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Changed Plasma Levels of Zinc and Copper to Zinc Ratio and Their Possible Associations with Parent- and Teacher-Rated Symptoms in Children with Attention-Deficit Hyperactivity Disorder

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Attention-deficit hyperactivity disorder (ADHD) is associated with alterations in the metabolism of some trace elements which may participate in the pathogenesis of this disorder. The aims of the present study were to investigate the trace element status (copper (Cu), zinc (Zn), copper to zinc ratio (Cu/Zn ratio), selenium (Se), and lead (Pb)) of ADHD children and compare them with the control group. Associations between examined elements and ratings of ADHD symptoms were also assessed. Fifty-eight ADHD children and 50 healthy children (aged 6-14 years) were included in the study. The concentrations of Cu, Zn, and Se in the plasma and Pb in the whole blood were measured by atomic absorption spectrometry. We found lower Zn level (p = 0.0005) and higher Cu/Zn ratio (p = 0.015) in ADHD children when compared with the control group. Copper levels in ADHD children were higher than those in the control group, but not significantly (p > 0.05). No significant differences in levels of Se and Pb between both groups were found. Zinc levels correlated with parent-rated score for inattention (r = -0.231, p = 0.029) as well as with teacher-rated score for inattention (r = -0.328, p = 0.014). Cu/Zn ratio correlated with teacher-rated score for inattention (r = 0.298, p = 0.015). Significant associations of Se and Pb with parent- and teacher-rated symptoms were not observed. The results of this study indicate that there are alterations in plasma levels of Cu and Zn as well as significant relationships to symptoms of ADHD.
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Changed Plasma Levels of Zinc and Copper to Zinc Ratio
and Their Possible Associations with Parent- and Teacher-Rated
Symptoms in Children with Attention-Deficit Hyperactivity
Disorder
Alena Viktorinova
1
&Monika Ursinyova
2
&Jana Trebaticka
3
&Iveta Uhnakova
2
&
Zdenka Durackova
1
&Vlasta Masanova
2
Received: 10 March 2015 /Accepted: 1 June 2015
#Springer Science+Business Media New York 2015
Abstract Attention-deficit hyperactivity disorder (ADHD) is
associated with alterations in the metabolism of some trace
elements which may participate in the pathogenesis of this
disorder. The aims of the present study were to investigate
the trace element status (copper (Cu), zinc (Zn), copper to zinc
ratio (Cu/Zn ratio), selenium (Se), and lead (Pb)) of ADHD
children and compare them with the control group. Associa-
tions between examined elements and ratings of ADHD
symptoms were also assessed. Fifty-eight ADHD children
and 50 healthy children (aged 614 years) were included in
the study. The concentrations of Cu, Zn, and Se in the plasma
and Pb in the whole blood were measured by atomic absorp-
tion spectrometry. We found lower Zn level (p=0.0005) and
higher Cu/Zn ratio (p=0.015) in ADHD children when com-
pared with the control group. Copper levels in ADHD chil-
dren were higher than those in the control group, but not
significantly (p>0.05). No significant differences in levels of
Se and Pb between both groups were found. Zinc levels cor-
related with parent-rated score for inattention (r=0.231, p=
0.029) as well as with teacher-rated score for inattention (r=
0.328, p=0.014). Cu/Zn ratio correlated with teacher-rated
score for inattention (r=0.298, p=0.015). Significant
associations of Se and Pb with parent- and teacher-rated
symptoms were not observed. The results of this study indi-
cate that there are alterations in plasma levels of Cu and Zn as
well as significant relationships to symptoms of ADHD.
Keywords Trace element status .Zinc .Copper .Copper to
zinc ratio .Oxidative stress
Introduction
Alterations in the metabolism of some trace elements may
contribute to the pathogenesis of attention-deficit hyperactiv-
ity disorder (ADHD). It is well known that ADHD is a highly
prevalent neurobehavioral disorder with genetic, environmen-
tal, and biologic etiologies that persists into adolescence and
adulthood in a sizable majority of afflicted children of both
sexes. This disorder is characterized by behavioral symptoms
of inattention, distractibility, hyperactivity, and impulsivity
across the life cycle [13].
Several reports have highlighted the participation of oxida-
tive stress in pathogenesis of many pediatric diseases, includ-
ing autism, Down syndrome, and also ADHD [46]. In-
creased production of free radicals and oxidative stress may
affect the homeostasis of some trace elements. Abnormal me-
tabolism of some trace elements was detected in the children
with ADHD [7,8]. Trace elements such as Cu, Zn, and Se
play an essential role in the oxidant and antioxidant mecha-
nisms in the organism. Therefore, altered levels of these ele-
ments and their imbalance may lead to increased susceptibility
to oxidative damage of important cellular components, and
this may contribute to the pathogenesis of ADHD. Additional
studies have confirmed that Cu, Se, Pb, Fe, Cd, and Cr may
participate in the mechanisms of free radical produce which
*Alena Viktorinova
alena.viktorinova@fmed.uniba.sk
1
Institute of Medical Chemistry, Biochemistry, and Clinical
Biochemistry, Faculty of Medicine, Comenius University, Sasinkova
2, 811 08 Bratislava, Slovak Republic
2
Laboratory of Toxic and Essential Elements, Department of
Environmental Medicine, Slovak Medical University,
Bratislava, Slovak Republic
3
Department of Pediatric Psychiatry, Faculty of Medicine, Comenius
University, Bratislava, Slovak Republic
Biol Trace Elem Res
DOI 10.1007/s12011-015-0395-3
may result in DNA damage, lipid peroxidation, depletion of
glutathione and protein-bound sulfhydryl groups, and the oth-
er effects [9,10].
The etiology of ADHD is not been clearly identified, al-
though reported evidences support neurobiological and genet-
ic background [6]. Recent structural and functional studies
have suggested that dysfunction in the frontal-subcortical
pathways, especially imbalance in the dopaminergic and nor-
adrenergic systems, may be a contributing factor to the path-
ogenesis of ADHD. Therefore, some symptoms of ADHD
may be caused by dysfunction of catecholamines, in which
copper and zinc especially participate [11,12].
It is common knowledge that copper is necessary for the
catalytic activity of many enzymes which have an essential
role in neurophysiology of this disorder, including Cu/Zn su-
peroxide dismutase (antioxidant protection of cells), tyrosi-
nase and dopamine β-hydroxylase (metabolism of dopamine,
noradrenaline, and epinephrine), monoamine oxidase (degra-
dation of catecholamines), and ceruloplasmin for iron homeo-
stasis in the brain [13]. Several studies have pointed to the role
of copper as a pro-oxidant and its participation in the metal-
catalyzed formation of free radicals. In view of this, excessive
Cu levels and copper-mediated neurotoxicity may be related
to the formation of copper-dopamine complex followed by
oxidation of dopamine. This status may be associated with
physical and mental fatigue, depression, and other mental
problems such as schizophrenia, learning disabilities, hyper-
activity, and general behavioral problems [5].
Zinc is an important cofactor for metabolism of neurotrans-
mitters, prostaglandins, and melatonin and indirectly affects
dopamine metabolism. It is necessary for various
metalloenzymes and metal-protein complexes, particularly in
the central nervous system, and thus contributes to the struc-
ture and function of brain. Moreover, the dopamine transport
system has a zinc-binding site that is essential for transport
mechanisms in the brain [1416]. Zinc also acts as an antiox-
idant by protecting the sulfhydryl groups of proteins and en-
zymes against free radical attack in the body, particularly in
the brain. This element can also affect cell division, matura-
tion, and growth of the fetus and, later, neurodevelopment and
intellect of children [8]. Therefore, alterations in Zn metabo-
lism during oxidative stress can be important in the develop-
ment of neurological dysfunctions [10,17].
In addition to these functions, zinc plays a substantial role
in the formation and modulation of melatonin. Melatonin is a
hormone that has several functions in the body, including
control of reproductive processes and regulation of dopamine
metabolism as well as the sleep cycle. It has been confirmed
that Zn deficiency may be associated with changes in
neurodevelopment, cognition, emotion, and motor activity in
ADHD children [7,18]. As noted in other studies, zinc sup-
plementation may be a significant contributor to the treatment
of this disorder [19,20].
Selenium has an essential role as a major constituent of
many enzymes, some of which have antioxidant functions.
Protective effects of Se seem to be associated with its presence
in the glutathione peroxidase and thioredoxin reductase,
which are known to protect DNA and other cellular compo-
nents from oxidative damage. It occurs in the tissues mainly in
protein-bound form, as selenoproteins, in which the sulfur is
replaced by selenium, and most of them are expressed in the
brain [9]. The brain represents an organ with high amounts of
Se, which is susceptible on suboptimal Se levels. Therefore,
selenium deficiency may play a substantial role in the patho-
genesis of neurological and psychiatric disorders. The evi-
dence about the effects of selenium on the progress of neuro-
logical and psychiatric disorders in the children is very limited
[4,21].
Some heavy metals, especially lead, have a high affinity for
SH groups of numerous proteins that are an integral part of
the active site of the enzyme, and this status may lead to
changes in the function of attacked enzymes [22]. Lead is a
neurotoxic element, and the developing brain is vulnerable to
its toxic effects which can be dangerous for fetus and children
during their development and growth. It has been found that
Pb ions readily penetrate the placenta and occur in the same
concentration in both fetal and maternal blood [23]. Binding
of Pb to the biomolecules of placental tissue and its accumu-
lation in the placenta are affected by the state of pregnancy as
well as chemical form of Pb in the maternal blood (diffusible
fraction of Pb better enters into the placenta). The result of the
toxic effects of Pb during pregnancy is fetal damage with
subsequent retardation of growth and development of the cen-
tral nervous system. Moreover, Pb can cause dysfunction of
some neurotransmitters including dopaminergic, glutamater-
gic, and cholinergic systems. These neurotransmitter systems,
especially dopaminergic system, have been related to symp-
toms of ADHD in the children [24,25]. A recent study has
found slightly higher Pb levels in the blood among ADHD
children and also relationships between Pb levels and symp-
toms of hyperactivity and impulsivity. No association between
Pb levels and inattention was observed [26].
The aims of current study were to compare the status of
some trace elements (Cu, Zn, Cu/Zn ratio, Se, and Pb) of
ADHD children with healthy subjects and also to assess the
possibility of their association with parent- and teacher-rated
symptoms of ADHD.
Subjects and Methods
Study Population and Design
Of the 62 outpatients with ADHD treated at the Department of
Pediatric Psychiatry, Faculty of Medicine, Comenius Univer-
sity, Bratislava, 58 children (45 boys and 13 girls), aged 6
Viktorinova et al.
14 years (mean 9.4±2.1) were enrolled in the study. Four
children did not meet the inclusion criteria and were excluded
from this study.
Inclusion criteria were as follows: early onset of ADHD
(by 67 years) and chronicity of the disease (at least 6 months
of symptoms). Exclusion criteria were as designed: situational
hyperactivity, pervasive developmental disorders, schizophre-
nia, mood, anxiety, personality disorder and change due to a
general medical condition, mental retardation, conduct disor-
der, tics, chorea, and other dyskinesia; acute inflammatory
diseases; renal and cardiovascular disorders; and diabetes
mellitus.
The control group consisted of 50 healthy children, aged 6
14 years, recruited from the general population. Children who
participated in the study did not take nutritional supplements
and any drugs that are known to interfere with metabolism of
studied elements before this study. All parents gave a written
consent for participation of their children in this study. The
study was conducted in accordance with the Helsinki Decla-
ration and was approved by the Ethical Committee of the
Child University Hospital in Bratislava.
Clinical Evaluation of Cognitive and Neurobehavioral
Functions
Children with ADHD were included in the study after evalu-
ation of diagnostic criteria of ADHD as described by
Trebaticka et al. [27]. Clinical symptoms of ADHD children
were investigated by standard questionnaires: Child Attention
Problems (CAP) teacher rating scale, Conners Teacher Rat-
ing Scale (CTRS), Conners Parent Rating Scale (CPRS), and
Wechsler Intelligence Scale for children.
Sample Collection
Samples of venous blood were taken after overnight fasting
and collected into commercial tubes with sodium citrate (S-
Monovette, Sarstedt, Numbrecht, Germany) for analysis of
basic biochemical parameters. Metal-free tubes for the stan-
dard venipuncture technique (Vacutainer Trace Element
Tubes, Sarstedt, Numbrecht, Germany) were used for analysis
of Cu, Zn, and Se in the plasma and Pb in whole blood. The
first part of syringes with blood for the determination of basic
biochemical parameters was transported to the Biochemical
Clinical Laboratory of the University Hospital, Comenius
University in Bratislava. The second part of syringes with
blood for determination of trace element status was
transported to Institute of Medical Chemistry, Biochemistry,
and Clinical Biochemistry, Faculty of Medicine, Bratislava.
Subsequently, plasma was isolated by centrifugation under
standard conditions and aliquoted into metal-free Eppendorf
test tubes (Eppendorf AG, Hamburg, Germany), frozen, and
stored at 80 °C until further analysis.
Determination of Basic Biochemical Parameters
Plasma levels of basic biochemical parameters (glucose, lipid
profile, uric acid, bilirubin, alkaline phosphatase, aspartate
aminotransferase, alanine aminotransferase, gamma-
glutamyl transferase) were measured by standardized bio-
chemical methods at the Biochemical Clinical Laboratory of
the University Hospital, Comenius University in Bratislava.
The concentrations of measured parameters were compared
with reference values of this laboratory.
Determination of Trace Element Status
Flame technique of atomic absorption spectrometry was used
for determination of Cu and Zn concentrations in the plasma
(FAAS Varian AA240FS, Deuterium background correction,
Techtron Pty., Ltd., Springvale, Australia) [28]. Concentrations
of Se in the plasma and Pb in the whole blood were measured
by electrothermal technique (ETA AAS Varian AA 280Z, Zee-
man background correction, Electrothermic atomizer GTA 120,
Techtron Pty., Ltd., Springvale, Australia) [29,30]. The accura-
cy of determination was evaluated by measuring the metal con-
tents of certificated biological reference materials (Seronorm
Trace Elements, Nycomed Pharma, Oslo, Norway).
Statistical Analysis
Shapiro-Wilk Wtest was used to assess the normality or non-
normality distribution of data in investigated groups. Differ-
ences between ADHD group and control group were analyzed
with the Studentsttest for data with a normal distribution.
Results are shown as mean±SD. For comparison of data with
a non-normal distribution, non-parametric Mann-Whitney U
test was used. These results were expressed as median (first
quartile, third quartile). Spearman rank correlation test was used
to evaluate the relationships between measured parameters in
each group and expressed with the Spearmans rank correlation
coefficient. Statistical significance for all calculations was set at
the level of p<0.05. Data were analyzed using the program
StatsDirect
®
2.3.7 (StatsDirect Sale, Cheshire M33 3UY,
UK). Graphical representation of data was performed by the
Excel 2007 (Microsoft Office Excel Corporation, USA).
Results
The study consisted of 58 ADHD children aged 614 years
(mean 9.4±2.1) and 50 healthy children (mean 8.9±2.8). We
did not observe any significant difference between age of
ADHD children and age of the control group (p>0.05).
The plasma levels of Cu, Zn, Cu/Zn ratio, and Se and
whole blood levels of Pb in ADHD children and control group
are shown in Table 1. Plasma levels of biochemical parameters
Zinc and Copper to Zinc Ratio in ADHD Children
were in the range of physiological values in both investigated
groups (data not shown).
We found significantly lower level of Zn (p=0.0005) and
higher Cu/Zn ratio (p=0.015) in ADHD children when com-
pared with control group (Figs. 1and 2). Copper levels in
ADHD children tended to be higher than in the control group,
but this difference was not statistically significant (p>0.05).
We recorded that levels of Se and Pb in ADHD children were
similar to those in healthy children.
Moreover, we evaluated relationships between individual
levels of Cu, Zn, Cu/Zn ratio, Se, and Pb in both study groups.
An imbalance in the levels of Cu and Zn was observed in
ADHD children when compared with healthy children. As
shown in Table 2, there is significant correlation between Cu
and Zn in healthy children (p=0.038), but on the contrary, no
significant relationship between these elements in ADHD
children was found. Statistical analysis showed that there are
strong correlations between Cu/Zn ratio and Cu and also Zn in
both groups of children which were included into our study
(p<0.0001).
Interestingly, the correlation analysis confirmed the exis-
tence of weak correlations between age and Zn (r=0.238), Cu
(r=0.216), and Cu/Zn ratio (r=0.241) in control group
(p<0.05). On the contrary, inverse correlations between age
and Zn levels (r=0.206, p=0.154) and Cu/Zn ratio (r=
0.117, p=0.078) were found in ADHD children. The level
of Cu positively correlated with age in this group (r=0.292,
p=0.064). No significant associations between age and Se and
also Pb levels were found in both groups (data not shown).
We also investigated associations between levels of Cu, Zn,
Cu/Zn ratio, Se, and Pb and parent- and teacher-ratedscales of
clinical symptoms of ADHD. A detailed report describing
these ratings was previously published [27]. Decreased Zn
levels in ADHD children weakly inversely correlated (r=
0.231) with parent-rated score for inattention (CPRS inatten-
tion score) as well as with teacher-rated score for inattention
(CTRS inattention score) (r=0.328), but statistical signifi-
cantly (p=0.029; p=0.014)asdepictedinFig.3.Correlation
analysis between Cu/Zn ratio and parent- and teacher-rated
symptoms of ADHD showed that increased values of this ratio
significantly correlated (r=0.298, p=0.015) exclusively only
with CTRS inattention (Fig. 4). No significant correlations
between Cu level and ratings of ADHD symptoms and
also between Zn level and Cu/Zn ratio and parent- and
teacher-rated scores for hyperactivity were found (data
not shown).
Despite the fact that there were no differences in the levels
of Se and Pb (p>0.05) between investigated groups of chil-
dren (Table 1), we were also interested in whether there are
any correlations between these elements and the ratings of
Tabl e 1 Trace element status in
the children with ADHD and
control group
Parameter ADHD group (n=58) Control group (n=50) pvalue
Cu (μmol/L) 18.31± 3.34 17.64±2.83 >0.05
Zn (μmol/L) 10.63 (9.37; 11.28) 11.32 (10.56; 12.74) 0.0005
Cu/Zn ratio 1.78 (1.51; 1.99) 1.61 (1.39; 1.78) 0.015
Se (μmol/L) 0.92±0.12 0.93 (0.78; 0.98) >0.05
Pb (μmol/L) 0.116 ±0.08 0.113±0.04 >0.05
Data are given as mean±SD (standard deviation) for parametric variables or as median (first quartile; third
quartile) for nonparametric variables. nis the number of subjects per group. pvalue represents the difference
between measured parameters in ADHD group and control group (p<0.05 was defined as statistically significant)
Fig. 1 Comparison of Zn concentrations between ADHD children and
control group. *p=0.0005
Fig. 2 Comparison of Cu/Zn ratios between ADHD children and control
group. *p=0.015
Viktorinova et al.
ADHD symptoms. Significant associations of Se and Pb with
parent- and teacher-rated symptoms were not observed.
Discussion
In the past decades, a number of studies have disclosed that
the homeostasis of some trace elements is altered in the chil-
dren with ADHD and that these alterations may contribute to
the pathogenesis of this disorder [3]. Although, there has been
an increasing interest about understanding the participation of
trace elements in the pathophysiology of ADHD, but to date,
their role has not yet been elucidated. Several researchers have
studied the occurrence of trace element deficiency among
children with ADHD compared with control subjects. Some
of them found deficiencies of Cu, Zn, Fe, magnesium, and
calcium in ADHD children on the basis of analyses of serum,
red cell, and hair [31,32]. In contrast to the findings of these
studies, we observed that Cu levels in ADHD children were
higher than those in healthy children (Table 1). In addition, we
also found significantly lower levels of Zn and higher Cu/Zn
ratio in ADHD children in comparison to control group
(Figs. 1and 2).
The role of selenium in the pathophysiology of ADHD is
little described in the literature. Some authors have observed
decreased levels of Se in children with specific mental disor-
ders [4,33]. In comparison with these studies, no significant
differences in the levels of Se among both groups of children
included into this study as well as no significant associations
of Se with parent- and teacher-rated symptoms of ADHD were
recorded.
A few studies have described the participation of Pb ions in
the pathogenesis of ADHD and their relation to the symptoms
of this disorder [26,34]. In our study, no differences in Pb
levels between the study groups of children were observed.
Moreover, blood Pb level was not significantly associated
with parent- and teacher-rated symptoms of ADHD.
In view of the knowledge of the present literature, it ap-
pears that there is a link between the metabolisms of copper
and zinc, and imbalance of these elements is still actively
studied [4,16,18]. Reduced levels of Zn often result in ele-
vated levels of Cu due to the dynamic competition between
these metals in the body [35,36]. It has been proven that under
the condition of zinc deficiency, copper tends to accumulate in
the body. This status may be associated with hyperactivity,
learning disabilities, and depression [19,20]. Given the sta-
tistically non-significant trend toward higher levels of Cu
and significantly reduced levels of Zn in children with
ADHD when compared with control group, we assume
that there is a noticeable evidence of an imbalance be-
tween these elements. Our assumption was also support-
ed by correlation analysis (altered association between
these elements is shown in Table 2).
Tabl e 2 Correlation analysis of trace elements in the study groups
Variables ADHD group Control group
rpvalue rpvalue
Zinc
Cu 0.153 0.128 0.264 0.038
Se 0.375 0.002 0.402 0.003
Pb 0.619 0.058 0.168 >0.05
Cu/Zn ratio
Cu 0.696 <0.0001 0.475 0.0005
Zn 0.536 <0.0001 0.636 <0.0001
Se 0.226 0.047 0.077 0.313
Pb 0.357 >0.05 0.206 >0.05
ris Spearmans rank correlation coefficient. pvalue represents the differ-
ence between correlated parameters in ADHD group and control group
(p<0.05 was defined as statistically significant)
Fig. 3 Associations between Zn concentration and CPRS score for
inattention (r=0.231, p=0.029) as well as CTRS score for inattention
(r=0.328, p=0.014) in children with ADHD. CPRS Conners Parent
Rating Scale, CTRS Conners Teacher Rating Scale
Fig. 4 Association between Cu/Zn ratio and CTRS score for inattention
in children with ADHD (r=0.298, p=0.015). CTRS Conners Teacher
Rating Scale
Zinc and Copper to Zinc Ratio in ADHD Children
We considered that Cu/Zn ratio is a more important param-
eter in assessing the relationship between Cu and Zn than the
concentrationofeitherofthesetrace elements. This fact was
confirmed by strong positive correlation between Cu/Zn ratio
and Cu level as well as negative correlation between Cu/Zn
ratio and Zn level (Table 2). An altered ratio of copper and zinc
may be related to an impaired ability of the body to maintain or
regenerate the copper and zinc homeostasis after effect of
destabilizing factors on the metabolism of these elements.
It has been reported that the symptoms of variety psychiat-
ric and neurological disorders may be caused by dysfunction
of dopaminergic, serotonergic, and noradrenergic neurotrans-
mitter systems [11,12]. Optimal levels of copper and zinc are
required for the metabolism and function of neurotransmitters.
Copper is a cofactor for activity of some enzymes in neuro-
transmitter metabolism, such as dopamine hydroxylase and
monoamine oxidase. High levels of Cu can induce damage
of dopaminergic neurons by destroying the antioxidant de-
fense system as has been confirmed in animal experiments
[13]. Zinc may influence the metabolism of melatonin and,
thus, the functioning of the dopaminergic system. Melatonin
participates in the regulation of sleep cycles, and its changed
level can contribute to the symptoms of ADHD. It is known
that Cu metabolism is connected with Zn metabolism and
disturbed relationships between them can lead to delayed de-
velopment, attention deficit disorder, and anti-social behavior,
hyperactivity, autism, and learning difficulties [37].
The present study confirmed previous findings [12]that
decreased Zn levels are inversely associated with parent- and
teacher-rated scores for inattention in ADHD children, but not
with hyperactivity. Moreover, we observed that Cu/Zn ra-
tio positively correlated exclusively only with teacher-
rated score for inattention. Our findings support and
extend the hypothesis, which is based on the argument
that these trace elements can considerably contribute to
the pathogenesis of ADHD [38,39].
Altered levels of Cu, Zn, and the ratio of copper to zinc
may attenuate the antioxidant defense system and create the
conditions for increased oxidative stress in ADHD children.
This assumption is consistent with a recent study [14] focused
on the assessment of the possible role of oxidative stress in the
pathogenesis of ADHD by measuring various biochemical
markers of oxidative metabolism (products of lipid peroxida-
tion, levels of non-esterified fatty acids). Authors concluded
that increased levels of malondialdehyde, decreased Zn levels,
and their correlations with symptoms of inattention support
the oxidative stress theory in the pathogenesis of ADHD.
Conclusion
Based on our findings, we can postulate that an imbalance in
levels of trace elements under the structure of antioxidant
enzyme defense systems may cause damage to some functions
of cell components in the brain depending on the produce of
free radicals. This status may result to changes of behavior in
the children and contribute to the symptoms of ADHD. How-
ever, the precise mechanisms responsible for altered metabo-
lism of trace elements in ADHD children are unclear and
require following studies. Therefore, it is necessary to focus
further research to obtain more information about the relation-
ship between trace minerals, antioxidant defense systems, and
free radical formation in the pathophysiology of ADHD.
Acknowledgments This study was supported by MVTS TW-010002
grant of Ministry of Education, Slovak Republic. Authors wish to thank
all volunteers for their participationin this study and to Mrs. Husekova Z.
and Witkova V. for their technical assistance as well as the nurses for
taking blood samples from children.
Conflict of interest The authors declare that they have no conflict of
interest.
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Zinc and Copper to Zinc Ratio in ADHD Children
... The observed finding of the lowest Zn levels in ADHD/ASD patients generally corresponds to the study of Russo et al. (2012) demonstrating a significant inverse correlation between plasma Zn levels and hyperactivity in children with ASD [24]. Zn levels in ADHD were also found to be reduced, is also inversely associated with attention deficit [10,25]. Serum Zn levels were also shown to be inversely associated with parentteacher-rated inattention in ADHD children [26]. ...
... The majority of studies revealed no significant group difference in copper status in ADHD patients [27,55]. Viktorinova et al. (2016) demonstrated only a nonsignificant trend to increased plasma copper levels in ADHD [25]. At the same time, an Egyptian study demonstrated a high incidence of Cu deficiency in ADHD children [36]. ...
... The majority of studies revealed no significant group difference in copper status in ADHD patients [27,55]. Viktorinova et al. (2016) demonstrated only a nonsignificant trend to increased plasma copper levels in ADHD [25]. At the same time, an Egyptian study demonstrated a high incidence of Cu deficiency in ADHD children [36]. ...
Article
Background The existing data demonstrate that alteration of trace element and mineral status in children with neurodevelopmental disorders including ASD and ADHD. However, comparative analysis of the specific patterns of trace element and mineral metabolism in children with ASD and ADHD was not performed. Therefore, the primary objective of the present study was to assess hair trace element and mineral levels in boys with ADHD, ASD, as well as ADHD with ASD. Methods Boys with ADHD (n = 52), ASD (n = 53), both ADHD and ASD (n = 52), as well as neurotypical controls (n = 52) were examined. Hair analysis was performed using inductively-coupled plasma mass-spectrometry. Results The obtained data demonstrate that hair Co, Mg, Mn, and V levels were significantly reduced in children with ADHD and ASD, and especially in boys with ADHD + ASD. Hair Zn was found to be reduced by 20% (p = 0.009) only in children with ADHD + ASD as compared to healthy controls. Factor analysis demonstrated that ASD was associated with significant alteration of hair Co, Fe, Mg, Mn, and V levels, whereas impaired hair Mg, Mn, and Zn content was also significantly associated with ADHD. In regression models hair Zn and Mg were negatively associated with severity of neurodevelopmental disorders. The revealed similarity of trace element and mineral disturbances in ASD and ADHD may be indicative of certain similar pathogenetic features. Conclusion The obtained data support the hypothesis that trace elements and minerals, namely Mg, Mn, and Zn, may play a significant role in development of both ADHD and ASD. Improvement of Mg, Mn, and Zn status in children with ASD and ADHD may be considered as a nutritional strategy for improvement of neurodevelopmental disturbances, although clinical trials and experimental studies are highly required to support this hypothesis.
... Either hypomagnesemic or normomagnesemic individuals are prone to several pathological conditions and require medication, mainly in those hospitalized under intensive therapy. Hypomagnesemia is more frequent in patients with normal serum creatinine and has been associated with an increased mortality rate [53]. ...
... Magnesium deficiency is characterized by severe reduction in cognitive capacity and processing, and in particular reduced attention, together with increased aggression, fatigue, and lack of concentration [52]. Other common symptoms include easy irritation, nervousness, and changing humor [53]. Magnesium helps to generate ATP and energy, eliminate ammonia in the brain related to lack of attention, and convert essential fatty acids in DHA (docosahexaenoic acid), which is related to proper functioning and structure of the brain cells. ...
Article
Full-text available
During pregnancy, women undergo metabolic and physiological changes, and their needs are higher, to maintain growth and development of the fetus. If the nutritional status of the expectant mother is not satisfactory, some maternal and neonatal complications can occur. In the second and third trimester of pregnancy, there is a reserve of nutrients in the fetus that can be utilized after birth; thereby, children present an accelerated growth in the first years of life, which is a proven response to the available nutrition pattern. However, if such a pattern is insufficient, there will be deficits during development, including brain function. Therefore, despite many recent published works about gestational nutrition, uncertainties still remain on the mechanisms of absorption, distribution, and excretion of micronutrients. Further elucidation is needed to better understand the impacts caused either by deficiency or excess of some micronutrients. Thus, to illustrate the contributions of minerals during prenatal development and in children, iodine, selenium, iron, zinc, calcium, and magnesium were selected. Our study sought to review the consequences related to gestational deficiency of the referred minerals and their impact on growth and development in children born from mothers with such deficiencies
... Several studies highlight the role of oxidative stress as an important participating agent in the aetiology of ADHD. An increase in the production of free radicals and oxidative stress may be affected by and affect the homeostasis of certain trace elements [8]. Trace elements such as copper and zinc play an important role in pathways concerning oxidant and antioxidant mechanisms. ...
... From this study, it can be considered that Cu/Zn ratio is an important parameter in assessing a child with ADHD. A similar manifestation was determined by Viktorinova et al. in a population of Russian children, in which they had found significantly higher levels of Cu/Zn levels in serum [8]. A deranged copper-zinc ratio may be associated with a decreased capacity of the organism to maintain or regenerate copper-zinc homeostasis following the influence of destabilising events on these elements' metabolism. ...
Article
Full-text available
Background Attention deficit hyperactivity disorder (ADHD) is a neuro-developmental ailment diagnosed with inattention and hyperactivity-impulsivity. It is one of the most prevalent neurodevelopmental disorders and has complex aetiology, both genetic and environmental. There is a perceived decrease in skill acquirement, leading to insufficient income and job opportunities as adults, which drives them towards poor physical and mental outcomes compared to their contemporaries without ADHD. The impact of heavy metals on ADHD is a topic of interest but is much less studied. Copper has been implicated as a pro-oxidant and in the metal accelerated production of free radicals that may affect oxidative stress. Zinc also serves as an antioxidant, and changes in its concentrations may impact the homeostasis of oxidative stress. Methods Twenty-four children diagnosed with ADHD were taken as cases and matched with 24 healthy controls. Hair and urine samples were collected from all the study participants. The samples were collected in sterile containers according to established protocols. Acid digestion of hair samples was done using 65% nitric acid and 30% hydrogen peroxide. Urine samples were extracted by a solution of 0.1% Triton-X-100 and 1% ultrapure nitric acid. The levels of zinc and copper were determined in both samples by inductively coupled plasma optical emission spectrometry (ICP-OES). The copper/zinc ratio (Cu/Zn) was calculated from these values. Mann Whitney U Test and receiver operating characteristic (ROC) analysis were done to estimate statistical significance. Results The median age of the study population was eight years. Overall, 34 male and 14 female subjects participated. There was no significant difference in height, weight and BMI between the cases and controls. Hair zinc levels in the ADHD group (198.49 µg g-1 of hair) was significantly lower than the control group (527.05 µg g-1 of hair). However, hair copper levels were increased significantly in the ADHD children (14.01 µg g-1 of hair) compared to the controls (7.43 µg g-1 of hair). Urine zinc levels were significantly lower in cases than controls (525.7 µg g-1 of spot urine creatinine vs 1374.09 µg g-1 of spot urine creatinine). However, copper levels in urine were higher in the ADHD children (17.01 µg g-1 of spot urine creatinine compared to 7.26 µg g-1 of spot urine creatinine in controls). Both hair and urine copper to zinc ratio was significantly higher in the ADHD group. On ROC analysis, the hair Cu/Zn ratio had an area under the curve (AUC) of 0.920 (p-value <0.001), and the urine Cu/Zn ratio had an AUC of 0.967 (p-value <0.001). When used as a diagnostic classifier for ADHD based on the cut-off value determined by ROC, both hair and urine Cu/Zn ratio had high sensitivity and specificity. Conclusion Low zinc levels in the urine and hair of children and higher levels of copper may impact the aetiology of ADHD in these children. At an early stage, the Cu/Zn ratio in both hair and urine samples may be used as a precise biomarker to identify and monitor such children.
... Case-control trials in several geographical areas have demonstrated lower zinc levels in children diagnosed with ADHD compared to healthy controls [30,32,33,55,82,101,[121][122][123][124][125][126][127]. There has been discussion in literature on the lower values of zinc in children with ADHD [128], but without report of a range of normal levels clinical significance thereof is questionable. ...
... Since this trace element is an essential part of antioxidant enzymes, it can be linked to efficiency in lowering oxidative stress in ADHD. However, no significant differences in Se levels between controls and ADHD children could be found [126]. Low intake of Se was observed in ADHD groups compared to controls [55,56], although another study claimed to find no difference in Se intake [157]. ...
Article
Full-text available
In this study, we critically review the literature concerning the relation of Mg, Fe, Zn, Cu and Se and attention-deficit/hyperactivity disorder (ADHD). Elemental status is estimated using peripheral blood parameters, hair, urine, daily intake and response to supplementation. The observed associations between concentration levels of the elements Mg, Fe, Zn, Cu and Se and ADHD symptoms are contradictory. This is partly due to the heterogeneity and complexity of the disorder. As a trend, lower ferritin and zinc levels can be observed. However, this correlation is not causative, as illustrated by placebo-controlled trials reporting conflicting evidence on the efficacy of supplementation. Well-defined studies on changes in concentration levels of the elements in relation to ADHD symptoms before and after treatment with therapeutics it will be possible to shed more light on the significance of these elements in this behavioral disorder. The discussion on whether a change in concentration of an element is cause or consequence of ADHD is not within the scope of this article.
... Для комплексной оценки обмена цинка и меди проводили химический анализ образцов сыворотки крови, мочи и волос обследуемых. Полученные результаты позволяют определить не только краткосрочные, но и долгосрочные тенденции в изменении элементного статуса (Skalnaya, Skalny, 2018 П р и м е ч а н и е : данные представлены в виде Mean ± SD для количественных показателей, а также n (%) для категориальных. ...
... Несмотря на отсутствие выраженных нарушений обмена меди в организме детей с СДВГ, было выявлено достоверное повышение значений соотношения Cu/Zn в сыворотке крови. Данное наблюдение согласуется с результатами исследования Viktorinova с соавторами, которые также установили взаимосвязь между величиной Cu/Zn и родительской и учительской оценками невнимательности у детей с СДВГ (Viktorinova et al., 2016). Данные о непосредственных механизмах дисбаланса меди и цинка в патогенезе СДВГ отсутствуют, тем не менее справедливо предположить, что вовлеченные механизмы могут, по крайней мере, частично соответствовать таковым при аутизме, включая модуляцию окислительного стресса и передачи сигнала в головном мозге (Bjørklund, 2013). ...
... In a study, ADHD children had a higher copper than zinc which was correlated with observations made by the teacher. [27] Increase in blood copper was associated with a decrease in sustained attention and short-term memory. [28] In a randomized controlled trial on 80 adults with ADHD, lower baseline copper levels were associated with better response to treatment with a vitamin-mineral supplement. ...
Article
In the past two decades, rapid urbanization and globalization have adversely changed our lifestyle and diet habits. Our traditional healthy food habits have been replaced by processed foods with low nutritive value. These measures also saw a high prevalence of depression and other psychiatric disorders not only in western, urbanized countries but also in other developing countries as well. Long-term undernutrition due to deficiency of micronutrients such as iodine and iron can lead to increased chances of physical and mental disabilities. Undernourished children have less energy, decreased curiosity, and less interest in physical activities as well as they lack communication skills. These factors impair their physical, mental, and cognition. The aim of this article was to find the association of micronutrients especially minerals in patients with major depressive disorders. An adequate supply of nutrients is essential to regulate microbiome health and to improve the efficacy of other psychotherapeutic and psychopharmacological interventions. Lifestyle interventions in the form of dietary coaching could be used as promising, cost-effective, and practical intervention in depressed individuals. Nutritional interventions should be integrated in the multifactorial and treatment-resistant psychiatry patients.
... Except for one study 24 Twenty studies had case-control design and only two studies 13,28 were conducted by cross-sectional design. According to the Newcastle-Ottawa scale, nine studies were assigned to moderate quality 12,25,27,29,30,32,36,40,41 , and the rest of them had high quality ( Table 2). ...
Article
Full-text available
Previous studies regarding the zinc status in attention-deficit/hyperactivity disorder (ADHD) yielded inconsistent results. Thus, the present meta-analysis was aimed to estimate the association between hair and serum/plasma zinc levels and ADHD. Online databases of Medline, EMBASE, and Scopus were searched up to October 2020 with no limitation in time and language. Weighted mean differences (WMDs) of hair and serum/plasma zinc levels were calculated using a random-effects model. Overall, 22 articles with 1280 subjects with ADHD and 1200 controls were included. The pooled effect size indicated that serum/plasma zinc levels in subjects with ADHD were not statistically different than their controls (WMD = − 1.26 µmol/L; 95% CI − 3.72, 1.20). Interestingly, the exclusion of one study from the analysis showed that people with ADHD significantly have lower circulating levels of zinc compared to their controls (WMD: − 2.49 µmol/L; 95% CI − 4.29, − 0.69). Also, the pooled effect size indicated that hair zinc levels in cases with ADHD were not statistically different than their controls (WMD = − 24.19 μg/g; 95% CI − 61.80, 13.42). Present meta-analysis raises the possibility that subjects with ADHD are prone to have declined levels of zinc levels. Based on current findings, screening the zinc levels in subjects with ADHD could be reasonable. Further well-designed studies are needed to clarify the role of zinc in the etiology of ADHD.
... A large number of studies using several different approaches (e.g., neuroimaging, metabolic and genetic investigations) have been carried out with relative success, in order to find the underlying causes of ADHD and correlate them with specific biomarkers. Unfortunately, so far, none of those approaches has been able to find reliable biomarkers that can be used in a clinical environment to support a clinical diagnosis [15][16][17][18][19][20][21][22][23][24][25]. Schmidt et al. [26] defined a biomarker as a characteristic that can be objectively measured and evaluated as an indicator of a normal biological process, a pathogenic process or a response to a therapeutic intervention. ...
Article
Full-text available
Attention deficit and hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders of childhood. It affects ~10% of the world’s population of children, and about 30–50% of those diagnosed in childhood continue to show ADHD symptoms later, with 2–5% of adults having the condition. Current diagnosis of ADHD is based on the clinical evaluation of the patient, and on interviews performed by clinicians with parents and teachers of the children, which, together with the fact that it shares common symptoms and frequent comorbidities with other neurodevelopmental disorders, makes the accurate and timely diagnosis of the disorder a difficult task. Despite the large effort to identify reliable biomarkers that can be used in a clinical environment to support clinical diagnosis, this goal has never been achieved hitherto. In the present study, infrared spectroscopy was used together with multivariate statistical methods (hierarchical clustering and partial least‐squares discriminant analysis) to develop a model based on the spectra of blood serum samples that is able to distinguish ADHD patients from healthy individuals. The developed model used an approach where the whole infrared spectrum (in the 3700–900 cm−1 range) was taken as a holistic imprint of the biochemical blood serum environment (spectroscopic biomarker), overcoming the need for the search of any particular chemical substance associated with the disorder (molecular biomarker). The developed model is based on a sensitive and reliable technique, which is cheap and fast, thus appearing promising to use as a complementary diagnostic tool in the clinical environment. Keywords: attention deficit and hyperactivity disorder (ADHD); FTIR spectroscopy; chemometrics; PLS‐DA
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Iron and zinc have been associated with attention-deficit/hyperactivity disorder (ADHD), executive functioning, and response to methylphenidate, given their link with the dopaminergic system. This study aimed to investigate the effect of withdrawing methylphenidate after long-term treatment on serum levels of ferritin and zinc; and if baseline (pre-discontinuation) serum levels of these nutritional markers moderated the effects of withdrawing methylphenidate on ADHD and oppositional defiant disorder (ODD) symptoms, and working memory. Blood samples were collected from 63 children and adolescents who participated in a randomized, placebo-controlled methylphenidate discontinuation study. They were assigned to either seven weeks of continued treatment with methylphenidate or to gradual withdrawal to placebo. With mixed models for repeated measures we (i) compared changes in ferritin and zinc serum levels between both groups, and (ii) investigated moderating effects of ferritin and zinc on the effects of discontinuation on ADHD and ODD symptoms, and working memory. We additionally explored correlations of baseline and change serum levels with respective symptom scores. Withdrawing methylphenidate led to a decrease in ferritin levels. Higher baseline ferritin was associated with a larger increase (i.e., worsening) of teacher-rated hyperactivity-impulsivity and ODD symptoms after withdrawal; and higher baseline zinc with a larger increase in number of errors on the working memory task after withdrawal. Serum levels did not correlate with ADHD and ODD symptoms. Our preliminary results suggest that ferritin and zinc may be potential biomarkers for the effectiveness of long-term treatment with methylphenidate.
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Exposure to single metals have been linked to childhood behavior problems, But little is known about the effects of metals mixtures on children. We aimed to evaluate associations of multiple metals exposures in urine with childhood behavior in China. For this population-based study, the children eligible for inclusion provided urine samples and their parents agreed to take in-person interview. A total of 831 children were remained from three cities for the final analysis. Urinary metals concentrations were measured by inductively coupled plasma mass spectrometry (ICP-MS). The childhood behavior scores was calculated by the Conners' Parent Rating Scale (CPRS). Variable selection was achieved by the least absolute shrinkage and selection operator (LASSO) regularization and stepwise regression to for all metals in the study. Linear regression models and Bayesian kernel machine regression (BKMR) were applied to estimate the associations of urinary metals concentrations with children's behavior. In BKMR models, the overall effect of mixture was significantly associated with conduct problems, learning problems and hyperactive index when urinary metals concentrations were all above the 50th percentile compared to all of them at their medians. The models also suggested marginally significant interaction effects of Se and Fe as well as Se and Sb (PSe∗Fe = 0.063; PSe∗Sb = 0.061), with a decline in estimate of Se on learning problems when Sb/Fe levels were relatively high. The concentrations of 22 metals in boys were higher than girls. In summary, multiple metals are associated with an increased risk of childhood behavioral problems in China. Potential interaction effects of Se and Fe as well as Se and Sb on childhood behavior should be taken into consideration.
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Proteins of the ProSAP/Shank family act as major organizing scaffolding elements within the postsynaptic density of excitatory synapses. Deletions, mutations or the downregulation of these molecules has been linked to autism spectrum disorders, the related Phelan McDermid Syndrome or Alzheimer's disease. ProSAP/Shank proteins are targeted to synapses depending on binding to zinc, which is a prerequisite for the assembly of the ProSAP/Shank scaffold. To gain insight into whether the previously reported assembly of ProSAP/Shank through zinc ions provides a crossing point between genetic forms of autism spectrum disorder and zinc deficiency as an environmental risk factor for autism spectrum disorder, we examined the interplay between zinc and ProSAP/Shank in vitro and in vivo using neurobiological approaches. Our data show that low postsynaptic zinc availability affects the activity dependent increase in ProSAP1/Shank2 and ProSAP2/Shank3 levels at the synapse in vitro and that a loss of synaptic ProSAP1/Shank2 and ProSAP2/Shank3 occurs in a mouse model for acute and prenatal zinc deficiency. Zinc-deficient animals displayed abnormalities in behaviour such as over-responsivity and hyperactivity-like behaviour (acute zinc deficiency) and autism spectrum disorder-related behaviour such as impairments in vocalization and social behaviour (prenatal zinc deficiency). Most importantly, a low zinc status seems to be associated with an increased incidence rate of seizures, hypotonia, and attention and hyperactivity issues in patients with Phelan-McDermid syndrome, which is caused by haploinsufficiency of ProSAP2/Shank3. We suggest that the molecular underpinning of prenatal zinc deficiency as a risk factor for autism spectrum disorder may unfold through the deregulation of zinc-binding ProSAP/Shank family members.
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Objective: To study the effects of intranigral injection of different doses of CuSO4.5H2O on dopaminergic neuron in the nigrostriatal system of rats. Methods: Wistar rats were divided into four groups, including control group, 10 nmol, 50 nmol and 200 nmol copper injected into left substantia nigra (SN) groups. Seven days after the intranigral injection of copper, dopamine (DA) contents in the striatum (Str) were measured by high performance lipid chromotophotography (HPLC); the density of tyrosine hydroxylase (TH) positive axons in the Str was measured by TH staining method; TH and Caspase-3 mRNA expression in the SN were measured by semi-quantitative RT-PCR. We detected the activity of superoxide dismutase (SOD) in the lesioned midbrain of rats using biochemical methods. Results: DA and its metabolites contents had no significant difference between control group and low dose (10 nmol) copper group. But from 50 nmol copper group, DA contents in the lesioned sides were reduced with the increase in the copper doses injected, showing a significant linear correlation (F = 34.16, P < 0.01). In the 50 nmol copper group, TH positive axons in the Str decreased compared with those of the control and unlesioned sides (F = 121.9, P < 0.01). In the 50 nmol copper group, TH mRNA expression decreased (t = 3.12, P < 0.01) while Caspase-3 mRNA expression increased (t = 8.96, P < 0.01) in the SN compared with the control. SOD activity decreased in the midbrain of rats treated with 50 nmol copper compared with that of the control (t = 2.33, P < 0.01). Conclusion: Copper could induce damage of dopaminergic neurons in the SN of rats through destroying antioxidant defenses and promoting apoptosis.
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Attention deficit hyperactivity disorder is a behavioral syndrome of childhood characterized by inattention, hyperactivity and impulsivity. There were many etiological theories showed dysfunction of some brain areas that are implicated in inhibition of responses and functions of the brain. Minerals like zinc, ferritin, magnesium and copper may play a role in the pathogenesis and therefore the treatment of this disorder. This study aimed to measure levels of zinc, ferritin, magnesium and copper in children with attention deficit hyperactivity disorder and comparing them to normal. This study included 58 children aged 5-15 years with attention deficit hyperactivity disorder attending Minia University Hospital from June 2008 to January 2010. They were classified into three sub-groups: sub-group I included 32 children with in-attentive type, sub-group II included 10 children with hyperactive type and sub-group III included 16 children with combined type according to the DSM-IV criteria of American Psychiatric Association, 2000. The control group included 25 apparently normal healthy children. Zinc, ferritin and magnesium levels were significantly lower in children with attention deficit hyperactivity disorder than controls (p value 0.04, 0.03 and 0.02 respectively), while copper levels were not significantly different (p value 0.9). Children with inattentive type had significant lower levels of zinc and ferritin than controls (p value 0.001 and 0.01 respectively) with no significant difference between them as regards magnesium and copper levels (p value 0.4 and 0.6 respectively). Children with hyperactive type had significant lower levels of zinc, ferritin and magnesium than controls (p value 0.01, 0.02 and 0.02 respectively) with no significant difference between them as regards copper levels (p value 0.9). Children with combined type had significant lower levels of zinc and magnesium than controls (p value 0.001 and 0.004 respectively) with no significant difference between them as regards ferritin and copper levels (p value 0.7 and 0.6 respectively). Children with attention deficit hyperactivity disorder had lower levels of zinc, ferritin and magnesium than healthy children but had normal copper levels.
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The determination of Se in serum by atomic absorption spectrometry with electrothermal atomization is presented. The method has the detection limit of 12.9 pg Se, which was determined with 100 μl samples. The method was verified using the standard reference material - Seronorm™ Trace Element Serum, NYCOMED PHARMA AS, Norway. The median level of Se in the serum of healthy volunteers from Bratislava (Slovakia) was 83.6 μg.1-1. The median concentrations of Se in the serum of male donors were higher (85.7 μg.l-1) than in female donors of the similar age (80.1 μg.1-1).
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This study systematically reviews the randomized clinical trials examining the effect of zinc on attention-deficit hyperactivity disorder (ADHD), searching the PubMed/Medline and Scholar Google databases. All randomized controlled trials that examined zinc as the intervention, and ADHD as the primary outcome were included. Only three randomized controlled trials, one which included a community sample and two that included clinical samples, met inclusion criteria. The only trial that was well controlled and randomized according to the baseline zinc level showed that using zinc, either alone or in combination with stimulants, did not improve ADHD. Considering the lack of clear evidence for the effect of zinc on ADHD and the possible effect of zinc on the nervous system, more clinical studies are needed to prove or disprove the effect of zinc as a monotherapy or adjuvant therapy.European Journal of Clinical Nutrition advance online publication, 21 November 2012; doi:10.1038/ejcn.2012.177.
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In 36 children of 3-8 years old with minimal cerebral dysfunction there were evaluated both concentrations of malonic dialdehyde in blood plasma, erythrocytes and platelets as well as the content of 25 elements (K, Mg, Ca, Na, P, Se, Zn, Co, Cr, Cu, Fe, Mn, Mo, Si, Li, Ni, V, Pb, Sn, Cd, Al, As, Be, Bi, Ti) in hairs. These indices were estimated both before and after course of cerebrolysin therapy (the a dose 2-5 ml intramuscularly during 1 month). There was observed positive influence of the drug on the clinical manifestations of the disease, oxidant and elements homeostasis. Nuclear-emission analysis of the elements' composition of cerebrolysin revealed quite high content in the drug of magnesium, potassium, phosphorus, and selenium which had neuroactive and antioxidant properties.
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The dopamine transporter is regulated by zinc (Zn2+), which directly interacts with the transporter protein as a potent non-competitive blocker of substrate translocation (dopamine transport inward and outward). The fact that dysfunction of the dopamine transporter is involved in the pathogenesis of attention-deficit hyperactivity disorder (ADHD) is interesting in the context of studies that suggest the involvement of zinc deficiency in patients with ADHD. In this article, we present a hypothesis exploring the causative mechanism of zinc deficiency in ADHD and why zinc might be beneficial as a supplementary medication and/or adjunct to psychostimulants (methylphenidate, amfetamine) in zinc-deficient ADHD patients. The hypothesis is based on published in vitro observations that the human dopamine transporter contains a high-affinity zinc binding site (His-193, His-375, Glu-396) on its extracellular face that modulates transporter function, and in vivo studies suggesting that response to stimulants is reduced in zinc-deficient ADHD patients. It seems likely that zinc supplementation in zinc-deficient ADHD patients improves the binding status of insufficiently occupied zinc binding sites on the dopamine transporter. We propose to test our hypothesis by recruiting zinc-deficient ADHD patients who will undergo positron emission tomography with the 11C-raclopride displacement method to investigate whether zinc increases extracellular dopamine levels.
Article
Autism is a multi-factorial pathology observed in children with altered levels of essential and elevated levels of toxic elements. There are also studies reporting a decrease in nutritional trace elements in the hair and nail of autistic children with healthy controls; moreover, bioelements have been shown to play an important role in the central nervous system. Therefore, the purpose of the present study was to assess the levels of trace elements like copper (Cu), zinc (Zn), magnesium (Mg), and selenium (Se) and toxic elements like mercury (Hg), and lead (Pb) in the hair and nail samples of autistic children and to evaluate whether the level of these elements could be correlated with the severity of autism. The subjects of the study were 45 autistic children with different grades of severity (low (LFA), medium (MFA), and high (HFA) functioning autism) according to Childhood Autism Rating Scale, n = 15 children in each group and 50 healthy children (age and sex matched). The boys and girls ratio involved in this study was 4:1, and they were 4-12 years of age. The study observed a valid indication of Cu body burden in the autistic children. The children with different grades of autism showed high significance (p < 0.001) in the level of copper in their hair and nail samples when compared to healthy controls. The level of Cu in the autistic children could be correlated with their degree of severity (more the Cu burden severe is autism). The study showed a significant elevation (p < 0.001) in the levels of toxic metals Pb and Hg in both hair and nail samples of autistic children when compared to healthy control group. The elevation was much pronounced in LFA group subjects when compared among autistic groups MFA and HFA. The levels of trace elements Mg and Se were significantly decreased (p < 0.001) in autistic children when compared to control. The trace element Zn showed significant variation in both hair and nails of LFA group children when compared to control group and other study groups. The significant elevation in the concentration of Cu, Pb, and Hg and significant decrease in the concentration of Mg and Se observed in the hair and nail samples of autistic subjects could be well correlated with their degrees of severity.