Journal of Molecular Neuroscience (2024) 74:46
https://doi.org/10.1007/s12031-024-02220-8
RESEARCH
Expression Patterns of miRNAs in Egyptian Children with ADHD:
Clinical Study with Correlation Analysis
Hala M. Zeidan1 · Neveen Hassan Nashaat1 · Maha Hemimi1 · Adel F. Hashish1
Nagwa Abd EL-Ghaffar2 · Suzette I. Helal1 · Nagwa A. Meguid1
· Amal Elsaeid1
·
Received: 20 January 2024 / Accepted: 4 April 2024 / Published online: 23 April 2024
© The Author(s) 2024
Abstract
ADHD has huge knowledge gaps concerning its etiology. MicroRNAs (miRNAs) provide promising diagnostic biomarkers of human pathophysiology and may be a novel therapeutic option. The aim was to investigate the levels of miR34c-3p, miR-155, miR-138-1, miR-296-5p, and plasma brain-derived neurotrophic factor (BDNF) in a group of children
with ADHD compared to neurotypicals and to explore correlations between these measures and some clinical data. The
participants were children with ADHD in Group I (N = 41; age: 8.2 ± 2) and neurotypical ones in Group II (N = 40; age:
8.6 ± 2.5). Group I was subjected to clinical examination, the Stanford Binet intelligence scale-5, the preschool language
scale, and Conner’s parent rating scale-R. Measuring the expression levels of the miRNAs was performed by qRT-PCR
for all participants. The BDNF level was measured by ELISA. The lowest scores on the IQ subtest were knowledge and
working memory. No discrepancies were noticed between the receptive and expressive language ages. The highest scores
on the Conner’s scale were those for cognitive problems. Participants with ADHD exhibited higher plasma BDNF levels
compared to controls (p = 0.0003). Expression patterns of only miR-34c-3p and miR-138-1 were downregulated with
significant statistical differences (p˂0.01). However, expression levels of miR-296-5p showed negative correlation with
the total scores of IQ (p = 0.03). MiR-34c-3p, miR-138-1, while BDNF showed good diagnostic potential. The downregulated levels of miR-34c-3p and miR-138-1, together with high BDNF levels, are suggested to be involved in the etiology
of ADHD in Egyptian children. Gender differences influenced the expression patterns of miRNAs only in children with
ADHD.
Keywords ADHD · microRNA · BDNF · Children · Cognition · Gender
Hala M. Zeidan
halazeidan@yahoo.com
Suzette I. Helal
suzettehelal@yahoo.com
Neveen Hassan Nashaat
dr.neveennashaat@gmail.com
Nagwa A. Meguid
meguidna@yahoo.com
Maha Hemimi
mahahemaimy@hotmail.com
Adel F. Hashish
aladelomar@gmail.com
Amal Elsaeid
omar_elsaeid_amal@yahoo.com
1
Research on Children with Special Needs Department,
Medical Research and Clinical Studies Institute, National
Research Centre, El-Buhouth St., Dokki 12622, Cairo, Egypt
2
Clinical and Chemical Pathology Department, Medical
Research and Clinical Studies Institute, National Research
Centre, El-Buhouth St., Dokki 12622, Cairo, Egypt
Nagwa Abd EL-Ghaffar
nagwa_62@yahoo.com
13
46 Page 2 of 11
Introduction
The prevalence of attention deficit hyperactivity (ADHD)
in worldwide population is estimated to be 5.9% among
youths and 2.5% among adults (Faraone et al. 2021). Diagnosis of ADHD is challenging due to missing gaps related
to knowledge of its etiology (Dypås et al. 2024). Individuals
with ADHD were reported to have differences in their brain
processes, which produce changes in personal, social, academic, and occupational functioning (American Psychiatric
Association 2022). The etiology of ADHD is still poorly
recognized. However, there are indications of genetic and
environmental factors contributing to this disorder (Koutsoklenis et al. 2023). On the other hand, epigenetic changes,
especially microRNAs, have been suggested to be involved
in factors that govern the progress of ADHD.
MiRNAs are non-coding small RNAs (19- to 24-nucleotides) that regulate gene expression post-transcriptionally.
Moreover, they bind to the 3-untranslated region of the target messenger RNAs (mRNAs). Their role is suggested to
inhibit mRNA translation or its degradation, acting as positive regulatory factor (Garcia-Martínez et al. 2016). Many
miRNAs participate in synaptic plasticity, synaptogenesis,
cell proliferation, cell differentiation, and apoptosis in the
central nervous system (Wang et al. 2022b). Growing evidence for miRNAs has been suggested to play an important
role serving as potential therapeutic targets for ADHD treatment (Kandemir et al. 2014; Srivastav et al. 2018).
Expression levels of many types of miRNAs were
investigated in individuals with ADHD and were found to
be dysregulated. These, includes miR-34c-3p, miR-155,
miR-138-1, and miR-296-5p, miR-140-3p, miR-126-5p,
miR-4516, miR-6090, miR-4763-3p, miR-4281, miR-4466,
miR-107, miR-183-96-182, miR-641, miR-101-3p, miR130a-3p, miR-195-5p, and miR-106b-5p (Garcia-Martínez
et al. 2016; Martinez and Peplow 2024; Zadehbagheri et
al. 2019). Furthermore, the genes controlled by these miRNAs were involved in their mechanism of action and were
reported to be altered in children with ADHD (Srivastav et
al. 2018).
The miR-34 family specifically participates in stem cell
differentiation, neuronal development, aging, and some
metabolic functions. MiR-34c was reported to be downregulated in the amygdala, substantia nigra, and frontal cortex
in Parkinson’s disease, where it was linked to Alzheimer’s
disease, anxiety, or preclinical manifestations of Huntington’s disease (Garcia-Martínez et al. 2016). It was reported
that aberrant expression of miR-34b and miR-34c in the
peripheral blood of subjects with autism spectrum disorder
(ASD), was linked to ADHD (Garcia-Martínez et al. 2016).
On the other hand, miR-155a-5p levels were reported by
Kandemir et al. (2014) to be upregulated in children with
13
Journal of Molecular Neuroscience (2024) 74:46
ADHD compared to neurotypical children. MiR-138 was
reported to inhibit proliferation inducing apoptosis; it is furtherly identified as having a negative correlation between its
expression and DNA methylation (Sha et al. 2017).
Brain-derived neurotrophic factor (BDNF) was reported
to be involved in cellular growth and neuronal differentiation in addition to synaptic plasticity, especially in brain
areas involved in memory and learning. Both miR-138-1
and miR-296-5p were reported to be involved in controlling the BDNF pathway and its mechanism of action (Wu et
al. 2017). BDNF has been reported to be altered in ADHD
and learning disorders. High level of BDNF was reported
in children with ADHD (El Ghamry et al. 2021; Gumus et
al. 2022), and reduced in children with learning disorders
(Elhadidy et al. 2019). On the other hand, some studies
did not detect alterations in BDNF level compared to neurotypical individuals (Bilgiç et al. 2017; Scassellati et al.
2014). The involvement of BDNF in the control of neuronal
development and survival is complicated. Some brain neurotransmitters are interrelated with this neurotrophic factor
(Bathina and Das 2015). Moreover, it was reported to be
involved in the etiology of ADHD (Liu et al. 2015).
Children with ADHD exhibited different cognitive discrepancies even when the total intelligence quotient (IQ) is
within the normal range. Verbal communication was one of
the major affected cognitive functions affected in these children. On the other hand, language development has an essential function in overall cognitive and social progress. Many
children with ADHD were reported to manifest delayed
language development (Sciberras et al. 2014). Children
with ADHD with comorbid language impairments usually
manifested verbal and semantic fluency disorders (Kilany
et al. 2022). Where some of them exhibited limited utterance, reduced syntactic complexity, and phonological errors
(Kim and Kaiser 2000). There is an overlap between language disorder and language delay in children with ADHD.
Therefore, identifying their performance in receptive and
expressive language abilities is essential for determining
points of weakness and strength in their abilities, in addition
to the nature of the associated language deficits (MéndezFreije et al. 2024). They could manifest delays in executive
function performance and working memory tasks (Gremillion and Martel 2012). These deficits were related to alterations in the levels of essential elements that are involved in
neuronal development and differentiation, such as miRNAs,
and BDNF (Martinez and Peplow 2024). To our knowledge,
none of these miRNAs have been previously investigated in
Egyptian children with ADHD.
The aim of this study was to investigate the levels of miR34c-3p, miR-155, miR-138-1, and miR-296-5p in a group
of children with ADHD compared to neurotypical children.
Estimating the levels of BDNF and exploring possible links
Journal of Molecular Neuroscience (2024) 74:46
between the miRNAs expression patterns, BDNF levels,
and some clinical measures were targeted.
Methods
The study included 81 children: Group I for children with
ADHD (N = 41; age: 8.2 ± 2; 34 males, 7 females) and
Group II for neurotypical children (age: 8.6 ± 2.5; 30 males,
10 females). The inclusion criteria for group I was the diagnosis of ADHD according to the criteria of the DSM-5
(American Psychiatric Association 2013), and their age
ranged from 6 to 12 years. The diagnosis was performed
via a semi-structured interview by a psychiatrist at the
time they were included in the study. Children were visiting the outpatient clinic of the research on children with
special needs department at the Medical Research Centre
of Excellence, National Research Centre, in the years 2021
and 2022. Children with comorbidities such as ASD, intellectual disability, developmental coordination disorder, and
chronic illnesses, in addition to those with features suggestive of syndrome involvement, delays in gross motor
development, or those who were receiving medications,
were excluded from the study. The motor development
was checked by a physician based on the normal developmental charts in pediatrics. Comorbid psychiatric disorders
were excluded by a psychiatrist using a mini-international
neuropsychiatric interview for children and adolescents
(Ghanem et al. 2000). For Group II, children were included
when their age ranged from 6 to 12 years and they were
performing well in their schools. Children with a history
of delayed language or motor development were excluded.
They were volunteers who agreed to join the study. They
were subjected to history-taking and clinical examination,
which included verifying their proper motor and language
development by a physician. Children in Group I were subjected to history-taking and clinical examination, including
general, neurological, otorhinolaryngological, and phoniatric exanimation. The Stanford Binet intelligence scale, fifth
edition (Farag 2013), was performed to get the intelligence
quotients (IQ) of the participants by a skilled health professional in psychometry. The preschool language scale was
performed to obtain language age scores by a phoniatrician.
The ceilings of the preschool language scale regarding the
receptive language, expressive language, and total language
ages were 6.58, 7, and 6.9, respectively. This scale measures
the language performance regarding these 3 parameters
from the age of 2 months to the age of 7.5 years. When children older than 7.5 years obtained the highest scores of the
scale, they were given the scores of the test ceiling, and their
language performance was considered to be fully developed
according to the test manual. The scaled scores were used to
Page 3 of 11 46
determine the presence or absence of an associated language
delay. Obtaining scaled scores greater than 77.5 in any of
the parameters indicated normal language development
(El-Sady et al. 2011). The Conners’ Parent Rating ScalesRevised (CPRS-R) was performed to determine the severity
of ADHD by expert physicians (Conners 1997).
Venous blood samples (5 ml) were obtained from all participants in RNase-free sterile tubes containing EDTA and
placed on ice for RNA extraction. The plasma was separated
by centrifugation of the blood sample for 10 min at 1900
xg at 4 °C. The plasma was transferred carefully into new
RNase-free, sterile eppendorf tubes. The plasma was centrifuged again for 10 min at 12,000 xg at 4 °C to avoid contamination of cellular nucleic acid. The hemolyzed plasma
samples were excluded from the study and re-collected
from the patients or controls. The aliquots of the resultant
plasma samples were stored at -80 °C until BDNF measurement. The total RNA was immediately extracted from the
200 µl plasma of the participants by using the miRNeasy
serum/plasma cell lysate kit (Qiagen, Germany), according to the manufacturer’s instructions. The RNA purity and
integrity were screened by using a nanodrop spectrophotometer (2000 c, Thermoscientific, USA) and kept at -80 °C
until further processing. Reverse-transcription was carried
out for cDNA synthesis by using a miScript HiSpec buffer
supplied in the miScript II RT Kit (Qiagen, Germany), following the supplier’s instructions. The expression profiles
of the selected miRNAs were carried out using quantitative real-time polymerase chain reaction (qRT-PCR) (DNA
Technology, Moscow, Russia) using miScript SYBR Green
PCR master mix (Qiagen, Germany) with miScript primer
assays (Qiagen, Germany) specific for the selected miR138-1, miR-296-5p, miR-34c-3p, and miR-155. MiR-16
was used as the endogenous control (Huang et al. 2010).
The reaction mixture was carried out in a total volume of
20 µl containing 4 µl of cDNA (100 ng/µl). A quantity of
300 nM of each primer, 10 µl of SYBR Green Master Mix,
and nuclease-free water were used to complete the total
reaction volume up to 20 µl. The thermal cycling profile was
initial denaturing at 95 °C for 15 min, followed by 40 cycles
of 95 °C for 30 s, annealing at 55 °C for 30 s, and extension
at 72 °C for 45 s. The miRNAs-fold changes were calculated using the 2−∆∆ct method (Schmittgen and Livak 2008).
BDNF levels were measured in plasma samples (Chul et al.
2009) for each participant using the Human Brain Derived
Neurotrophic Factor ELISA Kit (SinoGeneClon Biotech,
China), following suppliers’ instructions.
Written informed consent was obtained from the parents of each participant. The medical research ethics
committee of the National Research Centre approved the
study (no. 19355). This cross-sectional study followed
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Table 1 Comparison between age and sex distribution among the participants
Group I
Group II
P
Age (years)
0.4$
8.2 ± 2
8.6 ± 2.5
Sex distribution (male percentage) 82.9%
75%
0.3^
$ t test; ^ chi-square test
Table 2 Results of the Stanford Binet intelligence scale subtests, the
preschool language scale, and the Conner’s parent rating scale-R in
children with ADHD
Items
Mean SD
Items
Mean SD
Fluid
98.75 10.35 Oppositional
69.6 13.3
reasoning
Knowledge 92.78 8.88 Cognitive problems
74.8 10.5
Quan99.5 10.14 Inattention/hyperactivity 64.8 17.8
titative
reasoning
Visuo95.96 9.31 Anxious-shy
64.3 8.9
spatial
Working
93.25 12.57 Perfectionism
55
12.4
memory
Non-verbal 94.9 11.47 Social problems
70.1 15.4
IQ
Verbal IQ
97.71 10.57 Psychosomatic
69.8 12.2
Total IQ
96.8 11.78 Restless
70.7 17
Receptive
5.76 1.42 Emotional liability
66.6 12.2
language
age (years)
Expressive
5.98 1.75 ADHD index
20.4 0.9
language
age (years)
Total lan5.95 1.62 guage age
(years)
ADHD: attention deficit hyperactivity disorder; IQ: intelligence quotient; SD: standard deviation
the strengthening the reporting of observational studies
(STROBE) checklist (Cuschieri 2019).
Statistical Analysis
Data were analyzed using the Statistical Package for Social
Sciences, version 22.0 (SPSS) and GraphPad Prism, version
6. The quantitative data were presented in the form of mean
and standard deviation or standard error, and the qualitative
data were presented as number and percentage. The numerical datasets were compared by the student t test for parametric data or the non-parametric Mann-Whitney U test.
The effect size (Cohen’s d) was calculated. Qualitative variables were compared using the Chi-square test. A two-tailed
p-value of ≤ 0.05 was considered statistically significant.
The Spearman correlation coefficient test was used for testing correlations. Correlations between the miRNAs expression levels and each other and between miRNAs expression
levels and BDNF levels, age, IQ, and CPRS-R subitems, in
13
Journal of Molecular Neuroscience (2024) 74:46
Table 3 Comparison between the levels of expression of miRNAs and
BDNF levels in children with ADHD and neurotypical children
Parameter Group I (ADHD)
Group II
P-value
Mean ± SEM
(Neurotypicals)
Mean ± SEM
miR0.225 ± 0.036
1.016 ± 0.158
< 0.0001****
34c-3p
miR-155 1.010 ± 0.089
0.7273
1.011 ± 0.108
miR0.0005**
0.462 ± 0.076
0.918 ± 0.107
138-1
miR0.1812
0.745 ± 0.056
1.161 ± 0.165
296-5p
BDNF
1455.676 ± 387.363 1018.605 ± 105.685 0.0006**
(ng/µl)
ADHD: attention deficit hyperactivity disorder; BDNF: brain-derived
neurotrophic factor; miR: microRNA; ng: nanogram; µl: microliter;
SEM: standard error of the mean;
*: p < 0.05; **: p < 0.01; ***: p < 0.001; ****: p < 0.0001; Mann-Whitney U test
addition to receptive, expressive, and total language ages,
were investigated. The receiver operating characteristic
(ROC) curve was plotted to assess the fitness of miR-34,
miR-155, miR-138, miR-296-5p, and BDNF as diagnostic
biomarkers for ADHD.
Results
Comparisons between the two groups regarding age and sex
distribution revealed non-significant statistical differences
(Table 1). The range of the IQ was 77–130. The lowest
scores on the Stanford Binet intelligence scale were those
for knowledge and working memory subitems. The highest
scores were the quantitative reasoning scores. The ranges
of the receptive, expressive, and total language ages were
3.5–6.58; 3–7; and 3-6.9 years, respectively. Children who
manifested delays in language development were those with
a chronological age less than 8 years (N = 14; 34.1%). In
these children, the difference between receptive and expressive language ages did not exceed 6 months. The results
of the IQ and language scales for Group I are presented in
Table 2. The highest scores of the CPRS-R were obtained
in cognitive problems, restlessness, social problems, and
oppositional traits. The results of the CPRS-R are presented
in Table 2. The expression levels of miR-138-1 and miR34c-3p were significantly downregulated in Group I. The
effect size estimation revealed that the d values for these
two types of miRNAs were 0.01 and 4.9, respectively,
which reflect the strength of using miR-34c-3p in ADHD
cases. The miR-155 and miR-296-5p expression patterns
did not show significant differences. The patterns of expression of the four types of miRNAs are presented in Table 3;
Fig. 1. The BDNF levels were higher in Group I compared
Page 5 of 11 46
Journal of Molecular Neuroscience (2024) 74:46
Fig. 1 The expression patterns
of the four miRNAs in ADHD
children compared to neurotypical controls. A miR-34c-3p, B
miR-138-1, C miR-155, D miR296-5p. ***: p < 0.001; ****:
p < 0.0001
Fig. 2 ROC curve of the miRNAs and BDNF levels in children with ADHD
to Group II, with significant statistical differences (Table 3).
The estimated d value for the BDNF level was 5, which
indicated the strength of measuring it in ADHD cases.
Correlation analysis revealed that expression levels of
miR-34c-3p were negatively correlated with miR-138-1 (r
= -0.41, p = 0.007). The miR-296-5p showed a negative correlation with the total scores of IQ (r = -0.32, p = 0.03). No
other correlations were detected. In the control group, a significant positive correlation was found between miR-34c-3p
and miR-296-5p expression levels (r = 0.37; p = 0.01). Furthermore, a significant positive correlation between miR155 and miR-138-1 expression levels has been observed
(r = 0.35; p = 0.02). No correlations were found between the
studied miRNAs and the BDNF levels in the ADHD group
or the neurotypical children.
The ROC curve analysis for miR-34c-3p showed
excellent discrimination accuracy (AUC = 0.8293, 95%
CI = 0.7355 to 0.9231, p < 0.0001). The sensitivity and
specificity at the cutoff point of 0.4157 were 81.58% and
72.22%, respectively. The miR-138-1 and BDNF showed
acceptable discrimination accuracy (AUC = 0.7352, 95%
CI = 0.6217 to 0.8486, p = 0.0007, and AUC = 0.7450, 95%
CI 0.6301 to 0.8598, p = 0.0004, respectively). For miR138-1, the sensitivity and specificity at the cutoff point of
0.8611 were 75.61% and 60%, whereas those for BDNF
were 76.47% and 60.53%, respectively, at the cutoff value
of 1255ng/µl. The miR-155 and miR-296-5p did not show
discrimination between cases and controls (Fig. 2).
The gender differences in the ADHD group concerning the levels of the miRNAs were statistically significant
only regarding miR-34c-3p and miR-155 being higher in
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46 Page 6 of 11
Journal of Molecular Neuroscience (2024) 74:46
Table 4 Gender differences in miRNAs expression profiles and plasma BDNF levels in ADHD and neurotypical groups
Parameter
ADHD Group
Neurotypical Group
P-value
Male (n = 34)
Female (n = 7)
Male (n = 30)
Female (n = 10)
Mean ± SEM
Mean ± SEM
Mean ± SEM
Mean ± SEM
miR-34c-3p
0.02*
0.174 ± 0.032
0.344 ± 0.077
1.026 ± 0.188
0.730 ± 0.183
miR-155
0.0002***
0.916 ± 0.090
2.220 ± 0.398
1.208 ± 0.172
0.937 ± 0.179
miR-138-1
0.1178
0.458 ± 0.074
0.122 ± 0.054
0.833 ± 0.096
1.878 ± 0.510
miR-296-5p
0.9916
0.770 ± 0.061
2.095 ± 1.002
0.946 ± 0.114
5.158 ± 1.992
BDNF (ng/µl)
0.4691
1455.46 ± 331.7
1410 ± 648.6
1056.75 ± 727
886.6 ± 113.801
ADHD: attention deficit hyperactivity disorder; BDNF: brain-derived neurotrophic factor; miR: microRNA; ng: nanogram; µl:
SEM: standard error of the mean;
P-value
0.6911
0.6446
0.0703
0.0726
0.3747
microliter;
*: p < 0.05 ***: p < 0.001; Mann-Whitney U test
Table 5 Gender comparison between ADHD and control groups regarding miRNAs expression and BDNF levels
Parameter
Males
Females
P-value
ADHD (n = 34)
Control (n = 30)
ADHD (n = 7)
Control (n = 10)
Mean ± SEM
Mean ± SEM
Mean ± SEM
Mean ± SEM
miR-34c-3p
0.02*
0.174 ± 0.032
1.026 ± 0.188
< 0.00001
0.344 ± 0.077
0.730 ± 0.183
***
miR-155
0.2
0.009*
0.916 ± 0.090
1.208 ± 0.172
2.220 ± 0.398
0.937 ± 0.179
miR-138-1
0.0005***
0.005*
0.458 ± 0.074
0.833 ± 0.096
0.122 ± 0.054
1.878 ± 0.510
miR-296-5p
0.4
0.9
0.770 ± 0.061
0.946 ± 0.114
2.095 ± 1.002
5.158 ± 1.992
BDNF (ng/µl)
0.01*
0.05
1455.46 ± 331.7
1056.75 ± 727
1410 ± 648.6
886.6 ± 359
ADHD: attention deficit hyperactivity disorder; BDNF: brain-derived neurotrophic factor; miR: microRNA; ng: nanogram; µl: microliter;
SEM: standard error of the mean;
*: p < 0.05 ***: p < 0.001; Mann-Whitney U test
females, whereas the BDNF levels were lower in females of
both ADHD and control groups without a significant statistical difference. These differences concerning miR34c-3p and
miR-155 were not detected in the control group (Table 4).
Correlation analysis in males with ADHD revealed that
expression levels of miR-34c-3p remained negatively correlated with miR-138-1 (r = -0.48, p = 0.003). The miR296-5p showed a correlation with the total scores of IQ in
males (r = -0.3, p = 0.02). Correlations between the levels
of expression of miRNAs and each other and with BDNF
levels in females with ADHD were non-significant. No correlations were detected between the clinical measures and
the levels of the miRNAs or the BDNF levels in males and
females with ADHD. In the control group, the correlation
between miR-34c-3p and miR-296-5p expression levels
remained significant in the male group (r = 0.4; p = 0.01).
The correlation between miR-155 and miR-138-1 expression levels remained significant in the male group (r = 0.42;
p = 0.01). No correlations were detected in the female group.
Comparisons between males in the ADHD group and
males in the control group revealed significant statistical
differences regarding miR-34c-3p and miR-138-1 being
downregulated. The expression of miR-155 was downregulated in males with ADHD without a significant statistical
difference. Nevertheless, the expression of miR-155 was
upregulated in females with ADHD, with a significant statistical difference contradicting the overall results. The levels
13
of BDNF were higher in males and females with ADHD
compared to controls. However, the difference remained
significant only in males with ADHD (Table 5).
Discussion
ADHD is a common neurodevelopmental disorder, which
interferes with an individual’s cognitive and language performance. Understanding the etiology and pathophysiology
of this disorder, in addition to its possible influence on the
aptitudes of children with ADHD, could offer attainable
therapeutic targets for better intervention. It is necessary to
explore patterns of expression of miRNAs in different populations, considering the complex nature of ADHD and the
interaction between genes and environment regarding the
development of its symptoms (Nuzziello et al. 2019).
In this study, memory abilities and knowledge were found
to be the least developed among participants. These results
indicated the disadvantages of this disorder for the cognitive abilities of children. These findings are in agreement
with Kilany et al. (2022), who reported that working memory scores were the lowest among the IQ subitems. Nevertheless, it was the visuospatial ability, not the knowledge,
which also revealed low scores in their sample. The memory
problems could be related to the altered levels of BDNF,
which was involved in memory consolidation. BDNF was
Journal of Molecular Neuroscience (2024) 74:46
reported to enhance neuronal growth and synaptic plasticity
(Miranda et al. 2019). It has been involved in pre- and postsynaptic control of neurotransmitter release and regulation
such as serotonin, glutamate, GABA, dopamine, and catecholamines (Colucci-D’Amato et al. 2020; Lima Giacobbo
et al. 2019; Wang et al. 2022a). MiR-34 plays a critical role
in memory formation, which is processed by the amygdala
(Murphy and Singewald 2019). MiR-138 was found to control neuronal connections in the hippocampus in mice. The
hippocampus has an essential role in memory consolidation
(Daswani et al. 2022).
Receptive and expressive language skills in the current
study were found to be delayed in children younger than
8 years old. The absence of discrepancies between receptive and expressive language ages in those with delayed language performance indicated that the language problems in
these children were delays in development rather than a specific language impairment. The presence of language delays
is in agreement with Hawkins et al. (2016), who reported
that impairments in cognitive functions such as executive
function interfere with language development in children
with ADHD. On the other hand, basic language skills measured by the used language scale in children older than 8
years, including syntax and semantics, were not delayed.
Goh et al. (2020) emphasized the relationship between early
language problems and ADHD, which could be related to
problems in some cognitive abilities in these children.
Considering that language and cognition are interrelated, alterations in essential neurobiological processes
could impact both of them. The elevated levels of BDNF
noticed in the ADHD participants of this study could have
contributed to the deficits noticed in the abilities and behavior of participants with ADHD. High levels of BDNF could
have led to deficits in the pruning of synapses responsible
for the processing of memory and executive functions or to
changes in the neurotransmitters’ levels, which were interrelated with BDNF and/or influenced by its action. Changes
in synaptic quality influence connectivity between different
brain areas involved in cognitive, language, and behavioral
development (Liao et al. 2023). Increased interhemispheric
connectivity was associated with reduced connectivity in
the prefrontal cortex bilaterally and the right frontostriatal and frontoparietal neural networks (Chen et al. 2023).
Furthermore, Yeom et al. (2016) reported that high BDNF
levels had a negative influence on IQ and on indicators of
behavioral problems in preschool children. The behavioral
and cognitive problems in children with ADHD could also
be related to changes in the levels of serotonin, glutamate,
GABA, and dopamine, which were reported to be reduced
in individuals with ADHD in previous reports, whereas levels of catecholamines were reported to be elevated. These
neurotransmitters are essential for proper brain functioning
Page 7 of 11 46
(Banerjee and Nandagopal 2015; Dvořáková et al. 2007;
Maltezos et al. 2014).
Heinrich et al. (2017) and Srivastav et al. (2018) depicted
the regulatory role of miRNAs on BDNF gene expression. The downregulation of miR-138-1 could have led to
overexpression of BDNF, increasing its level compared to
controls. In the current study, we reported higher level of
plasma BDNF in children with ADHD compared to their
neurotypical peers with significant statistical difference.
This finding aligned with previous studies, which targeted
Egyptian children (El Ghamry et al. 2021) or other ethnic
cohorts with ADHD (Gumus et al. 2022; Shim et al. 2008).
The reduced expression of miR-138-1 was in agreement
with Wu et al. (2017), who reported downregulation of miR138-1 in the prefrontal cortex of animal models with ADHD.
They suggested that this downregulation was related to
abnormalities in the miR-138-1 gene. This gene has been
involved in visual perception processing. Interestingly, they
discovered that the overexpression of the Nr3c1 gene was
related to this miRNA downregulation. This gene has been
linked to the hypothalamic-pituitary-adrenal axis and low
cortisol levels, which were involved in ADHD development
(Chen et al. 2019). The prefrontal cortex was among the
brain areas that were reported to be altered in individuals
with ADHD. This area was involved in attention and executive function control and processing (Wu et al. 2023). Martinez and Peplow (2024) reported that miR-138-1 expression
levels were correlated with IQ scores, which could indicate
its involvement in cognitive functioning. In this study, no
correlations were detected between miR-138-1 and clinical
measures. On the other hand, miR-138 was found by Zadehbagheri et al. (2019) to be upregulated in Iranian children
with ADHD, which disagrees with the results of the present
study. These differences in expression patterns highlight the
importance of investigating miRNAs expression levels in
different populations and in different gender distributions.
Alterations in the expression patterns of miR-34-c, either
over or under the normal expression, would lead to perturbations in the processes that it is involved in. Abnormalities
in this type of miRNA have been linked to polymorphisms
in genes that were previously implicated in ADHD, such
as BCL2, MET, and CREB1 (Garcia-Martínez et al. 2016).
These genes were related to neuron development, neurotransmission, axonal growth, and cellular projection, as
well as to lipid biosynthesis and metabolism. These genes
were involved in central nervous system derangements and
psychiatric disorders, including ADHD. Furthermore, miR34-c is an essential component of the calcium-triggering
mechanism, which aids neurotransmitter release in ADHD
(Kim et al. 2014). The results of the downregulation of miR34-c disagree with Garcia-Martínez et al. (2016), who investigated the level of miRNAs in a Spanish population and
13
46 Page 8 of 11
reported upregulation of this type of miRNA. Their study
was conducted on adults with ADHD, and the males’ distribution was less than this study, which could also contribute
to disagreement besides the population heterogeneity.
Correlation analysis in this study revealed that miR34-c levels were negatively correlated with miR-138-1
levels. The detected correlation could stem from the opposing actions of these two miRNAs. Neuronal development
is induced by miR-34, whereas apoptosis is induced by
miR-138, which also inhibits proliferation. Despite having
opposing actions, these two miRNAs were reported to be
involved in memory processing. The importance of the proliferation of neurons and dendrites is as essential as their
apoptosis. A proper balance between long-term potentiation
and long-term depression is required for the optimal functioning of neurons and other brain cells. This balance contributes to memory processing and the proper development
of other cognitive functions, including language integration,
in developing brains (Stacho and Manahan-Vaughan 2022).
The correlation results detected in the ADHD group were
not identified in the control group.
The absence of significant differences in expression levels of miR-155 and miR-296-5p disagrees with Kandemir et
al. (2014) and Wu et al. (2017), who reported significant differences between individuals with ADHD and neurotypicals
in the form of upregulation of miR-155 and downregulation
of miR-296-5p. This disagreement could be related to differences in the populations included, who were Chinese and
Turkish. Nonetheless, a significant negative correlation was
detected in the present study between miR-296-5p and the
total IQ. MiR-296-5p was reported to regulate BDNF activity via Bhlhb2 gene suppression. This gene was reported to
be involved in ADHD pathogenesis (Wu et al. 2017). It is
worth noting that the expression of miRNAs is regulated
by various factors, such as miRNA biogenesis, transcription factors, DNA copy number, and DNA methylation
(Misiewicz-Krzeminska et al. 2019). This could explain the
absence of correlations between the targeted miRNAs and
other clinical measures in this study.
Some differences between males and females regarding
the features of ADHD were reported. Females with ADHD
exhibited more inattention problems compared to males
(Graetz et al. 2005). However, few studies investigated the
biochemical and miRNA levels using gender-based analysis. Szakats et al. (2023) explored the miRNA expression
differences in males and females in animals. They detected
gender differences in the patterns of expression in seven
out of ten types of miRNAs they investigated, such as miR206-3p, miR-200c-3p, and miR-205-5p. Although these
types were not investigated in this study, the detected gender differences indicated the influence of biological sex on
the expression of some types of miRNAs. Interestingly, the
13
Journal of Molecular Neuroscience (2024) 74:46
same pattern was noticed in the expression levels of the
miRNAs and BDNF levels. Notwithstanding, the expression
of miR-155 was found to be upregulated in females only
with significant statistical differences. This is in agreement
with Kandemir et al. (2014), who reported upregulation of
this miRNA. However, they did not examine gender-based
differences in their study. Wang et al. (2019) investigated
the BDNF levels in children with ADHD, followed by a
stratified gender analysis of these levels. The overall levels
of BDNF did not differ from the control group. Nevertheless, the males with ADHD showed higher BDNF levels
compared to controls, whereas the females showed lower
BDNF levels. This is partially in agreement with this study
considering the higher levels of BDNF detected in males
and females with ADHD compared to controls, but they
showed a significant statistical difference only in males. The
differences between males and females could be attributed
to hormonal differences, differences in polymorphisms of
the targeted genes, or differences in the mRNA levels that
miRNAs are controlling (Szakats et al. 2023; Wang et al.
2019). These findings highlight the importance of investigating gender differences in neurodevelopmental disorders.
The small sample size in this study could be considered
a limitation. The stringent inclusion and exclusion criteria could have contributed to reducing the number of participants. Furthermore, the possible environmental factors,
such as prenatal and perinatal histories, have not been compared between the groups. The participants were recruited
from one clinic. However, it is a referral center for children
with special needs, and it is frequently visited by participants from all Egyptian governorates. Despite these limitations, the inclusion and exclusion criteria were determined
to eliminate factors that could influence the miRNA expression patterns. Moreover, this study is the first to investigate
the miRNA expression patterns in Egyptian children with
ADHD. The gender difference influenced the expression
patterns in children with ADHD despite the low number of
female participants in the ADHD group, which necessitates
investigating this issue with a larger sample size in future
studies. The expression levels of miR-34c-3p and miR-1381, in addition to plasma BDNF concentrations, showed good
discrimination accuracy between subjects with and without
ADHD. Therefore, miR-34c-3p, miR-138-1, and BDNF can
be candidate diagnostic biomarkers for ADHD.
Conclusion
The downregulation of miR-34c-3p and miR-138-1 is suggested to be involved in the etiology of ADHD in Egyptian children. Both miRNAs, in addition to BDNF, can also
be introduced as possible biomarkers for the diagnosis of
Page 9 of 11 46
Journal of Molecular Neuroscience (2024) 74:46
ADHD. The expression levels of miR-296-5p may have an
impact on the cognitive functions of children with ADHD.
Considering that both miR-138-1 and miR-296-5p were
involved in controlling BDNF levels, the BDNF level and
its role in ADHD pathogenesis need further investigation.
Interestingly, the gender difference in the included children
with ADHD influenced the expression patterns of miRNAs
within the ADHD group, but it did not show such influence in the control group. Furthermore, the gender difference influenced the discrepancy between cases and controls,
which highlights the importance of investigating such differences in children with ADHD.
Acknowledgements National Research Centre, Egypt to support this
work.
Author Contributions All authors contributed to the study concept,
design, work, data analysis, and interpretation. All authors edited, reviewed, and approved the final draft of the manuscript.
Funding This study was funded by the National Research Centre, Cairo, Egypt. The project number (E120506). The principal investigator
of the project is Hala Moustafa Mahmoud Zeidan.
Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian
Knowledge Bank (EKB).
Data Availability Data and materials are available from the corresponding author on reasonable request.
Declarations
Ethics Approval and Consent to Participate The parents of participants
provided written informed consent. The study was conducted in accordance with the Declaration of Helsinki and the Medical Research
Ethics Committee of the National Research Centre (Ethical Approval
Number: 19355).
Consent to Participate Not applicable.
Competing Interests The authors declare no competing interests.
Open Access This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format,
as long as you give appropriate credit to the original author(s) and the
source, provide a link to the Creative Commons licence, and indicate
if changes were made. The images or other third party material in this
article are included in the article’s Creative Commons licence, unless
indicated otherwise in a credit line to the material. If material is not
included in the article’s Creative Commons licence and your intended
use is not permitted by statutory regulation or exceeds the permitted
use, you will need to obtain permission directly from the copyright
holder. To view a copy of this licence, visit http://creativecommons.
org/licenses/by/4.0/.
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