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The Influence of Micronutrients on Cognitive Function and Performance

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There has been much media speculation (often sensationalist and conflicting) regarding the potential influence of micronutrients on cognitive function and performance. Our aim was to identify the micronutrients specifically implicated in cognitive function and to review the literature to identify original sources underlying the media coverage. Literature searches were carried out to identify recent clinical trials, reviews, editorials and meetings describing the biochemical and physiological role of individual micronutrients. No attempt was made to grade the evidence. The searches confirmed that the water-soluble vitamins (B group and C), together with the minerals, calcium, magnesium and zinc, are most relevant to cognitive performance. Clinical evidence revealed that marginal deficiencies of one or more of these micronutrients are not uncommon, even in the developed countries, and that such deficiencies may affect cognitive performance, especially in vulnerable groups such as the elderly and those individuals who are exposed to occupational pressures and a stressful lifestyle.
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DOI: 10.1177/147323000703500101
2007 35: 1Journal of International Medical Research
E Huskisson, S Maggini and M Ruf
The Influence of Micronutrients on Cognitive Function and Performance
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The Journal of International Medical Research
2
007; 35: 1 – 19
1
The Influence of Micronutrients on
Cognitive Function and Performance
E HUSKISSON
1
, S MAGGINI
2
AND M RUF
2
1
Consultant Physician, King Edward VII Hospital, London;
2
Bayer Consumer Care AG, Basel, Switzerland
There has been much media speculation
(often sensationalist and conflicting)
regarding the potential influence of
micronutrients on cognitive function and
performance. Our aim was to identify the
micronutrients specifically implicated in
cognitive function and to review the
literature to identify original sources
underlying the media coverage. Literature
searches were carried out to identify
recent clinical trials, reviews, editorials
and meetings describing the biochemical
and physiological role of individual
micronutrients. No attempt was made to
grade the evidence. The searches confirmed
that the water-soluble vitamins (B group
and C), together with the minerals,
calcium, magnesium and zinc, are most
relevant to cognitive performance.
Clinical evidence revealed that marginal
deficiencies of one or more of these micro-
nutrients are not uncommon, even in the
developed countries, and that such
deficiencies may affect cognitive perform-
ance, especially in vulnerable groups such
as the elderly and those individuals who
are exposed to occupational pressures and
a stressful lifestyle.
KEY WORDS: VIT
AMINS
; MINERALS; COGNITIVE
FUNCTION
; COGNITIVE
PERFORMANCE
;
B
VITAMINS; MICRONUTRIENTS
Introduction
Doctors in the developed world will just
about remember diseases like beriberi from
their student days but apart from pernicious
anaemia, these diseases are no longer part of
their everyday work. They will be aware that
the situation is different for their colleagues
in other parts of the world. The general
population, by contrast, is bombarded with
claims regarding the effects of vitamin
supplements on their skin, sexual function
and general well-being, as well as their value
in the prevention of everything from the
common cold to more serious problems, such
as cancer and heart disease. In these
circumstances, it is obviously essential to rely
on hard evidence only
.
It should come as no surprise that
vitamins have potential benefits for cerebral
function, since their deficiencies are
characterized by dramatic neurological mani-
festations.
W
er
nicke–Korsakoff syndrome
associated with thiamine deficiency causes
amnesia, ataxia, confusion, psychosis and
may eventually lead to coma. Dementia
occurs in pellagra (combined deficiency of
niacin and tryptophan). Vitamin B
12
deficiency damages the spinal cord.
1
One
2
E Huskisson, S Maggini, M Ruf
I
nfluence of micronutrients on cognitive function and performance
notes the potential role of excessive alcohol
intake as well as dietary deficiency in the
causation of vitamin deficiencies.
T
wo groups of people in the western world
are particularly at risk of developing micro-
nutrient deficiency: (i) individuals who are
exposed to occupational pressure and a
stressful lifestyle, accompanied by a poor
diet, and (ii) the elderly. Both these groups
are booming.
This review highlights evidence of the
effects of vitamin and mineral supplements
on behaviour and mental performance; the
ability to concentrate, to be clear-headed, to
be alert, composed and energetic and to feel
good. It may make doctors think again about
the importance of vitamins in their everyday
work. Their patients will be reassured by the
hard evidence, although many will have
already noticed that vitamin and mineral
supplements make them feel better.
Biochemistry, physiology
and mechanisms
WHICH MICRONUTRIENTS ARE
ESSENTIAL FOR COGNITIVE
PERFORMANCE?
The micronutrients that have been most
closely associated with cognitive performance
are listed in Table 1 and include all the water-
soluble vitamins, as well as some minerals.
The inter-relationships between diet, the
brain and behaviour are complex. However,
these micronutrients are known to have a
direct influence on cognitive function
through their involvement in the energy
metabolism of neurons and glia cells, the
synthesis of neurotransmitters, receptor
binding and the maintenance of membrane
ion pumps.
2
Marginal deficiency of these
micronutrients results in a number of non-
specific symptoms, many of which are
related to cognitive performance.
In the first part of this article, the current
knowledge of the physiological roles of the
micronutrients most closely associated with
c
ognitive performance will be reviewed, with
particular reference to the central nervous
system (CNS). In the second part of this
article, the consequences of deficiencies are
discussed with reference to clinical data.
ROLE OF WATER-SOLUBLE VITAMINS
IN THE CNS
In this section the physiological roles of all
water-soluble vitamins and their roles in the
nervous system are briefly described (for
more detailed information, please refer to
publications such as those of the Institute of
Medicine
3,4
).
Vitamin B
1
(thiamine)
The principal physiological role of
thiamine is as a coenzyme in carbohydrate
metabolism. The thiamine coenzyme
thiamine pyrophosphate is required for
several stages in the breakdown of glucose to
provide energy. It also plays a role in the
conduction of nerve impulses. The brain and
the peripheral nerves contain significant
amounts of thiamine, which has numerous
roles within nerve tissue.
Vitamin B
2
(riboflavin)
After intestinal absorption, riboflavin is
converted to the coenzymes flavin
mononucleotide and flavin adenine
dinucleotide. Physiologically, riboflavin acts
as an intermediary in numerous
oxidation–reduction reactions. Thus, it is
essential for the metabolism of
carbohydrates, fats and proteins, and in
energy production. Importantly
, riboflavin is
essential for the conversion of pyridoxine
(vitamin B
6
) and folic acid into their
coenzyme forms, and for the transformation
of tryptophan to niacin.
TABLE 1:
Micronutrients that are most closely associated with cognitive performance*
Vitamins Minerals
Vitamin B
1
(thiamine) Calcium
Vitamin B
2
(riboflavin) Magnesium
Niacin Zinc
Vitamin B
6
(pyridoxine)
Folic acid
Vitamin B
12
(cobalamin)
Biotin
Pantothenic acid
Vitamin C (ascorbic acid)
*The term ‘performance’ has been used to include those aspects of cognitive function, such as concentration,
learning, memory and reasoning, that do not involve psychiatric or neurological diagnoses.
3
E Huskisson, S Maggini, M Ruf
I
nfluence of micronutrients on cognitive function and performance
Niacin
The term niacin refers to both nicotinic acid
and its amide derivative nicotinamide
(niacinamide). In cells, niacin is converted
into its coenzyme forms, nicotinamide
adenine dinucleotide (NAD) and NAD
phosphate (NADP), both of which play
an important role in energy metabolism.
At least 200 enzymes are known to
be dependent on NAD or NADP. Most
of the NAD-dependent enzymes are
involved in catabolic reactions, such as the
oxidation of fuel molecules, whereas NADP
more commonly functions in reductive,
biosynthetic reactions of such compounds as
fatty acids and steroids. Niacin is also
involved in the conversion of riboflavin and
vitamin B
6
into their active for
ms.
V
itamin B
6
(pyridoxine)
Vitamin B
6
is converted in the liver and other
tissues to pyridoxal phosphate and
pyridoxamine phosphate. These coenzymes
are distributed throughout the tissues, and
serve primarily as coenzymes in trans-
amination reactions. Pyridoxal phosphate
acts as a cofactor for a large number of
enzymes involved in the synthesis, catabolism,
decarboxylation, racemization and other
transformations of amino acids, and in the
metabolism of lipids and nucleic acids. It is
also the essential coenzyme for phos-
phorylation of glycogen and approximately
half of all the vitamin B
6
in the body is found
in the phosphorylase of skeletal muscle. In the
central and peripheral nervous systems,
vitamin B
6
is essential for the synthesis of
adrenaline (epinephrine), serotonin, dopamine,
gamma amino butyric acid (GABA), tyramine
and other neurotransmitters.
V
itamin B
6
participates in the conversion
of tr
yptophan to the vitamin niacin, and
pyridoxine deficiency blocks this process.
Other vitamins of the B complex (niacin,
riboflavin and biotin) are thought to act
synergistically with pyridoxine. Niacin and
riboflavin are required for the interconversion
of the different forms of vitamin B
6
.
4
E Huskisson, S Maggini, M Ruf
I
nfluence of micronutrients on cognitive function and performance
Folic acid
Folic acid (vitamin B
9
) is the name given to a
family of compounds known as folates,
w
hich are found in a wide variety of foods.
Folic acid is widely distributed in the tissues.
The principal storage organ is the liver,
which contains about half of the body’s
stores. Tetrahydrofolic acid, which is the
active form of folate in the body, acts as a
coenzyme in numerous essential metabolic
reactions. It plays an important role in the
metabolism of amino acids, including
homocysteine (Hcy), in the synthesis of
nucleic acids and in the formation of blood
cells and nerve tissue. It is essential for
growth and for the proper functioning of the
bone marrow and nervous tissue.
Proper folate utilization and metabolism
depend on an adequate supply of other
vitamins of the B group.
5
Vitamin B
12
(cobalamin)
Vitamin B
12
refers to a group of cobalt-
containing compounds known as cobalamins.
In the human body, the predominant forms
are adenosylcobalamin, methylcobalamin
and hydroxycobalamin. The cobalamins are
found mainly in the liver, but the kidneys,
heart and brain also contain higher than
average concentrations. The pituitary gland
has the highest concentrations per gram of
tissue of any organ in the body.
The specific biochemical reactions in
which cobamide coenzymes play a role are
of two types: (i) those catalysed by
adenosylcobalamin, and (ii) those catalysed
by methylcobalamin. Adenosylcobalamin
catalyses a reaction in the pathway for the
degradation of certain amino acids and odd-
chain fatty acids. Methylcobalamin plays an
important role in the transformation of Hcy
into the amino acid methionine. Vitamin B
6
and folate are also necessary for this reaction
and in their absence Hcy accumulates.
B vitamins and homocysteine
Homocysteine is an amino acid essential
for normal cellular functions. While low
l
evels are harmless, higher concentrations
can undermine normal cellular
functioning, especially in rapidly dividing
tissue, and are linked to a growing number
of diseases. The average Hcy level in the
body is 5 – 15 µmol. Levels exceeding
15 µmol are considered a sign for
hypercysteinaemia and correlate with an
increased risk for cardiovascular disease.
6
Growing evidence suggests that elevated Hcy
levels may lead to a permanent impairment
of cognitive function.
Absent from any alimentary source, Hcy
is produced by the demethylation of dietary
methionine. Hcy is back-recycled into
methionine through a re-methylation
pathway involving folic acid and vitamin B
12
as cofactor and co-substrate: the methyl
group of methyltetrahydrofolate (an active
form of folic acid) is transferred to Hcy to
form methionine and tetrahydrofolate, and
the enzyme responsible for this reaction
requires vitamin B
12
as a cofactor. When
methionine is in excess or cysteine is
required, Hcy is converted in an alternative
‘trans-sulphuration’ pathway to cysteine
using vitamin B
6
as coenzyme.
7
Deficiencies
of folic acid, vitamin B
6
and vitamin B
12
can
lead to an accumulation of Hcy observed in
the blood and urine.
8
Biotin
Biotin is a member of the vitamin B complex
and is a cofactor in four carboxylase
enzymes located in the brain, kidney
, heart
and liver. These biotin-dependent enzymes
are involved in the metabolism of fatty acids,
amino acids and the utilization of other B
vitamins. In the respective enzymatic
reactions the biotin moiety plays the role of
a carboxyl carrier during CO
2
transfer.
5
E Huskisson, S Maggini, M Ruf
I
nfluence of micronutrients on cognitive function and performance
Pantothenic acid
Pantothenic acid is a member of the B
complex vitamins. High concentrations are
f
ound in the brain, liver, kidney and heart.
The primary physiological role of
pantothenic acid is as a constituent of
coenzyme A, which plays a key role in the
metabolism of carbohydrates, proteins and
fats. It is thus involved in the maintenance
and repair of all cells and tissues, and in the
synthesis of sterols, hormones, antibodies
and neurotransmitters.
Vitamin B
12
is thought to facilitate the
conversion of pantothenic acid to coenzyme
A. Other B vitamins, including folic acid,
biotin and vitamin B
6
, are necessary for
proper utilization of pantothenic acid, and
vitamin C has been shown to ameliorate
pantothenic acid deficiency.
Vitamin C (ascorbic acid)
Vitamin C is distributed to most tissues, with
the highest concentrations being found in the
pituitary gland (400 mg/kg) and brain;
however, the body’s storage capacity is low.
Vitamin C is principally required for the
synthesis of collagen, it is also needed for the
synthesis of bile acids and aids in the
absorption of dietary iron. In the nervous
system, vitamin C is essential for the
synthesis of the neurotransmitters dopamine
and noradrenaline. Other important roles of
vitamin C include: the synthesis of a number
of hormones (e.g., noradrenaline or
hormones activated via vitamin C-dependent
amidation such as, calcitonin, vasopressin,
oxytocin, cholecystokinin, gastrin), the
immune system function, redox/antioxidant
function, and protection against the
for
mation of potentially carcinogenic
nitrosamines from nitrite-containing foods
such as smoked meats.
Vitamin C is essential for the metabolism
and utilization of folic acid and also acts
synergistically with zinc in collagen
formation (such that lack of either leads to
skin changes and delayed wound healing).
ROLE OF CALCIUM, MAGNESIUM
AND ZINC IN THE CNS
Calcium
Calcium plays a central role in nerve
excitability, as an intracellular messenger
and in the regulation of neurotransmission.
Plasma calcium is also essential for the regu-
lation of numerous vital cell functions: includ-
ing muscle contraction, nerve conduction,
blood clotting and membrane permeability.
Intake of calcium up to about 120 mg in
a meal is mainly absorbed by active
transport; amounts above this level are
absorbed by diffusion. Since diffusion is a
relatively inefficient process, the proportion
of calcium absorbed decreases as dietary
calcium increases, but the absolute amount
absorbed continues to increase.
Because of the large reservoirs of calcium
in bone, hypocalcaemia (low blood calcium)
is relatively rare and, when it does occur,
is usually due to drug treatment, such
as vigorous diuresis, rather than due to
dietary deficiency. Hypercalcaemia is more
common, usually caused by parathyroid
abnormalities, but occasionally by excessive
consumption of vitamin D tablets, with or
without calcium (vitamin D intoxication
or hyper
vitaminosis D).
Calcium-dependent processes, such as
growth and development of bones and teeth,
and functioning of the nervous system, are
also dependent on vitamin C and the B
vitamins. V
itamin B
6
is thought to regulate
calcium influx into vascular smooth muscle.
Magnesium
Magnesium (Mg) is vital for the activity of
more than 300 enzymes and plays an
important role in neurochemical transmission
6
E Huskisson, S Maggini, M Ruf
I
nfluence of micronutrients on cognitive function and performance
and muscular excitability. The Mg–adenosine
triphosphate (Mg–ATP) complex is involved
in all-important biosynthetic processes:
g
lycolysis, formation of cyclic adenosine
monophosphate (cAMP), energy-dependent
membrane transport and transcription of the
genetic code.
Many of these enzymes also require a
B vitamin as a cofactor. Specifically,
magnesium is essential for all enzymes
requiring vitamin B
1
as a cofactor. Both
magnesium and vitamin B
2
are required for
the conversion of vitamin B
6
into its active
form. Extra-cellular magnesium is critical for
the maintenance of nerve and muscle
membranes and for the transmission of
impulses across neuromuscular junctions.
There are also a number of antagonistic
and synergistic interactions between
magnesium and calcium. Of particular
relevance here is the interaction between
magnesium and calcium in the regulation of
the permeability of nerve and muscle cells,
which governs neuromuscular excitability.
So constant is this relationship that
mathematical formulae have been derived
that allow excitability to be calculated from
the concentration of electrolytes in the
surrounding intercellular fluid:
Excitability = (K
+
)•(Na
+
)
(Ca
+
)•(Mg
2+
)•(H
+
)
Since excitability is related to the reciprocal
of the magnesium and calcium concen-
trations, it can be seen that deficiency of either
or both micronutrient leads to an increase in
excitability
. Clinically
, deficiency of either ion
may lead to muscle disturbances (e.g. cramps,
tetany), cardiac abnor
malities, neurological
system symptoms (e.g. paraesthesias,
irritability) or to psychiatric disturbances.
Contrary to widespread belief, data show
that no competition exists between
magnesium and calcium for absorption in
the intestine. Calcium supplementation does
not decrease magnesium absorption
9
and an
i
ntake of up to 800 mg magnesium does not
affect intestinal calcium absorption.
10
Zinc
Zinc is required as a component of more
than 200 enzymes and as a structural
component of many proteins, hormones,
hormone receptors and neuropeptides.
11
In
the CNS, zinc has an additional role as a
neurosecretory product and cofactor. In this
role, zinc is highly concentrated in the
synaptic vesicles of the so-called ‘zinc-
containing’ neurons. These neurons are
found almost exclusively in the forebrain.
12
While the precise role of zinc in the brain still
remains to be discovered, it has been
established that neuropsychological impair-
ment is one major health consequence of
zinc deficiency.
13
Zinc is absorbed mainly in the proximal
small intestine by an active transport
mechanism. Absorbed zinc is bound to
albumin and transported to the liver in the
portal system. From the liver, zinc is
distributed to all tissues, with the highest
concentrations found in skeletal muscle.
Turnover is rapid and, although the liver
may retain zinc, there are no specific stores.
A marked reduction in dietary zinc is quickly
followed by signs of zinc deficiency
. It is
thought that even in developed countries
many people are zinc deficient. In a recent
study of rural, community-dwelling elderly
people in the USA, it was estimated that
more than 25% were zinc deficient.
14
Black
15
cites evidence that zinc deficiency is ‘a major
public health problem’ in the USA.
Besides the impairment of cognitive
function, zinc deficiency causes an impaired
collagen formation, skin changes, delayed
wound healing and susceptibility to infection.
16
TABLE 2:
Some examples of the impact of water-soluble vitamins on neurotransmitter synthesis via
their involvement in amino acid metabolism
7
E Huskisson, S Maggini, M Ruf
I
nfluence of micronutrients on cognitive function and performance
HOW MICRONUTRIENTS INFLUENCE
COGNITIVE PERFORMANCE
No other organ system of the body depends
m
ore intimately on its nutrient supply
than the CNS. Individual micronutrients
are especially important for cognitive
performance and mood because the effective
functioning of the CNS depends, in part, on
an adequate and constant nutrient supply.
In his comprehensive review, Haller
2
identified three main mechanisms – two
direct and one indirect – by which
micronutrients affect cognitive function. In
the past decade, it has become clear that a
fourth indirect mechanism, mediated by
Hcy, is also important.
1. Neurotransmitter synthesis
B complex vitamins and vitamin C are
required for the synthesis of amino acids,
biogenic amines, neurotransmitters and
steroids. Specifically within the CNS, the
metabolism of dopamine and noradrenaline
requires vitamin B
2
, vitamin B
6
, vitamin B
12
,
nicotinamide, folate and vitamin C. Synergy
between vitamin C and B vitamins also
o
ccurs in the breakdown of histamine and
tryptophan in the brain (Table 2).
In animal studies, thiamine deficiency
has been shown to lead to a fall in GABA
concentrations in the brain and to a
reduction in the pool size and turnover of
acetylcholine.
17
Pyridoxine deficiency also
leads to reduced synthesis of GABA and can
lead to convulsions in infants.
2. Neuronal membrane and receptor
modification
One of the metabolites of thiamine,
thiamine triphosphate, is found exclusively
in the neuronal membrane and appears to
be involved in the maintenance of the
transmembrane potential difference. In
isolated nerve preparations, destruction of
thiamine by ultraviolet light leads to a loss
of membrane potential and no action
Vitamin B
1
: Glutamic acid GABA
(γ-aminobutyric acid)
Vitamin B
2
: Tyrosine Noradrenaline
Serotonin
Benzylamine
Vitamin B
6
: Glutamic acid GABA
tyrosine
Dopamine
Adrenaline
Noradrenaline
T
r
yptophan
5-Hydroxytr
yptamine
Serotonin
Histidine Histamine
Nicotinamide: Tryptophan
5-Hydroxytryptamine
Serotonin
V
itamin C:
T
yrosine
Dopamine
Noradrenaline
8
E Huskisson, S Maggini, M Ruf
I
nfluence of micronutrients on cognitive function and performance
potentials are generated. These changes can
be reversed by addition of thiamine to the
perfusate and suggest that thiamine has a
s
pecific role in nerve conduction.
Pyridoxine deficiency leads to changes in
receptor binding of a number of
neurotransmitters, including glutamate and
glycine. In animal studies, pyridoxine
deficiency led to decreased GABAergic
binding.
18
In addition to modulating the
receptor binding of neurotransmitters,
vitamin B
6
also modulates binding of
steroids to steroid receptors. This is relevant
in discussion of cognitive performance, since
corticosteroids are known to affect mood.
3. Energy metabolism
Another way in which micronutrients may
influence cognitive performance has to do with
the fact that the brain, while accounting for
only about 3% of the total body weight,
consumes at rest about 25% of the total blood
glucose. Several B vitamins, but also mag-
nesium, play crucial roles as essential cofactors
in the degradation of blood glucose, via
glycogenolysis, the citric acid cycle and the
respiratory chain to produce physiological
energy in the form of ATP. In addition, B
vitamins plus vitamin C are involved at
different stages of the intermediary meta-
bolism, transforming the macronutrients fat
and amino acids into acetyl coenzyme A or
pyruvic acid, respectively
, which can then
again be used by the citric acid cycle and
respiratory chain to produce ATP. Obviously
deficiencies in one or more of these micro-
nutrients may interfere with energy meta
-
bolism which, because of its high-energy needs,
is likely to have early effects on the brain.
4. B vitamins and homocysteine metabolism
Research has identified two mechanisms,
hypomethylation and elevated Hcy, by
which folate, together with vitamins B
12
and
B
6
as catalysing cofactors, influence
cognitive function.
7,19 – 22
Both vitamin B
12
and folate are necessary to ensure adequate
m
ethylation by
S-
adenosylmethionine in the
synthesis of neurotransmitters such as the
monoamines (e.g. dopamine, noradrenaline
and serotonin), myelin, and membrane
phospholipids such as phosphatidylcholine,
as well as other compounds important to the
CNS. Hypomethylation can thus lead to
neuropathologies, cognitive impairment,
and affective or mood disturbances. On the
other hand, elevated Hcy has an indirect,
long-term, negative effect on brain
functions. B vitamins may function to
preserve and protect the integrity of the CNS
via their role in the reduction of Hcy thus
preventing vascular disease, which is in turn
crucial to cognitive function.
23 – 26
The possibility that Hcy toxicity might be
a risk factor for neuropathology and/or
cognitive disturbances was first proposed in
the early 1990s.
27
The same paper also
proposed that with reference to neuro-
cognitive impairment, vitamin concentrations
are less predictive than are concentrations of
Hcy. Work in the succeeding decade showed
that the intermediate metabolites of Hcy –
methylmalonic acid (MMA), 2-methylcitric
acid (2-MCA) and cystathionine (CYSTA) –
are more sensitive indicators of vitamin B
12
,
vitamin B
6
and folate deficiency than Hcy
itself.
28
Henning et al.
29
showed that after
short-term (eight times over 21 days)
administration of high-dose vitamin
supplements, vitamin levels returned to pre-
treatment levels within 3 months, but total
Hcy
, MMA and 2-MCA levels decreased
significantly during the treatment period
and had not retur
ned to baseline after
8 months. A very recent review of the
relationship between B vitamins, Hcy levels
and cognitive function concluded that
elevated Hcy levels lead to cognitive
9
E Huskisson, S Maggini, M Ruf
I
nfluence of micronutrients on cognitive function and performance
impairment and that ’lowering homo-
cysteine by B vitamin supplementation may
protect cognitive function.’
30
E
llinson
e
t al.
31
c
arried out a systematic
review of all studies in English on the
association between low serum vitamin
B
12
/folate and raised total Hcy with cognitive
impairment. It was found that total Hcy was
significantly higher in all cases of cognitive
impairment when compared with controls,
but there was wide variation for both serum
vitamin B
12
and folate.
In cohort studies, the total Hcy – but not
serum folate or B
12
could predict the rate of
decline in cognitive function, although one
study from the USA
32
reported a significantly
higher risk of Alzheimer’s when both folate
and B
12
levels were low. In addition, this
study found that both high Hcy and low
B vitamins were predictive of cognitive
decline in a group of 321 ageing men
followed over 3 years.
32
Micronutrients and
cognitive performance –
evidence overview
CONSEQUENCES OF DEFICIENCIES
FOR COGNITIVE PERFORMANCE
The water-soluble B vitamins, vitamin C and
the mineral micronutrients magnesium and
zinc are stored in the body only to a limited
extent, and upon any reduction of intake,
impairment of absorption or increase in
requirements, the body status begins to fall
and may become deficient. Isolated
deficiency of individual B vitamins seems to
be rare since all members of the complex
tend to occur in similar foods.
The role of the B vitamin and mineral
cofactors in the synthesis of brain neuro-
transmitters and in the maintenance of
neuron cell function has been discussed
above. Deficiency of all or any of a number
of these micronutrients could have direct
physiological effects on brain function and
therefore on cognition (Table 3).
T
hat frank vitamin deficiency can have a
profound effect on cognitive function has
been known for many years. The
Wernicke–Korsakoff syndrome as a result of
thiamine deficiency is characterized by
symptoms ranging from mild confusion and
depression to psychosis and coma. If
treatment is delayed, the memory may be
permanently impaired. In vitamin B
6
deficiency, the signs and symptoms include
electroencephalogram abnormalities, nerve
degeneration and peripheral neuritis.
Pellagra, as a result of niacin deficiency, is
associated with the three ‘Ds’, diarrhoea,
dermatosis and dementia. However, it is only
in the past 20 years or so that a potential
link between borderline vitamin deficiencies
and cognitive function has been explored.
The concept of marginal vitamin deficiencies
was first proposed by Pietrzik.
34
He suggested
that there are in fact five stages of deficiency.
The first stage is characterized by a lowering of
tissue vitamin content; the second by reduced
synthesis of vitamin metabolites followed by
depressed activity of vitamin dependent
enzymes and hormones (stage three). The
fourth stage is characterized by morphological
or functional disturbances, followed by the
emergence of clinical symptoms (the fifth and
final stage). Pietrzik proposed that marginal
deficiency be represented by the transition from
the third to the fourth stages and that
biologically based functional parameters
should be established for its assessment.
Following from this work, Chomé
et al.
35
investigated the effects of suboptimal vitamin
status on behaviour
, concluding that an
‘insufficient supply’ of vitamins, especially of
thiamine, riboflavin, vitamin B
12
and vitamin
C, adversely affects different psychological and
behavioural functions.
10
E Huskisson, S Maggini, M Ruf
I
nfluence of micronutrients on cognitive function and performance
TABLE 3:
Consequences of water-soluble vitamin deficiencies on cognitive performance
3,4,27,33
Vitamin Consequence
Vitamin B
1
Fatigue, mental changes (e.g. apathy, decrease in short-term memory,
confusion and irritability), visual difficulties
Frank deficiency: beriberi, Wernicke–Korsakoff syndrome
Vitamin B
2
B
2
deficiency is most often accompanied by other micronutrient deficiencies
Severe B
2
deficiency may impair the metabolism of vitamin B
6
and the
conversion of tryptophan to niacin
Vitamin B
6
Depressed mood and neurological disturbances
Frank deficiency: peripheral neuropathy, convulsions, depression and
confusion
Vitamin B
12
Fatigue and weakness, irritability, depressed mood, loss of concentration to
memory loss, mental confusion, disorientation
Frank deficiency: peripheral neuropathy, subacute combined system
degeneration, frank dementia
Folic acid Symptoms of folate deficiency include depression, insomnia, forgetfulness
and difficulty in concentrating, irritability, apathy, fatigue and anxiety
Biotin Irritability, depressed mood, central nervous system abnormalities
Nicotinamide Marginal deficiency: irritability, weakness, mental confusion and dizziness
Frank deficiency: pellagra, dementia
Panthotenic acid Irritability and restlessness, fatigue, apathy and malaise, neurobiological
symptoms, such as numbness, muscle cramps. Myelin degeneration
Vitamin C Weakness, fatigue, depression
In a review of nutritional factors in
physical and cognitive functions of elderly
people, Rosenberg and Miller
27
concluded
that the evidence suggests that mild or
subclinical vitamin deficiencies might affect
nervous system function.
Ideally, a sufficient and balanced diet
should cover the overall micronutrient
requirements. Unfortunately, even in
industrialized countries many segments of
the population do not get the essential
vitamins and minerals needed within their
diet. Those who are particularly predisposed
to develop a vitamin deficiency in a pre-
clinical state have been identified (Tables 4
and 5) and should be treated adequately.
Those groups at risk comprise: growing
children, pregnant and lactating women, the
elderly, people with restricted dietary intake
due to disease, as well as those on a diet
or eating an unbalanced diet, those
experiencing demanding situations such as
during extensive physical exercise or in
situations of emotional and physiological
stress and demanding cognitive tasks,
women taking contraceptive pills, smokers,
drinkers, after a prolonged therapy with
antibiotics, etc.
39 – 45
11
E Huskisson, S Maggini, M Ruf
I
nfluence of micronutrients on cognitive function and performance
As well as the risk caused by medical
conditions like digestive disorders or
infection, the risk groups for micronutrient
deficiencies can be classified into two main
categories: those at risk as a result of what
might be called lifestyle and those at risk
because of lifestage.
The
lifestyle category includes the large
group of individuals who are at risk because
of increased needs and/or insufficient intake
of micronutrients because of a demanding
lifestyle. This categor
y mainly includes
young to middle-aged adults with high
occupational pressure or the double burden
of family and work, for whom time is always
in short supply. In this group, deficiencies
are likely to occur as a result of lifestyle
associated behaviour like snatched meals,
unhealthy food choices, chronic or periodical
dieting, and stress-related behaviour like
smoking, excessive alcohol and coffee
consumption. The link between micro-
nutrients and cognitive performance is of
special interest in this group, because the
combination of stressful lifestyle and risk for
marginal micronutrient deficiency may
cause a vicious circle.
The
lifestage group comprises older adults
who are at risk of micronutrient deficiency
because of their changing needs and life
situation. Surveys have shown that even in
affluent societies up to 40% of older persons
living in single households consume
insufficient amounts of one or more essential
nutrients.
41
Therefore it is not surprising that
this group is widely recognized as one of the
TABLE 4:
Factors responsible for the reduced absorption of micronutrients
Reduced intake Reduced uptake Increased excretion
Dieting Vomiting/hyperemesis Diarrhoea
Loss of appetite Digestive disorders Diuresis
Unbalanced diet
Nausea
Gingivitis
TABLE 5:
Factors responsible for the increased requirements for micronutrients
Increased needs Drug interaction
36 – 38
During infection Antibiotics
Chronic inflammatory diseases Contraceptives
Smoking Analgesics
Diabetes Antidepressants
Physical activity Laxatives
Stress Diuretics
12
E Huskisson, S Maggini, M Ruf
I
nfluence of micronutrients on cognitive function and performance
most important risk groups.
46
In the light of
the current demographic revolution and the
alarmingly increasing numbers of persons
s
uffering from age-related cognitive decline,
the clinical data exploring the link between
micronutrients and cognitive performance
become highly relevant.
47
In the following paragraphs, the review
will focus on two major risk groups that
regularly present to general practitioners:
middle-aged adults with high occupational
pressure and the elderly. The signs and
symptoms of marginal micronutrient
deficiencies are often non-specific and
therefore difficult to diagnose. It is therefore
important for primary care health workers to
be alert to the particular risk of these groups
and to know about the potential of
multivitamin supplementation as a
preventive measure.
Lifestyle and micronutrient deficiencies
Although the level of psychological stress
itself is difficult to measure and individual
ability to deal with stress is very variable,
stress does manifest in ways that are
measurable: changes in mood, memory,
concentration and problem-solving. It has
b
een suggested that there may be a vicious
cycle of stress (Fig. 1), whereby external stress
factors trigger the release of stress hormones.
These in turn lead to increased micronutrient
requirements which, if unmet, lower the
resistance to stress and at the same time com-
promise cognitive and physical well-being.
Because of greater interest in the role of
micronutrients in cognitive development of
children and in the maintenance of cognitive
performance in the elderly, fewer studies
have been carried out in younger adults.
However, in the past decade a number of
preliminary studies have been published.
In Haller’s review of the effects of vitamins
and other nutrients on the brain,
2
the author
concluded that many studies show specific
effects, particularly on cognitive function
and mood, and that vitamins in high doses
have a pharmacological action which may
only become apparent many months after
blood levels have risen to a higher level.
FIGURE 1: The ‘vicious cycle’ of stress (adapted from Schlebusch et al.
48
)
External stress
factor
Stress
hormones
Stress-related
behaviour
Metabolism
Vitamin and
mineral
requirements
Vitamin and
mineral status
Risk for
deficiency
Resistance
to stress
Performance
Irritability,
fatigue,
muscular tension,
poor concentration
13
E Huskisson, S Maggini, M Ruf
I
nfluence of micronutrients on cognitive function and performance
These effects go beyond normalizing the
vitamin deficiencies that are present in a
small number of subjects and suggest that
r
aised blood and tissue vitamin levels lead
to gradual neurochemical changes in the
brain and perhaps to trophic changes in the
nervous and glial cells.
In a placebo-controlled study, the
interaction of vitamins with mental per-
formance was investigated in a large group
(
n = 1081) of healthy young men aged 17 –
21 years.
49
Following determination of
vitamin status by a battery of psychometric
and bioanalytical measurements and tests,
the subjects were randomized to receive a
vitamin supplement containing B complex
vitamins and vitamins A, C and E, or a
matching placebo over a period of 8 weeks.
When the codes were broken, it was found
that subjects whose analyses showed them to
have had low vitamin status at the start of
the study, and who received supple-
mentation showed an improvement in
behaviour and mental performance, whereas
the control group showed no improvement
in cognitive performance after 8 weeks of
multivitamin supplementation.
In 1996, Benton
et al.
50
carried out a
double-blind study in which 120 young adult
females were randomized to receive a 50 mg
thiamine supplement or placebo daily for a
period of 2 months. An improvement in
thiamine status was associated with reports
of being more clear-headed, composed and
energetic, but had no influence on memory.
A small-scale double-blind study in which
24 young men were randomized to receive a
multivitamin–mineral supplement or placebo
for 28 days demonstrated a reduced cardio-
vascular response to stress tasks, but no
change in psychological parameters.
51
A
larger, open, multicentre study was
conducted in 136 patients (mean age 46
years) suffering from stress.
52
After 28 days of
treatment with a multivitamin–mineral
supplement, the investigators reported a
66% improvement in concentration and a
6
7% reduction in depression, together with
an 82% reduction in symptoms of tiredness.
In a multicentre double-blind study in
307 adults, permanently exposed to
occupational stress, multivitamin–mineral
supplementation over a period of 30 days led
to significant improvements in psychological
and physical status.
53
A similar double-blind
study in 300 subjects, pre-selected for high-
stress levels, was also conducted over a short
period of 30 days.
48
Patients who received the
multivitamin–mineral supplement showed a
clinically and statistically significant improve-
ment for all psychometric instruments
(Hamilton Anxiety Rating Scale [HARS],
Psychological General Well-being Schedule
[PGWS], visual analogue scale [VAS] for six
subjective ratings of stress, and a general
stress index [Berocca Stress Index, BSI];
Fig. 2). The authors concluded that the multi-
vitamin–mineral combination was, ‘well
tolerated and could be used as part of a treat-
ment programme for stress-related symptoms.’
In 2000, a German group carried out an
intervention study over a period of 6 months
to test the effect of a daily multivitamin
compound in 42 adult men and women
suffering from stress or exhaustion.
54
At the
end of the evaluation period, significant
improvements in stress-related parameters
were noted. Also in 2000, a British group
published the results of a double-blind study
of a vitamin–mineral supplement versus
placebo in 80 healthy young men over a
period of 28 days which showed that, relative
to placebo, multivitamin–mineral supple-
mentation was associated with consistent and
statistically significant reductions in anxiety
and perceived stress.
55
Subjects who received
the supplement also rated themselves as more
alert and better able to concentrate (Fig. 3).
14
E Huskisson, S Maggini, M Ruf
I
nfluence of micronutrients on cognitive function and performance
Lifestage and micronutrient deficiencies
The consequences of micronutrient
deficiencies on cognitive function and the
effects of supplementation have been more
thoroughly investigated in the elderly than
in younger age groups. Cognitive function
declines with ageing, but to varying degrees.
There has also been much debate as to
FIGURE 2: Significant improvements in psychometric parameters with multi-
vitamin–mineral supplementation. The graph shows reduction in raw scores for each
psychometric instrument (BSI, Berocca Stress Index; HARS, Hamilton Anxiety Rating
Scale; VAS, visual analogue scale for six subjective ratings of stress; and PGWS,
Psychological General Well-being Schedule). All reductions were statistically
significant (adapted from Schlebusch
et al.
48
)
50.00
Reduction in score (%)
BSI HARS VAS PGWS
40.00
30.00
20.00
10.00
0.00
A
ctive Group
Placebo Group
BSI P = 0.0344 HARS P = 0.0148 VAS = P = 0.0044 PGWS P = 0.0136
37.79
30.70
41.76
31.55
28.55
20.43
27.16
17.81
FIGURE 3: Significant improvements in concentration and tiredness with multivitamin–
mineral supplementation. Participants were asked to rate, on a scale of 1 (‘not at all’)
to 7 (‘very’), to what extent they felt unable to concentrate and were tired during the
last 2 weeks (adapted from Carroll
et al.
55
)
Reduction of
concentration problems
(P 0.05)
Reduction in
rated tiredness
(P 0.06)
Day
1
Day
28
Day
1
Day
28
Day
1
Day
28
Day 1
Day
28
Main rating
Main rating
Active Group Placebo Group
3.05
2.92
3.26
2.61
3.54
3.76
3.79
3.34
15
E Huskisson, S Maggini, M Ruf
I
nfluence of micronutrients on cognitive function and performance
whether this age-related decline is associated
with the decline in nutritional status often
found in elderly people, or is independent of
i
t. The weight of recent evidence suggests
that there is indeed an association. Ortega
et al.
56
found that subjects with higher scores
in two tests of cognitive function had higher
intakes of total food, fruit, carbohydrate and
micronutrients than subjects with lower
scores. It was concluded that a diet with
more carbohydrate, fibre and micronutrients
is beneficial, ‘not only to improve the
general health of the elderly, but also to
improve cognitive function.’ A number of
recent studies have demonstrated that
micronutrient supplementation may help to
maintain cognitive performance in the
elderly. Gray
et al.
57
carried out a long-term
study of antioxidant vitamins plus minerals
supplementation in 2082 community-
dwelling elderly people. After 7 years, it was
found that supplement users had a 34%
lower risk of developing cognitive
impairment than non-users. A Spanish study
of institutionalized elderly people showed
that dietary deficiency of vitamin B
12
and
folic acid was associated with a higher risk of
cognitive impairment.
58
A review of B vitamins, cognition and
ageing concluded that recent studies
had confirmed an association between
B vitamins and many aspects of cognitive
per
formance and that even subclinical
differences in nutritional status could have
subtle effects on cognition
19
. The same
review also concluded that the evidence
supported the effectiveness of micronutrient
supplementation in enhancing cognitive
performance in older adults. However, in
elderly people not affected by micro-nutrient
deficiency, studies aimed at improving
cognitive performance by means of
micronutrient supplementation have
generally proved unsuccessful
59,60
and those
that have reported success
61
have
subsequently been criticized for poor
methodology. Nevertheless, an editorial in
T
he American Journal of Clinical Nutrition
(‘B vitamins and cognitive function: do we
need more and larger trials?’)
62
concluded
that, although no randomized trials of
B vitamin supplementation have provided
evidence for improvement of cognition,
further trials are warranted because the
suggested mechanisms are plausible and
strong associations have been established
between these mechanisms and cognitive
dysfunction in several high quality
epidemiological studies.
Micronutrient supplementation in an
attempt to prevent cognitive decline must
lead to discussion of neurological deficits such
as dementias, rather than the psychological
deficits that were the original remit of this
review. However, two studies published in
2005 have caused such interest that they
should be mentioned. The first study was
presented by a Dutch group at the
International Conference on Prevention of
Dementia held in Washington DC, USA in
June 2005.
63
The authors selected 818 healthy
older adults (aged 50 – 75 years), none of
whom was suffering from dementia, and
randomized them to receive a daily tablet
containing 800
µg folic acid (approximately
twice the European recommended dietary
allowance [RDA]) or placebo. After 3 years,
the subjects taking the folic acid had scores on
memory tests that were similar to those of
persons 5 years younger. They also had scores
of information processing and muscle speed
that were similar to someone 2 years younger
.
Supporting evidence came in a further study
published in July 2005 from the Johns
Hopkins University.
64
A total of 579 non-
demented men and women (who were part of
the ongoing Baltimore Longitudinal Study of
Aging) provided detailed dietary diaries over
16
E Huskisson, S Maggini, M Ruf
I
nfluence of micronutrients on cognitive function and performance
a period of 6 years. Ultimately, 57 of the
original 579 participants developed
Alzheimer’s disease, but the researchers found
t
hat those with higher intakes of folates,
vitamin E and vitamin B
6
had lower
comparative rates of the disease. But, when
the three vitamins were analysed together,
only folates were associated with a
significantly decreased risk. No association
was found between vitamin C, beta carotene
or vitamin B
12
intake and decreased risk of
Alzheimer’s disease. Professor Corrada
commented that, ‘participants who had
intakes at or above the 400 µg RDA of folates
had a 55% reduction in risk of developing
Alzheimer’s, but most people who reached
that level did so by taking folic acid
supplements, which suggests that many
people do not get the recommended
amounts of folates in their diets.’
Conclusions
Two main groups of micronutrients essential
for optimum cognitive performance can be
differentiated: the water-soluble vitamins
(B complex and C), as well as the minerals
calcium, magnesium and zinc.
Because of their metabolic interdependence,
the B complex vitamins have to be regarded as
a functional unit whose individual members
act like links in a chain of biochemical
reactions. Within intermediate metabolism,
transfor
mations exist which require all eight
B vitamins as cofactors for the various
enzymes.
65
Many interactions are also known
between the different members of the complex.
Although vitamin C is essential for collagen
synthesis in the skin, it is noteworthy that the
highest concentrations of this vitamin are
found in brain tissue. Brain vitamin C is known
to interact synergistically with B complex
vitamins in the maintenance of several aspects
of cognitive function and performance.
The minerals calcium, magnesium and
zinc are required as cofactors for numerous
vitamin-dependent enzymes and also play a
direct and crucial role in membrane
e
xcitability and neurotransmission. With
the exception of calcium, none of these
micronutrients is stored in the body in
significant quantities and it is therefore
essential that the daily consumption
is adequate.
Four major mechanisms can be identified
by which micronutrients influence cognitive
function: through their role in
neurotransmitter synthesis; by neuronal
membrane and receptor modification; by
influencing brain energy requirements; and
via their role in Hcy metabolism.
Review of the clinical evidence leads to the
conclusion that:
(a) Even in developed countries, large
sections of the population are at risk for
marginal micronutrient deficiencies.
Major risk groups are the young to
middle-aged adults with demanding
lifestyles and too little time, and the
elderly.
(b) Micronutrient deficiencies can impair
cognitive performance in all stages of
life and are associated with age-related
cognitive decline.
Micronutrient supplementation can
help prevent deficiencies in those at risk
and may therefore help to maintain
cognitive per
formance.
Doctors confronted with stressed or elderly
patients complaining of non-specific,
especially cognitive, symptoms should
consider the possibility of marginal
micronutrient deficiency and the potential
benefits of micronutrient supplementation.
Conflicts of interest
Silvia Maggini and Michael Ruf are
employed by Bayer Consumer Care, a
manufacturer of multivitamins.
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Address for correspondence
Dr M Ruf
Bayer Consumer Care AG, 4052 Basel, Switzerland.
Email: michael.ruf.mr@bayer
.ch
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