 132
Environmental influences, 27 epilepsy and, 112–113
EPA. See Eicosapentaenoic acid (EPA) MS and, 103, 106
Epilepsy, 4, 19, 39, 110–117 FondaMental Foundation, 5
birth month and, 114–115 Free radicals, 22, 139
overview of, 110–112 Frontotemporal dementia (Pick’s disease),
pharmaceutical treatments for, 111 59, 61
prevalence of, 111
ω-3 fatty acids and, 112–114 G
Episodic memory, 47, 50, 216–217 Galen, 1
Ergocalciferol (vitamin D2), 40, 206 Genetics
Essential fatty acids, 7, 197–198; See also cognitive decline and, 54–55, 61–62
ω-3 fatty acids; ω-6 fatty acids cognitive development and, 27
brain development and, 7–19 cognitive function and, 74
cognitive development and, 27–32 multiple sclerosis and, 102
dietary allowances of, 198–203 Parkinson’s disease and, 96
Eukaryotes, 1 Global deterioration scale, 221–222
Executive function, 52, 59 Glycerol, 212
tests of, 219–221 Gobley, Nicolas, 1
Executive memory, 47 Grand mal seizures, 116
F H
Fatty acids; See also ω-3 fatty acids; HDL. See High-density lipoprotein (HDL)
ω-6 fatty acids Herring, 208
cognitive development and, High-density lipoprotein (HDL), 82–83
36–39 Hippocampus, 30, 47, 150
deficiency, 2 Holman, R., 27
functions of, 3–4 Homicide rates, 126, 166–167
marine, 1, 3 Homo habilis, 3
phosphatidylcholine, 36–37 Homo sapiens, 3
phosphatidylserine, 37–39 Hopkins Symptom Checklist 90 (SCL-90),
saturated, 30 162–163
Fetal development, 8, 9 5-hydroxyindolacetic acid (5-HIAA), 163, 176
Fish consumption, 8, 18, 30, 197–201 Hypertension, 45, 67
Alzheimer’s and, 63
cognitive decline and, 47–54
I
depressive disorders and, 127,
128–130, 132 Impulsivity, 31, 151, 169, 183–184
drug use and, 165 Infant formulas, 17, 18, 201–202
homicide and, 166–167 Infants
multiple sclerosis and, 103–104 foods for, 201–202
in pregnancy, 198, 200 preterm, 13
schizophrenia and, 144 Inflammation, 129, 134, 139, 180
suicidal behavior and, 176 Information processing, 31
vascular dementia and, 68 Intelligence quotient (IQ), 11, 12, 14
Index 231
Intelligence tests, 222–224 Maternal nutrition, 7, 8, 17–18

Interferons, 134 McCarthy Scales of Children’s
Interleukins, 134 Abilities, 222
International Classification of Diseases Mediterranean-DASH Intervention for
(ICD), 123 Neurodegenerative Delay
Iron deficiency, 35 (MIND) diet, 64
Mediterranean diet, 64
Melatonin, 136
K
Memory, 31, 34
Kaufman Assessment Battery for Children, antioxidants and, 78–79
11, 223–224 cholesterol and, 81
Ketogenic diet, 113, 115 declarative, 36, 46, 216–217
Kraepelin, Emil, 143 disorders, 46, 47, 59
Krill oil, 36 episodic, 47, 50, 216–217
evaluation of, 217–219
executive, 47
L long-term, 216–217
Language development, 11, 21 nondeclarative, 217
Lassek, W. D., 29, 30 relational, 30
L-DOPA, 95, 96 semantic, 50, 216, 217
Lecithins, 36–37, 212–213 spatial, 46
Levodopa, 95 types of, 214–217
Life expectancy, 5, 45 working, 31, 46, 215–216
“light boxes,” 114 Mental disorders, 123–184
Light therapy, 135–136 ADHD, 150–156
Limbic system, 30 aggressive behavior, 163–174
Linoleic acid, 126, 197–200 autism, 156–162
Linolenic acid, 2, 3, 8, 10, 11, 16–17, 19, 35, behavior disorders, 162–163
197–198 bipolar disorder, 140–143
deficiency, 27 classification of, 123
excess, 47–48 costs of, 5, 123
recommended dietary intake, 199–200 depressive disorders, 124–140
suicide and, 177 dietary approach to, 4–5
LipiDiDiet, 67 overview of, 123
Lipid oxidation, 139 personality disorders, 162–163
Long-term memory, 216–217 prevalence of, 5, 123
Lutein, 58–59, 70, 205 psychotic disorders, 143–150
Lymph system, 1 schizophrenia, 143–150
suicidal behavior, 174–184
Mercury, 52, 53, 198, 200, 203
M Mild cognitive impairment (MCI), 45–49,
Mackerel, 49, 209 59, 61
Macula, 58 Milk, 209
Mad cow disease, 37–38 MIND diet, 64
Magnetic resonance imaging (MRI), 50, 61, 150 Mini-Mental State Examination (MMSE), 47,
Major Depressive Inventory (MDI), 224–225 61, 72, 217–219
Mania, 140 Mitochondria, 1
MAPT. See Multidomain Alzheimer MMSE. See Mini-Mental State
Preventive Trial (MAPT) Examination (MMSE)
Marine animals, depletion of, 3–4 Monkeys, 9
Marine fatty acid, 1, 3; See also Monoamines, 139
Fish consumption; Fish oil Montaigne Institute, 5
232 Index
Mood disorders, 4 P
bipolar disorder, 140–143
PAQUID study, 63, 136
depressive disorders, 124–140
Parkinson’s disease, 95–101
suicide and, 180
MooDFOOD study, 133 diagnosis of, 96
genetics and, 96
Motor development, 10
Multidomain Alzheimer Preventive Trial prevalence of, 96
(MAPT), 66
Multiple sclerosis (MS), 4, 19, 39, 101–110, 149
genetics and, 102
Peabody picture vocabulary test, 222
geographical distribution of, 106
Personality disorders, 162–163
overview of, 101–102
Pharmaceutical companies, 5
pharmacological treatments for, 102
Phosphate, 206
prevalence of, 102
Phosphatidylcholine, 36–37, 212–213
Phosphatidylserine, 37–39, 213
Phospholipids, 212–213
Myelin development, 14
Photoreceptor lipids, 2
Myelin sheath, 2, 27
Phytoplankton, 7–8
Pick’s disease, 59
N PISA test scores, 16–17
Plato, 1
Nerve growth factor, 148 Pollution, 52, 53, 198, 200, 203
Nervous system, 19, 21, 27, 35, 78 Polyunsaturated fatty acids (PUFAs), 177,
Neurogenesis, 8, 18 199–200
Neurological disorders Postpartum depression, 130, 132–133
epilepsy, 110–117 Prefrontal cortex, 27, 141
multiple sclerosis, 101–110 Pregnancy
Parkinson’s disease, 95–101 depression during, 125
Neuronal plasticity, 7 dietary supplementation in, 10–14, 18
Neurotransmitters, 46, 135, 144, 165 fish consumption in, 53, 198, 200
Newborns, low-weight, 7, 10 time of year of, 19, 39, 107, 114–115, 155,
Nielsen, N. C., 2 160–161, 181
Nondeclarative memory, 217 vitamin D in, 19–21
Norepinephrine, 135 Preterm infants, 13
Nucleus, 1 Program for International Student
Nurses Health Study, 58 Assessment (PISA), 16–17
Nutraceuticals, 33 Proline, 149
Nutrigenomics, 54 Prostaglandins, 14, 127
Nutrition Prostanoids, 127
brain development and, 7 Psoriasis, 69
cognitive decline and, 47–48 Psychiatric disorders. See Mental disorders
maternal, 7, 8, 17–18 Psychometric tests, 61, 72
postpartum depression and, 133 Psychotic disorders, 143–150
O
R
O’Brien, John S., 1–2
Orbitofrontal cortex, 129 Rats, 9, 36
Osteomalacia, 114 Reading ability, 31
Oxford Project to Investigate Memory and Reisberg scale, 221–222
Aging (OPTIMA) study, 66 Relational memory, 30
Oxidative stress, 22, 100, 129, 134, 139 Retina, 1, 2, 58
Index 233
Retina-midbrain-epiphysis neuroendocrine Suicide, 124, 140, 173

pathway, 135 Sun exposure, 19–20, 103, 106–107, 115, 136,
Retinoic acid, 68–69 155, 160–161, 181, 207, 208
Retinoids, 57–58, 203–204 Swordfish, 49
Rotterdam study, 47–48
T
S
Targretin, 69
Salmon, 49, 50, 53, 141, 167, 208 Tau protein, 83
Sardine oil, 36 Third National Health and Nutrition
Sardines, 49 Examination Survey, 136
Saturated fatty acids, 30 Thudichum, Johann, 1
Schizophrenia, 19, 39, 107, 143–150 Tocopherols, 209–211
causes of, 144–145 Tocotrienols, 210
epidemiological investigations Trail Making Test (TMT), 47, 61, 72, 220
on, 144 Tuna, 49, 209
intervention studies on, 144–147
overview of, 143–144
prevalence of, 144 U
Unified Parkinson Disease Rating Scale,
96–97
SDAS. See Social Dysfunction and
Unipolar disorders. See Depressive disorders
Aggression Scale (SDAS)
Seafood consumption, 197–198
Alzheimer’s and, 63
V
cognitive decline and, 48–54
drug use and, 165 Van Leeuwenhoek, Antoni, 1
Seasonal depression, 135–136 Vascular dementia, 59, 68
Seizures. See Epilepsy Vauquelin, Nicolas, 1
Semantic memory, 50, 216, 217 Veal liver, 209
Senile dementia, 59 Vegan diet, 8
Serotonin, 133, 135, 139, 150, 163, Vegetable oils, 8
164, 176 Vegetarian diet, 126–127
Short-term memory, 215–216 Violence. See Aggressive behavior
Skin cancer, 19 Vision, 11, 12, 205
Smoking, 22, 165 Vitamin A, 203–204
Social Dysfunction and Aggression Scale Alzheimer’s disease and, 68–70
(SDAS), 166, 225 cognitive decline and, 57–58
Socioeconomic level, 51 dementia and, 68–70
Soy lecithin, 37, 38 dietary recommendations for, 204
Spatial memory, 46 Vitamin B6, 66
Spongiform encephalopathy, 37–38 Vitamin D, 4, 7, 8, 19–21, 205–209
Stanford-Binet Intelligence ADHD and, 154–156
Scales, 222 aggressive behavior and, 170–171, 180
Statins, 83–84, 182, 207 Alzheimer’s disease and, 70–77
Sterols, 211–212 autism and, 159–162
Suicidal behavior, 174–184 cognitive development and, 39–40
cholesterol and, 181–184 deficiency, 19, 71, 73, 98, 106–108,
overview of, 174–175 115–117, 149, 162, 206–207
prevalence of, 175 dementia and, 70–77
vitamin D and, 180–181 depressive disorders and, 135–139
ω-3 fatty acids and, 176–180 dietary recommendations for, 207–208
234 Index
epidemiological investigations on, drug addiction and, 164–165

71–74, 135–138, 159–161 epidemiological investigations on, 27–32,
epilepsy and, 114–117 48–54, 62–64, 126–130, 144, 152,
functions of, 70 157–158, 164–167
intervention studies on, 74–77, 99, epilepsy and, 112–114
108–110, 115–117, 138, 161–162 intervention studies on, 32–35, 54–57,
multiple sclerosis and, 105–110 64–68, 104–105, 112–114, 130–135,
Parkinson’s disease and, 98–99 144–147, 153–154, 158–159,
schizophrenia and, 148–150 167–170
sources of, 208–209 multiple sclerosis and, 103–105
suicidal behavior and, 180–181 Parkinson’s disease and, 97–98
Vitamin E, 7, 21–22, 209–211 schizophrenia and, 144–147
Alzheimer’s disease and, 77–81 sources of, 198–201
depressive disorders and, 139–140 suicidal behavior and, 176–180
dietary recommendations for, 210 supplementation, 18, 32–35, 54–57,
epidemiological investigations on, 78–79 97, 104–105, 130–135, 144–147,
functions of, 78 158–159, 167–170, 197–198,
intervention studies on, 79–80, 100–101 202–203
Parkinson’s disease and, 100–101 ω-3 index, 165, 166, 197
sources of, 210–211 ω-6 fatty acids, 13, 14, 47–48, 51, 197–198
aggressive behavior and, 165
W biosynthetic pathways of, 199
depressive disorders and, 126–127
ω-3 fatty acids, 1–4, 7–19, 197–198 suicide and, 177–178
ADHD and, 152–154 ω-6/ω-3 fatty acid ratio, 29, 51, 126, 130, 178,
age-related cognitive decline and, 182–183
47–57 Wechsler Intelligence Test, 222–223
aggressive behavior and, 164–170 Working memory, 31, 46, 215–216
Alzheimer’s disease and, 62–68 World Alzheimer Report, 60
autism and, 157–159 World Health Organization (WHO), 5, 14,
biosynthetic pathways of, 199 123, 177
bipolar disorder and, 140–143
cognitive development and, 27–36
deficiency, 8–9, 144–145 Z
dementia and, 62–68
depressive disorders and, 126–135 Zeaxanthin, 58, 70, 205

Dietary Lipids For Healthy Brain Function

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Dietary Lipids for

Healthy Brain Function

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Chapter 1 Introduction .................................................................................. 1

Chapter 2 Brain development ...................................................................... 7

Chapter 3 Cognitive development ............................................................ 27

Chapter 4 Cognitive decline and Alzheimer’s disease......................... 45

4.2.2 Vitamin A and carotenoids ................................................... 68

Chapter 5 Other neurological diseases .................................................... 95

Chapter 6 Mental disorders...................................................................... 123

6.1.4 Attention-deficit hyperactivity disorder............................ 150

Chapter 7 Annexes ..................................................................................... 197

7.9.6 Wechsler intelligence test..................................................... 222

Knowledge facilitates better insights, answers, and medical treat-

Prof. William Camu

describe accurately the fatty acid composition of several lipid fractions

an improvement of learning capacities in young rats born from these

encourage the development of a controlled aquaculture of fish or algae pro-

2.1 ω-3 Fatty acids

–30 –20 –10 +10 +20 +30

A confirmation of this hypothesis was reported in 1990 among low-

language development in children aged 18 months or 4 years (Makrides

worst results on visual acuity and IQ based on verbal expression are

A follow-up of the large DOMInO trial is presently being carried out

if it is recalled that arachidonic acid is a key component of cell membranes,

United Kingdom Norway

–2.2 –2.0 –1.8 –1.6 –1.4 –1.2 –1.0

by the Program for International Student Assessment (PISA). Notably, PISA,

Although the findings are relevant, it remains yet to inform pregnant

third trimester of pregnancy, in summer in the Northern Hemisphere, prob-

related to their verbal and reasoning performances (Peabody Picture

Makrides, M. 2016. Understanding the effects of docosahexaenoic acid (DHA) sup-

3.1 ω-3 Fatty acids

The first indications of a possible link between these essential fatty

that are necessary for a broad knowledge. The determination of amounts of

• The scores of cognitive tests were positively related to the amount of

suffering sleep problems. It is easy to understand the value of such studies

3.1.2 Intervention studies

Fortunately, for the future of treatments with these compounds, now

• In 2010, one of the most comprehensive studies was conducted by a

The fMRI technique combined with neuropsychological tests has allowed

to conclude that in adults aged 24 years, an EPA-rich supplementation

In summary, the current state of research on the relationships between diet-

3.2 Fatty acids

populations, or their brain damage. A meta-analysis conducted in 2003

or to the whole lipid molecule. The mechanism of the phosphatidylserine

functions with that vitamin, a guarantee of better health in adulthood. The

Cognitive decline and

4.1 Age-related decline

number of affected cognitive domains. Concrete progress is therefore

4.1.1 ω-3 Fatty acids

4.1.1.1 Epidemiological investigations

• The French study, published in 2009, is part of a wide epidemiologi-