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Increased Serum Netrin-1 Levels among Children Diagnosed with ADHD

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Title: Increased Serum Netrin-1 Levels among Children Diagnosed with ADHD
Language: English
Authors: Hümeyra Hilal Öztürk (ORCID 0009-0008-1101-1211), Selen Sezen (ORCID 0009-0008-2919-9347), Elçin Çağlar (ORCID 0000-0002-8362-266X), Serenay Elgün Ülkar (ORCID 0000-0002-1751-090X), Sadettin Burak Açıkel (ORCID 0000-0002-8964-9513)
Source: Journal of Attention Disorders. 2026 30(6):765-772.
Availability: SAGE Publications. 2455 Teller Road, Thousand Oaks, CA 91320. Tel: 800-818-7243; Tel: 805-499-9774; Fax: 800-583-2665; e-mail: journals@sagepub.com; Web site: https://sagepub.com
Peer Reviewed: Y
Page Count: 8
Publication Date: 2026
Document Type: Journal Articles
Reports - Research
Descriptors: Attention Deficit Hyperactivity Disorder, Children, Physiology, Symptoms (Individual Disorders), Brain, Correlation, Pathology, Foreign Countries
Geographic Terms: Turkey (Ankara)
Assessment and Survey Identifiers: Conners Rating Scales, Social Responsiveness Scale, Wechsler Intelligence Scale for Children
DOI: 10.1177/10870547251408127
ISSN: 1087-0547
1557-1246
Abstract: Objective: ADHD is a common neurodevelopmental disorder of childhood characterized by altered projections of dopaminergic neurons and connectivity issues in various brain regions. In our study, we aim to investigate the potential effects of axon guidance molecules, Netrin-1 and Semaphorins 3A, 4D, and 7A, on these connectivity problems by examining the levels of these molecules in the peripheral blood of children with ADHD compared to healthy controls. Methods: A total of 43 children with ADHD and 40 healthy controls 6 to 12 years of age were included in the study. The K-SADS-PL was administered to exclude any additional psychopathologies (excluding ODD in the ADHD group). The Revised Child Anxiety and Depression Scale was provided to the children, while parents completed the revised Conners' Parent Rating Scale (CPRS-R), the Social Responsiveness Scale (SRS), and the Behavior Rating Inventory for Executive Functioning (BRIEF). Additionally, teachers of the ADHD group were given the Conners' Teacher Rating Scale. Furthermore, the WISC-4 was administered to assess the IQ profile of 35 children in the ADHD group. Results: Netrin-1 was found to be statistically higher in the ADHD group. When the R-CADS scores were recalculated taking the covariate into account, the significant increase in the ADHD group remained. There was no statistically significant difference between the two groups for semaphorin 3A, 4D, and 7A. The positive correlation of Netrin-1 with the hyperactivity subscores on the CPRS-R and the Global Executive Score on the BRIEF scale is noteworthy. Conclusion: Netrin-1 may play a role in the etiopathogenesis of ADHD. Further studies are needed to clarify the relationship between Netrin-1 and ADHD.
Abstractor: As Provided
Entry Date: 2026
Accession Number: EJ1504311
Database: ERIC
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  Value: <anid>AN0193250480;gs001jun.26;2026Apr28.02:16;v2.2.500</anid> <title id="AN0193250480-1">Increased Serum Netrin-1 Levels Among Children Diagnosed With ADHD </title> <p>Objective: ADHD is a common neurodevelopmental disorder of childhood characterized by altered projections of dopaminergic neurons and connectivity issues in various brain regions. In our study, we aim to investigate the potential effects of axon guidance molecules, Netrin-1 and Semaphorins 3A, 4D, and 7A, on these connectivity problems by examining the levels of these molecules in the peripheral blood of children with ADHD compared to healthy controls. Methods: A total of 43 children with ADHD and 40 healthy controls 6 to 12 years of age were included in the study. The K-SADS-PL was administered to exclude any additional psychopathologies (excluding ODD in the ADHD group). The Revised Child Anxiety and Depression Scale was provided to the children, while parents completed the revised Conners' Parent Rating Scale (CPRS-R), the Social Responsiveness Scale (SRS), and the Behavior Rating Inventory for Executive Functioning (BRIEF). Additionally, teachers of the ADHD group were given the Conners' Teacher Rating Scale. Furthermore, the WISC-4 was administered to assess the IQ profile of 35 children in the ADHD group. Results: Netrin-1 was found to be statistically higher in the ADHD group. When the R-CADS scores were recalculated taking the covariate into account, the significant increase in the ADHD group remained. There was no statistically significant difference between the two groups for semaphorin 3A, 4D, and 7A. The positive correlation of Netrin-1 with the hyperactivity subscores on the CPRS-R and the Global Executive Score on the BRIEF scale is noteworthy. Conclusion: Netrin-1 may play a role in the etiopathogenesis of ADHD. Further studies are needed to clarify the relationship between Netrin-1 and ADHD.</p> <p>Keywords: ADHD; brain plasticity; children; diagnosis; mental health</p> <hd id="AN0193250480-2">Introduction</hd> <p>ADHD is one of the most common neurodevelopmental disorders of childhood characterized by hyperactivity, inattention, and impulsivity (Sharma & Couture, 2013). According to DSM-5 diagnostic criteria, the prevalence of ADHD is 11.3% in children under 12 years of age and 12.7% in adolescents aged 12 to 18 years ([<reflink idref="bib49" id="ref1">49</reflink>]). In a study conducted in Turkey, the prevalence of ADHD among primary school children was 12.7% ([<reflink idref="bib20" id="ref2">20</reflink>]).</p> <p>Its etiopathogenesis has been reported to involve dopaminergic dysfunction, particularly in the mesocortical, mesolimbic, and nigrostriatal pathways ([<reflink idref="bib16" id="ref3">16</reflink>]; [<reflink idref="bib53" id="ref4">53</reflink>]). It is thought that dysfunction in the mesocortical dopamine pathway is associated with cognitive impairment, and that hypoactivity in the mesolimbic dopaminergic pathway plays a role in the motivational impairment seen in ADHD patients. The mesolimbic pathway is also an important part of the "reward" circuitry that is impaired in ADHD ([<reflink idref="bib41" id="ref5">41</reflink>]). At the same time, the striatum is the largest source of dopamine in the brain, suggesting an important role for dopamine in attention. Connections to the striatum are a major source of dopaminergic synapses and have been suggested to play a role in ADHD ([<reflink idref="bib18" id="ref6">18</reflink>]).</p> <p>ADHD is increasingly seen as a syndrome of dysconnectivity rather than a disorder defined by changes in specific brain regions ([<reflink idref="bib13" id="ref7">13</reflink>]). Study of functional connectivity in ADHD suggests that dopaminergic functional connectivity is a potential prognostic factor in ADHD (Zaher et al., 2024). It has also been demonstrated that ADHD patients exhibit significantly greater connectivity variability in the cingulo-temporal, cingulo-parietal, fronto-temporal, and fronto-parietal networks compared to typically developing children ([<reflink idref="bib42" id="ref8">42</reflink>]).</p> <p>Netrin and Semaphorins are molecules that regulate the connectivity of neurons in the brain, have important roles in axon guidance and therefore may have an effect on the etiology of ADHD. Netrin was first discovered in the 1990s as a vertebrate homologue of the laminin-associated UNC-6 protein found in Caenorhabditis elegans ([<reflink idref="bib50" id="ref9">50</reflink>]). Netrins are categorized into two families of receptors: The DCC (deleted in colorectal cancer) family, which includes DCC and neogenin, and the UNC5 family, which includes Unc5a, Unc5b, Unc5c, and Unc5d proteins ([<reflink idref="bib19" id="ref10">19</reflink>]; [<reflink idref="bib33" id="ref11">33</reflink>]; [<reflink idref="bib35" id="ref12">35</reflink>]).</p> <p>In the central nervous system, netrins influence cell and axon migration and have been demonstrated to facilitate axon arborization and synapse formation during neural development ([<reflink idref="bib54" id="ref13">54</reflink>]). Additionally, they are known to promote cortical axon branching ([<reflink idref="bib17" id="ref14">17</reflink>]). Beyond axon guidance, netrins are involved in synaptic plasticity, synaptogenesis, cell migration, cell survival, and axon regeneration ([<reflink idref="bib5" id="ref15">5</reflink>]; [<reflink idref="bib23" id="ref16">23</reflink>]; [<reflink idref="bib31" id="ref17">31</reflink>]; [<reflink idref="bib54" id="ref18">54</reflink>]). Studies indicate that netrin-1 may be implicated in the function, plasticity, and peripubertal reorganization of mesocorticolimbic dopaminergic systems ([<reflink idref="bib38" id="ref19">38</reflink>]). In animal models, the presence of netrin-1 has been shown to restore dopaminergic axonal projections in the striatum, whereas its absence is linked to dopaminergic cell loss in the substantia nigra ([<reflink idref="bib28" id="ref20">28</reflink>]). Moreover, netrin-1 has been found to maintain the integrity of the blood-brain barrier, mitigate neuroinflammation by reducing chemokine secretion from central nervous system endothelial cells, and exert an anti-inflammatory effect on the blood-brain barrier in response to cytokine-induced disruptions ([<reflink idref="bib48" id="ref21">48</reflink>]).</p> <p>Semaphorins (Sema) constitute a large, evolutionarily conserved family of proteins that function as both secreted and membrane-associated guidance cues ([<reflink idref="bib2" id="ref22">2</reflink>]). Research has demonstrated the essential role of semaphorin signaling in accurately directing specific subsets of afferent projections within the nervous system to their designated targets ([<reflink idref="bib57" id="ref23">57</reflink>]). Other functions in the central nervous system include facilitating synapse formation ([<reflink idref="bib27" id="ref24">27</reflink>]; [<reflink idref="bib40" id="ref25">40</reflink>]), contributing to homeostatic synaptic plasticity ([<reflink idref="bib46" id="ref26">46</reflink>]), promoting axon terminal branching ([<reflink idref="bib7" id="ref27">7</reflink>]; [<reflink idref="bib30" id="ref28">30</reflink>]), enabling axonal pruning ([<reflink idref="bib34" id="ref29">34</reflink>]), influencing dendritic morphogenesis and arborization ([<reflink idref="bib15" id="ref30">15</reflink>]; [<reflink idref="bib61" id="ref31">61</reflink>]), and aiding in the removal of ectopic synapses ([<reflink idref="bib43" id="ref32">43</reflink>]; [<reflink idref="bib58" id="ref33">58</reflink>]).</p> <p>Among the various semaphorins, Semaphorin 3A has been extensively studied, revealing numerous functions within the central nervous system. The interactions between Semaphorin 3A and neuropilin are pivotal for the migration of striatal and cortical interneurons ([<reflink idref="bib39" id="ref34">39</reflink>]). Furthermore, Semaphorin 3A has been associated with the inhibition of neurogenesis in the subventricular zone ([<reflink idref="bib55" id="ref35">55</reflink>]) and has implications in neuroprotection during neural stress ([<reflink idref="bib37" id="ref36">37</reflink>]). Sema4D is a biologically active molecule in both its membrane-associated and soluble forms ([<reflink idref="bib52" id="ref37">52</reflink>]) and is expressed by oligodendrocytes by oligodendrocytes, where it plays a role in inhibiting axon regeneration ([<reflink idref="bib44" id="ref38">44</reflink>]). Semaphorin 7A is unique as the only glycosylphosphatidylinositol (GPI)-anchored semaphorin identified to date, expressed in both glial and neuronal cells in the adult central nervous system ([<reflink idref="bib60" id="ref39">60</reflink>]). It is suggested to facilitate not only axon guidance and neuronal migration but also the inhibition of neurogenesis in the hippocampus ([<reflink idref="bib29" id="ref40">29</reflink>]; [<reflink idref="bib47" id="ref41">47</reflink>]). Additional roles of Semaphorin 7A include involvement in glial scar formation and maturation following spinal cord injury ([<reflink idref="bib32" id="ref42">32</reflink>]) as well as contributions to gliosis ([<reflink idref="bib24" id="ref43">24</reflink>]). These various functions suggest a potential role for Semaphorin 7A in neurodegenerative processes ([<reflink idref="bib24" id="ref44">24</reflink>]).</p> <p>The objective of this study is to explore the potential roles of netrin and semaphorin guidance molecules in the etiopathogenesis of ADHD, with a specific emphasis on their impact on the development of dopaminergic pathways and neural connectivity. The primary hypothesis posits that dysregulation of netrin-1 and semaphorin signaling contributes to the abnormal formation of dopaminergic circuits and synaptic plasticity that underlie the cognitive, motivational, and behavioral deficits observed in individuals with ADHD. Given the connectivity deficits associated with ADHD, our study will examine the blood levels of netrin-1, an important factor in dopamine axon guidance, as well as semaphorin 3A, 4D, and 7A, to investigate their roles in the etiopathogenesis of ADHD.</p> <hd id="AN0193250480-3">Materials and Methods</hd> <p></p> <hd id="AN0193250480-4">Participants</hd> <p>Children aged 6 to 12 years who were admitted to the outpatient clinics of Ankara University Faculty of Medicine, Department of Child and Adolescent Psychiatry, between June 2023 and February 2024 were included in this study. Informed consent was obtained from all children and their families who participated. The ADHD group comprised 48 patients who had recently received a diagnosis of ADHD and did not have any comorbid psychiatric disorders, aside from oppositional defiant disorder (ODD). In contrast, the control group consisted of 42 healthy participants who did not meet any psychiatric diagnostic criteria. The exclusion criteria for both groups included: known systemic illnesses, presence of any psychiatric diagnosis (aside from ODD in the ADHD group), regular medication use, infection-related illnesses within the past month, and illiteracy. Approval from the Ethics Committee at Ankara University Faculty of Medicine was secured (11.05.2023/I05-291-23).</p> <p>A total of 133 children were invited to participate in the study, including 56 for the control group and 77 for the ADHD group. In the control group, 14 children declined participation and were subsequently excluded from the study. In the ADHD group, 18 children either refused to participate or withdrew during the study; these participants were also excluded. Additionally, 11 children who provided blood samples but did not complete the Wechsler Intelligence Scale for Children Fourth Edition (WISC-4) were excluded from further analysis. Ultimately, 42 participants were included in the healthy control (HC) group, while 48 participants were included in the ADHD group, all aged between 6 and 12 years. Seven children (five from the ADHD group and two from the HC group) were excluded from the analysis due to missing blood values.</p> <hd id="AN0193250480-5">Procedure</hd> <p>The assessment of the children was conducted by the researcher using the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL-DSM-5-Turkish). The parents of all participants completed the Revised Conners' Parent Rating Scale (CPRS-R), the Social Responsiveness Scale (SRS), and the Behavior Rating Inventory for Executive Functioning (BRIEF) parent report. Additionally, teachers of children in the ADHD group completed the Conners' Teacher Rating Scale (CTRS).</p> <p>All participants were administered Turkish version of the Revised Child Anxiety and Depression Scale (RCADS) to screen for anxiety and depression scores. Additionally, the intelligence quotient (IQ) of children in the ADHD group was evaluated using the Wechsler Intelligence Scale for Children Fourth Edition (WISC-4).</p> <p>All participants underwent screening for anxiety and depression using the Turkish version of the Revised Child Anxiety and Depression Scale (RCADS). Furthermore, the intelligence quotient (IQ) of children in the ADHD group was assessed using the WISC-4. The CPRS-R is a widely utilized tool for evaluating ADHD and related behavioral concerns in children and adolescents, offering insights into inattention, hyperactivity, and oppositional behaviors based on reports from parents, teachers, or self-reports ([<reflink idref="bib10" id="ref45">10</reflink>]). The BRIEF is a standardized assessment tool that evaluates executive function in children and adolescents, measuring aspects such as working memory, emotional regulation, and cognitive flexibility through reports from parents, teachers, or self-reports ([<reflink idref="bib4" id="ref46">4</reflink>]; [<reflink idref="bib22" id="ref47">22</reflink>]). The RCADS is a self-report questionnaire employed to assess symptoms of various anxiety disorders and major depressive disorder based on DSM criteria ([<reflink idref="bib6" id="ref48">6</reflink>]). The SRS is a standardized measure that evaluates the severity of social impairments associated with autism spectrum disorders by assessing social communication, interaction, and restrictive behaviors across multiple contexts ([<reflink idref="bib11" id="ref49">11</reflink>]).</p> <hd id="AN0193250480-6">Biochemical Examination</hd> <p>For laboratory analysis, blood specimens were collected from all participants at 8:00 and 10:30 AM after a fasting period of at least eight hours. Blood samples collected in biochemistry tubes were centrifuged at 4000 × <emph>g</emph> for 10 min; the resultant sera were stored in Eppendorf tubes at −80°C until analysis. Serum samples were analyzed in the research laboratory of the Department of Medical Biochemistry at Ankara University, utilizing ELISA kits for these markers. The levels of Netrin-1 (Ntn1), Semaphorin 3A (SEMA3A), Semaphorin 4D (SEMA4D), and Semaphorin 7A (SEMA7A) in the serum samples were assessed using a sandwich ELISA method.</p> <p>The blood neutrophil-lymphocyte ratio (NLR) was also evaluated as an inflammatory parameter, derived from complete blood counts. While age, gender, and measurement methods may influence NLR values, a serum NLR ratio of approximately 0.7 to 3.5 is considered within the normal range ([<reflink idref="bib21" id="ref50">21</reflink>]). Therefore, children with an NLR ratio exceeding 3.5 were excluded from the study.</p> <hd id="AN0193250480-7">Statistical Analysis</hd> <p>Given the absence of comparable studies in the literature, the effect sizes proposed by [<reflink idref="bib8" id="ref51">8</reflink>] were utilized to determine the appropriate sample size ([<reflink idref="bib8" id="ref52">8</reflink>]). Assuming an effect size of 0.8, a type I error rate of 0.05, and a statistical power of 95%, the required sample size was calculated to be 84 participants, with 42 in each group ([<reflink idref="bib9" id="ref53">9</reflink>]).</p> <p>Statistical analyses were performed using the SPSS 25.0 software package. Descriptive analyses were conducted to examine demographic data, and the relationship between categorical variables between the two groups was analyzed using the chi-square test. Comparisons of biomarker levels and scale scores between the two groups were assessed using the <emph>t</emph>-test if the data met the assumptions of normal distribution; otherwise, the Mann-Whitney <emph>U</emph> test was employed. The relationship between scale scores and serum levels of biomarkers was analyzed through correlation analysis. To account for potential psychiatric confounders affecting biomarker levels between the two groups, anxiety and depression scores were included as covariates in an ANCOVA analysis. A <emph>p</emph>-value of less than.05 was considered statistically significant for all analyses.</p> <hd id="AN0193250480-8">Results</hd> <p>A total of 43 participants were included in the ADHD group (comprising 25 boys and 18 girls) and 40 participants in the healthy control group (including 22 boys and 18 girls). The mean age of participants in the ADHD group was 8.34 years (<emph>SD</emph> = 1.53), while the mean age of the control group was 8.85 years (<emph>SD</emph> = 1.64). No statistically significant differences were observed between the groups regarding gender (<emph>p</emph> =.773) or age (<emph>p</emph> =.150). Demographic data for the participants are presented in Table 1.</p> <p>Table 1. Demographic Data of the Participants.</p> <p>Graph</p> <p> <ephtml> <table><colgroup><col align="left" /><col align="char" char="." /><col align="char" char="." /><col align="char" char="." /><col align="char" char="." /><col align="char" char="." /></colgroup><thead><tr><th /><th align="center" colspan="2">ADHD</th><th align="center" colspan="2">Control</th><th align="center" rowspan="2"><italic>p</italic></th></tr><tr><th align="left">Variable</th><th align="center"><italic>n</italic> = 43</th><th align="center">%</th><th align="center"><italic>n</italic> = 40</th><th align="center">%</th></tr></thead><tbody><tr><td colspan="6">Gender</td></tr><tr><td>Girl</td><td>18</td><td>41.9</td><td>18</td><td>45</td><td rowspan="2"><italic>p</italic> =.773</td></tr><tr><td>Boy</td><td>25</td><td>58.1</td><td>22</td><td>55</td></tr><tr><th /><th align="center" colspan="2">Mean ± <italic>SD</italic></th><th align="center" colspan="2">Mean ± <italic>SD</italic></th><th align="center"><italic>p</italic></th></tr><tr><td>Age</td><td colspan="2">8.34 ± 1.53</td><td colspan="2">8.85 ± 1.642</td><td><italic>p</italic> =.15</td></tr></tbody></table> </ephtml> </p> <p>1 <emph>Note</emph>. Chi-square test, Independent Sample <emph>T</emph> test. <emph>SD</emph> = standard deviation.</p> <p>When comparing the R-CADS subscale scores between groups, no significant difference was found for the Total Anxiety score (<emph>p</emph> =.096). However, the Depression score (<emph>p</emph> =.004) and the Total Internalizing score (<emph>p</emph> =.039) were significantly higher in the ADHD group. Additionally, all subscale scores of the BRIEF were significantly elevated in the ADHD group compared to healthy controls (<emph>p</emph> <.001), and the total score of the SRS was also significantly higher in the ADHD group (<emph>p</emph> <.001). Among the CPRS-R subscale scores, all but the Perfectionism score (<emph>p</emph> =.140) were significantly higher in the ADHD group compared to the healthy control group, including scores for Psychosomatic (<emph>p</emph> =.003) and other subscales (<emph>p</emph> <.001).</p> <p>Serum Netrin-1 levels were significantly higher in the ADHD group compared to the control group (<emph>p</emph> =.016; refer to Table 2). Even when recalculated with covariates, the significant elevation of Netrin-1 levels in the ADHD group remained evident (<emph>f</emph> = 5.392, <emph>p</emph> =.023). Conversely, no significant differences were found between the two groups for serum levels of Semaphorin 3A, 4D, or 7A (<emph>p</emph> =.446,.099, and.676, respectively; Table 2). The serum NLR ratios are also summarized in Table 2.</p> <p>Table 2. Comparison of The Serum Levels of Markers Between Groups.</p> <p>Graph</p> <p> <ephtml> <table><colgroup><col align="left" /><col align="char" char="." /><col align="char" char="." /><col align="char" char="." /><col align="char" char="." /><col align="char" char="." /><col align="char" char="." /></colgroup><thead><tr><th /><th align="center" colspan="2">ADHD</th><th align="center" colspan="2">Control</th><th align="center" rowspan="2"><italic>t</italic></th><th align="center" rowspan="2"><italic>p</italic></th></tr><tr><th /><th align="center">Mean</th><th align="center"><italic>SD</italic></th><th align="center">Mean</th><th align="center"><italic>SD</italic></th></tr></thead><tbody><tr><td>Netrin-1</td><td>471.010</td><td>318.346</td><td>328.21</td><td>197.185</td><td>−2.475</td><td>.016<xref ref-type="table-fn" rid="tfn3">*</xref></td></tr><tr><td>Semaphorin 3A</td><td>13.971</td><td>7.172</td><td>13.00</td><td>3.998</td><td>−0.766</td><td>.446</td></tr><tr><td>Semaphorin 4D</td><td>7.332</td><td>5.049</td><td>5.730</td><td>3.626</td><td>−1.668</td><td>.099</td></tr><tr><td>Semaphorin 7A</td><td>13.411</td><td>9.098</td><td>12.706</td><td>5.712</td><td>−0.419</td><td>.676</td></tr><tr><td>Neutrophil/lymphocyte ratio</td><td>1.430</td><td>0.868</td><td>1.331</td><td>0.526</td><td>−0.614</td><td>.541</td></tr></tbody></table> </ephtml> </p> <ulist> <item>2 <emph>Note</emph>. Comparison of serum Netrin-1 levels with controls using Independent Sample <emph>T</emph> test. Netrin-1 pg/ml, Semaphorin 3A-4D-7A ng/ml. <emph>SD</emph> = standard deviation.</item> <item>3 <emph>p</emph> <.05.</item> </ulist> <p>Positive correlations were found between serum Netrin-1 levels and levels of Semaphorin 3A, 4D, and 7A (in the ADHD group: Sema3A, 4D, and 7A <emph>p</emph> <.001; in the healthy control group: Sema3A and 4D <emph>p</emph> <.001, Sema7A <emph>p</emph> =.004). Additionally, serum Netrin-1 levels were positively correlated with the CPRS-R subscores: Hyperactivity (<emph>r</emph> =.512, <emph>p</emph> =.001), DSM-4 Hyperactivity-Impulsivity (<emph>r</emph> =.396, <emph>p</emph> =.017), and DSM-4 Total score (<emph>r</emph> =.353, <emph>p</emph> =.037) in the ADHD group.</p> <p>Moreover, serum Netrin-1 levels were positively associated with various subscale scores of the BRIEF in the ADHD group, including the Inhibit score (<emph>r</emph> = 0.408, <emph>p</emph> =.007), Emotional Control score (<emph>r</emph> =.407, <emph>p</emph> =.007), Working Memory score (<emph>r</emph> =.371, <emph>p</emph> =.014), Organization of Materials score (<emph>r</emph> =.330, <emph>p</emph> =.031), Monitor score (<emph>r</emph> =.315, <emph>p</emph> =.040), Behavior Regulation Index score (<emph>r</emph> =.391, <emph>p</emph> =.010), Metacognition Index score (<emph>r</emph> =.334, <emph>p</emph> =.029), and Global Executive Score (<emph>r</emph> =.367, <emph>p</emph> =.015).</p> <p>Additionally, a significant positive correlation was observed between serum Netrin-1 levels and the total score of the SRS in the ADHD group (<emph>p</emph> =.040).</p> <hd id="AN0193250480-9">Discussion</hd> <p>In our study, we found that levels of the axon guidance molecule Netrin-1 were significantly elevated in children diagnosed with ADHD. In contrast, we observed no significant differences in the levels of other axon guidance molecules, namely Semaphorin 3A, 4D, and 7A.</p> <p>Netrin-1 is a key axon guidance molecule that plays a crucial role in neuron migration and in determining the trajectory of growing axons and dendrites during the embryonic development of the nervous system ([<reflink idref="bib26" id="ref54">26</reflink>]). It is particularly important for the development of dopaminergic neurons extending to the striatum, continuing through puberty, as well as for the proper formation of the mesocorticolimbic pathway ([<reflink idref="bib25" id="ref55">25</reflink>]). Dysfunction in axon guidance molecules has been implicated in various neurological disorders ([<reflink idref="bib59" id="ref56">59</reflink>]).</p> <p>Alterations in brain connectivity are also documented in neurodegenerative diseases such as Alzheimer's and Parkinson's disease ([<reflink idref="bib12" id="ref57">12</reflink>]; [<reflink idref="bib56" id="ref58">56</reflink>]). Notably, a study found that serum Netrin-1 levels in patients with Alzheimer's disease were significantly lower compared to healthy controls ([<reflink idref="bib63" id="ref59">63</reflink>]). Moreover, research by [<reflink idref="bib1" id="ref60">1</reflink>] in a Parkinson's animal model demonstrated that processes leading to decreased Netrin-1 levels may induce apoptosis in dopaminergic neurons. The findings of our study, which indicate elevated Netrin-1 levels, contrast with reports from Alzheimer's and Parkinson's disease research. This discrepancy may be attributable to the inclusion of younger participants in our study.</p> <p>Previous studies suggest that the striatal and cerebellar regions are capable of modulating behavior, refined through experiential learning, during childhood development. Such modulation may occur via afferent and efferent pathways to the prefrontal cortex ([<reflink idref="bib3" id="ref61">3</reflink>]; [<reflink idref="bib45" id="ref62">45</reflink>]). Furthermore, research by [<reflink idref="bib45" id="ref63">45</reflink>]. suggests that these pathways might be less robust in children diagnosed with ADHD, potentially affecting their behavioral regulation. [<reflink idref="bib14" id="ref64">14</reflink>]. provided evidence that the nucleus accumbens (NAcc) exhibits atypical connectivity with various cortical regions in children with ADHD. Additionally, these regions are associated with abnormal patterns of spontaneous neural activity in individuals diagnosed with ADHD. The abnormal regional connections and activity patterns observed in ADHD may result from increased Netrin-1 levels leading to excessive neuronal connections. In essence, while Netrin-1 facilitates the guidance of altered dopaminergic neurons in ADHD, it may also induce aberrant axonal connections through various mechanisms. The increased plasma levels of Netrin-1 observed in our study may represent a compensatory response to impaired axon connectivity.</p> <p>Moreover, we found that Netrin-1 levels were positively correlated with all BRIEF subscales, except for Plan/Organize, Initiate, and Set Shifting. The brain regions involved in executive functions include the prefrontal cortex, striatum, and hippocampus. Netrin-1 may influence the connectivity of prefrontal neurons through the DCC receptor, with potential effects on executive functions such as working memory. Additionally, Netrin-1 may enhance memory processes by increasing synaptic plasticity of hippocampal neurons ([<reflink idref="bib23" id="ref65">23</reflink>]). While lower levels of Netrin-1 are associated with impaired memory and hippocampal function ([<reflink idref="bib36" id="ref66">36</reflink>]), our findings suggest that elevated Netrin-1 correlates with executive function impairments. This indicates that maintaining Netrin-1 levels within an optimal range is essential for proper neural remodeling. Furthermore, our results indicated that serum Netrin-1 levels were positively correlated with hyperactivity and DSM-IV total scores on the CPRS-R. These findings underscore the significance of Netrin-1 in brain regions, such as the prefrontal cortex and NAcc, which are integral to behaviors associated with hyperactivity in ADHD.</p> <p>ADHD is a neurodevelopmental disorder with an incomplete understanding of its etiopathogenesis, which remains an area of active investigation. In our study, we propose that axon guidance molecules, previously overlooked in the context of neurodevelopmental disorders, may contribute to the etiology of ADHD and warrant further research. Currently, there are no biomarkers available for diagnosis or treatment monitoring in neurodevelopmental disorders. Thus, we sought to identify a biomarker that could assist clinicians in diagnosis and treatment. Axon guidance molecules, particularly Netrin-1, may be valuable in this regard. Future studies may enhance clinical practice by comparing plasma levels of Netrin-1 with treatment responses, especially as changes in Netrin-1 within the NAcc can influence the efficacy of stimulant medications.</p> <p>The strengths of our study include its status as the first investigation of axon guidance molecules in children with ADHD within the existing literature and the exclusion of additional clinical and psychiatric diagnoses in ADHD participants. However, our study has certain limitations, including its conduct at a single center with a clinical sample derived from outpatient settings, as well as the assessment of these molecules using peripheral blood samples. Additionally, our reliance on parent-report questionnaires without incorporating cognitive tests presents another limitation. In the analysis phase of our study, we did not observe any significant differences between groups for non-netrin markers. Therefore, to avoid the false discovery rate, we did not perform further analyses on these markers. Thus, there is a compelling need for further studies with larger and more diverse samples to validate and expand upon our findings</p> <ref id="AN0193250480-10"> <title> References </title> <blist> <bibl id="bib1" idref="ref60" type="bt">1</bibl> <bibtext> Ahn E. H., Kang S. S., Qi Q., Liu X., Ye K. (2020). Netrin-1 deficiency activates MST1 via UNC5B receptor, promoting dopaminergic apoptosis in Parkinson's disease. 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Molecular Neurobiology, 58(7), 3290–3307. https://doi.org/10.1007/s12035-021-02311-2</bibtext> </blist> </ref> <ref id="AN0193250480-11"> <title> Footnotes </title> <blist> <bibtext> Hümeyra Hilal Öztürk</bibtext> </blist> <blist> <bibtext>Graph</bibtext> </blist> <blist> <bibtext>https://orcid.org/0009-0008-1101-1211 Selen Sezen</bibtext> </blist> <blist> <bibtext>Graph</bibtext> </blist> <blist> <bibtext>https://orcid.org/0009-0008-2919-9347 Elçin Çağlar</bibtext> </blist> <blist> <bibtext>Graph</bibtext> </blist> <blist> <bibtext>https://orcid.org/0000-0002-8362-266X Serenay Elgün Ülkar</bibtext> </blist> <blist> <bibtext>Graph</bibtext> </blist> <blist> <bibtext>https://orcid.org/0000-0002-1751-090X Sadettin Burak Açıkel</bibtext> </blist> <blist> <bibtext>Graph https://orcid.org/0000-0002-8964-9513</bibtext> </blist> <blist> <bibtext> This study approved by Ankara University Faculty of Medicine Ethical Committee (approval date: 11.05.2023 approval number: İ05-291-23).</bibtext> </blist> <blist> <bibtext> Informed consent was obtained from all participant.</bibtext> </blist> <blist> <bibtext> The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by scientific research commicition of Ankara University (project number: TTU-2023-3049).</bibtext> </blist> <blist> <bibtext> The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.</bibtext> </blist> </ref> <aug> <p>By Hümeyra Hilal Öztürk; Selen Sezen; Elçin Çağlar; Serenay Elgün Ülkar and Sadettin Burak Açıkel</p> <p>Reported by Author; Author; Author; Author; Author</p> <p></p> <p>Hümeyra Hilal Öztürk, MD, graduated from the Department of Child and Adolescent Psychiatry, Ankara University Faculty of Medicine. Her research interests include neurodevelopmental disorders, attention-deficit/hyperactivity disorder, and neurobiological markers associated with psychiatric conditions.</p> <p>Selen Sezen, MD, graduated from the Department of Biochemistry, Ankara University Faculty of Medicine. Her research focuses on biochemical markers and their role in health and disease.</p> <p>Elçin Çağlar, MA, graduated from the Department of Psychology at Atılım University and has contributed to numerous studies in the field of child and adolescent psychiatry.</p> <p>Serenay Elgün Ülkar, MD, Professor of Biochemistry, graduated from the Department of Biochemistry at Ankara University Faculty of Medicine and currently serves as the Head of the Department. Her research focuses on the biochemical pathways involved in psychiatric disorders, including bipolar disorder, schizophrenia, and attention-deficit/hyperactivity disorder.</p> <p>Sadettin Burak Açıkel, PhD, Associate Professor, graduated from the Department of Child and Adolescent Psychiatry at Necmettin Erbakan University, Meram Faculty of Medicine. His research focuses on investigating the etiological factors underlying child and adolescent psychiatric disorders.</p> </aug> <nolink nlid="nl1" bibid="bib49" firstref="ref1"></nolink> <nolink nlid="nl2" bibid="bib20" firstref="ref2"></nolink> <nolink nlid="nl3" bibid="bib16" firstref="ref3"></nolink> <nolink nlid="nl4" bibid="bib53" firstref="ref4"></nolink> <nolink nlid="nl5" bibid="bib41" firstref="ref5"></nolink> <nolink nlid="nl6" bibid="bib18" firstref="ref6"></nolink> <nolink nlid="nl7" bibid="bib13" firstref="ref7"></nolink> <nolink nlid="nl8" bibid="bib42" firstref="ref8"></nolink> <nolink nlid="nl9" bibid="bib50" firstref="ref9"></nolink> <nolink nlid="nl10" bibid="bib19" firstref="ref10"></nolink> <nolink nlid="nl11" bibid="bib33" firstref="ref11"></nolink> <nolink nlid="nl12" bibid="bib35" firstref="ref12"></nolink> <nolink nlid="nl13" bibid="bib54" firstref="ref13"></nolink> <nolink nlid="nl14" bibid="bib17" firstref="ref14"></nolink> <nolink nlid="nl15" bibid="bib23" firstref="ref16"></nolink> <nolink nlid="nl16" bibid="bib31" firstref="ref17"></nolink> <nolink nlid="nl17" bibid="bib38" firstref="ref19"></nolink> <nolink nlid="nl18" bibid="bib28" firstref="ref20"></nolink> <nolink nlid="nl19" bibid="bib48" firstref="ref21"></nolink> <nolink nlid="nl20" bibid="bib57" firstref="ref23"></nolink> <nolink nlid="nl21" bibid="bib27" firstref="ref24"></nolink> <nolink nlid="nl22" bibid="bib40" firstref="ref25"></nolink> <nolink nlid="nl23" bibid="bib46" firstref="ref26"></nolink> <nolink nlid="nl24" bibid="bib30" firstref="ref28"></nolink> <nolink nlid="nl25" bibid="bib34" firstref="ref29"></nolink> <nolink nlid="nl26" bibid="bib15" firstref="ref30"></nolink> <nolink nlid="nl27" bibid="bib61" firstref="ref31"></nolink> <nolink nlid="nl28" bibid="bib43" firstref="ref32"></nolink> <nolink nlid="nl29" bibid="bib58" firstref="ref33"></nolink> <nolink nlid="nl30" bibid="bib39" firstref="ref34"></nolink> <nolink nlid="nl31" bibid="bib55" firstref="ref35"></nolink> <nolink nlid="nl32" bibid="bib37" firstref="ref36"></nolink> <nolink nlid="nl33" bibid="bib52" firstref="ref37"></nolink> <nolink nlid="nl34" bibid="bib44" firstref="ref38"></nolink> <nolink nlid="nl35" bibid="bib60" firstref="ref39"></nolink> <nolink nlid="nl36" bibid="bib29" firstref="ref40"></nolink> <nolink nlid="nl37" bibid="bib47" firstref="ref41"></nolink> <nolink nlid="nl38" bibid="bib32" firstref="ref42"></nolink> <nolink nlid="nl39" bibid="bib24" firstref="ref43"></nolink> <nolink nlid="nl40" bibid="bib10" firstref="ref45"></nolink> <nolink nlid="nl41" bibid="bib22" firstref="ref47"></nolink> <nolink nlid="nl42" bibid="bib11" firstref="ref49"></nolink> <nolink nlid="nl43" bibid="bib21" firstref="ref50"></nolink> <nolink nlid="nl44" bibid="bib26" firstref="ref54"></nolink> <nolink nlid="nl45" bibid="bib25" firstref="ref55"></nolink> <nolink nlid="nl46" bibid="bib59" firstref="ref56"></nolink> <nolink nlid="nl47" bibid="bib12" firstref="ref57"></nolink> <nolink nlid="nl48" bibid="bib56" firstref="ref58"></nolink> <nolink nlid="nl49" bibid="bib63" firstref="ref59"></nolink> <nolink nlid="nl50" bibid="bib45" firstref="ref62"></nolink> <nolink nlid="nl51" bibid="bib14" firstref="ref64"></nolink> <nolink nlid="nl52" bibid="bib36" firstref="ref66"></nolink>
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  Label: Title
  Group: Ti
  Data: Increased Serum Netrin-1 Levels among Children Diagnosed with ADHD
– Name: Language
  Label: Language
  Group: Lang
  Data: English
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AR" term="%22Hümeyra+Hilal+Öztürk%22">Hümeyra Hilal Öztürk</searchLink> (ORCID <externalLink term="https://orcid.org/0009-0008-1101-1211">0009-0008-1101-1211</externalLink>)<br /><searchLink fieldCode="AR" term="%22Selen+Sezen%22">Selen Sezen</searchLink> (ORCID <externalLink term="https://orcid.org/0009-0008-2919-9347">0009-0008-2919-9347</externalLink>)<br /><searchLink fieldCode="AR" term="%22Elçin+Çağlar%22">Elçin Çağlar</searchLink> (ORCID <externalLink term="https://orcid.org/0000-0002-8362-266X">0000-0002-8362-266X</externalLink>)<br /><searchLink fieldCode="AR" term="%22Serenay+Elgün+Ülkar%22">Serenay Elgün Ülkar</searchLink> (ORCID <externalLink term="https://orcid.org/0000-0002-1751-090X">0000-0002-1751-090X</externalLink>)<br /><searchLink fieldCode="AR" term="%22Sadettin+Burak+Açıkel%22">Sadettin Burak Açıkel</searchLink> (ORCID <externalLink term="https://orcid.org/0000-0002-8964-9513">0000-0002-8964-9513</externalLink>)
– Name: TitleSource
  Label: Source
  Group: Src
  Data: <searchLink fieldCode="SO" term="%22Journal+of+Attention+Disorders%22"><i>Journal of Attention Disorders</i></searchLink>. 2026 30(6):765-772.
– Name: Avail
  Label: Availability
  Group: Avail
  Data: SAGE Publications. 2455 Teller Road, Thousand Oaks, CA 91320. Tel: 800-818-7243; Tel: 805-499-9774; Fax: 800-583-2665; e-mail: journals@sagepub.com; Web site: https://sagepub.com
– Name: PeerReviewed
  Label: Peer Reviewed
  Group: SrcInfo
  Data: Y
– Name: Pages
  Label: Page Count
  Group: Src
  Data: 8
– Name: DatePubCY
  Label: Publication Date
  Group: Date
  Data: 2026
– Name: TypeDocument
  Label: Document Type
  Group: TypDoc
  Data: Journal Articles<br />Reports - Research
– Name: Subject
  Label: Descriptors
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Attention+Deficit+Hyperactivity+Disorder%22">Attention Deficit Hyperactivity Disorder</searchLink><br /><searchLink fieldCode="DE" term="%22Children%22">Children</searchLink><br /><searchLink fieldCode="DE" term="%22Physiology%22">Physiology</searchLink><br /><searchLink fieldCode="DE" term="%22Symptoms+%28Individual+Disorders%29%22">Symptoms (Individual Disorders)</searchLink><br /><searchLink fieldCode="DE" term="%22Brain%22">Brain</searchLink><br /><searchLink fieldCode="DE" term="%22Correlation%22">Correlation</searchLink><br /><searchLink fieldCode="DE" term="%22Pathology%22">Pathology</searchLink><br /><searchLink fieldCode="DE" term="%22Foreign+Countries%22">Foreign Countries</searchLink>
– Name: Subject
  Label: Geographic Terms
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Turkey+%28Ankara%29%22">Turkey (Ankara)</searchLink>
– Name: SubjectThesaurus
  Label: Assessment and Survey Identifiers
  Group: Su
  Data: <searchLink fieldCode="SU" term="%22Conners+Rating+Scales%22">Conners Rating Scales</searchLink><br /><searchLink fieldCode="SU" term="%22Social+Responsiveness+Scale%22">Social Responsiveness Scale</searchLink><br /><searchLink fieldCode="SU" term="%22Wechsler+Intelligence+Scale+for+Children%22">Wechsler Intelligence Scale for Children</searchLink>
– Name: DOI
  Label: DOI
  Group: ID
  Data: 10.1177/10870547251408127
– Name: ISSN
  Label: ISSN
  Group: ISSN
  Data: 1087-0547<br />1557-1246
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Objective: ADHD is a common neurodevelopmental disorder of childhood characterized by altered projections of dopaminergic neurons and connectivity issues in various brain regions. In our study, we aim to investigate the potential effects of axon guidance molecules, Netrin-1 and Semaphorins 3A, 4D, and 7A, on these connectivity problems by examining the levels of these molecules in the peripheral blood of children with ADHD compared to healthy controls. Methods: A total of 43 children with ADHD and 40 healthy controls 6 to 12 years of age were included in the study. The K-SADS-PL was administered to exclude any additional psychopathologies (excluding ODD in the ADHD group). The Revised Child Anxiety and Depression Scale was provided to the children, while parents completed the revised Conners' Parent Rating Scale (CPRS-R), the Social Responsiveness Scale (SRS), and the Behavior Rating Inventory for Executive Functioning (BRIEF). Additionally, teachers of the ADHD group were given the Conners' Teacher Rating Scale. Furthermore, the WISC-4 was administered to assess the IQ profile of 35 children in the ADHD group. Results: Netrin-1 was found to be statistically higher in the ADHD group. When the R-CADS scores were recalculated taking the covariate into account, the significant increase in the ADHD group remained. There was no statistically significant difference between the two groups for semaphorin 3A, 4D, and 7A. The positive correlation of Netrin-1 with the hyperactivity subscores on the CPRS-R and the Global Executive Score on the BRIEF scale is noteworthy. Conclusion: Netrin-1 may play a role in the etiopathogenesis of ADHD. Further studies are needed to clarify the relationship between Netrin-1 and ADHD.
– Name: AbstractInfo
  Label: Abstractor
  Group: Ab
  Data: As Provided
– Name: DateEntry
  Label: Entry Date
  Group: Date
  Data: 2026
– Name: AN
  Label: Accession Number
  Group: ID
  Data: EJ1504311
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=eric&AN=EJ1504311
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    Identifiers:
      – Type: doi
        Value: 10.1177/10870547251408127
    Languages:
      – Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 8
        StartPage: 765
    Subjects:
      – SubjectFull: Attention Deficit Hyperactivity Disorder
        Type: general
      – SubjectFull: Children
        Type: general
      – SubjectFull: Physiology
        Type: general
      – SubjectFull: Symptoms (Individual Disorders)
        Type: general
      – SubjectFull: Brain
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      – SubjectFull: Pathology
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      – SubjectFull: Foreign Countries
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      – SubjectFull: Turkey (Ankara)
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      – SubjectFull: Conners Rating Scales
        Type: general
      – SubjectFull: Social Responsiveness Scale
        Type: general
      – SubjectFull: Wechsler Intelligence Scale for Children
        Type: general
    Titles:
      – TitleFull: Increased Serum Netrin-1 Levels among Children Diagnosed with ADHD
        Type: main
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            NameFull: Hümeyra Hilal Öztürk
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            NameFull: Selen Sezen
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            NameFull: Elçin Çağlar
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            NameFull: Serenay Elgün Ülkar
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            NameFull: Sadettin Burak Açıkel
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            – D: 01
              M: 06
              Type: published
              Y: 2026
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            – Type: issn-print
              Value: 1087-0547
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              Value: 1557-1246
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            – Type: volume
              Value: 30
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            – TitleFull: Journal of Attention Disorders
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