Pathogenesis Of Attention Deficit Hyperactivity Disorder Research Articles

Metabolomics study of the prefrontal cortex in a rat model of attention deficit hyperactivity disorder reveals the association between cholesterol metabolism disorder and hyperactive behavior

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disease for which specific biomarkers and pathological mechanisms have yet to be identified. Methylphenidate (MPH) is commonly used to treat ADHD, but its therapeutic mechanisms and its impact on brain metabolites remain unclear. Metabolomics can help to discover biomarkers and identify pathophysiological mechanisms. We adopted an untargeted metabolomics approach based on gas chromatography-mass spectrometry to investigate the potential biomarkers and pathogenesis of ADHD. Ten Wistar-Kyoto (WKY) rats were chosen as healthy controls (vehicle, i.g.). Twenty young spontaneously hypertensive rats (SHR) were randomly allocated to the SHR group (vehicle, i.g.) and MPH group (2 mg/kg/day, i.g.). We identified 103 metabolites from the prefrontal cortex (PFC). Orthogonal partial least square-discriminate analysis showed the differential expression of these metabolites between the groups. Multivariate and univariate statistical analyses isolated 12 metabolites that differed significantly between the WKY and SHR groups: 3-hydroxymethylglutaric acid, 3-phosphoglyceric acid, adenosine monophosphate, cholesterol, lanosterol, and o-phosphoethanolamine; 3-hydroxymethylglutaric acid and cholesterol were reversed with MPH treatment. Pathway and enrichment analyses revealed that the altered metabolites belonged to the cholesterol metabolism pathways. ELISA and western blotting showed that the activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase and the expression of sterol regulatory element-binding protein-2 and ATP-binding cassette transporter A1 were reduced in the PFC of the SHR; the latter two proteins were upregulated by MPH. In conclusion, metabolomics analysis identified potential biomarkers that influence cholesterol metabolism and may be implicated in the development of ADHD-like behavior. MPH can regulate cholesterol metabolism in the PFC of ADHD models. This study uncovered potential biomarkers and pathways involved in ADHD, providing new insight into its pathogenesis.

Hair Aluminum and Manganese Levels in Children with Attention Deficit Hyperactivity Disorder

Attention Deficit Hyperactivity Disorder (ADHD) is a common neurobehavioral disorder among children. Aluminum (Al) and manganese (Mn) are neurotoxic metals to which children are continuously exposed and may be involved in the pathogenesis of ADHD. The aim of this work was to evaluate Mn and Al levels in the hair of a sample of Egyptian ADHD children in relation to the clinical presentation of this disorder. The study was carried out on 200 children, divided into two main groups: the ADHD group including 100 ADHD children and the control group that comprised 100 apparently healthy children. Hair samples were collected and digested using microwave. Mn and Al levels in hair samples were detected by inductively coupled plasma optical emission spectrometry (ICP- OES). A statistically significant difference was found between the ADHD and the control groups regarding Mn levels especially among the patients with the hyperactive presentation; meanwhile, there was no significant difference in hair Al levels between the two studied groups. On the other hand, patients with inattentive presentation showed relatively higher levels of Al. Keywords: Manganese; Aluminum; Hair; ADHD; Egyptian.

Altered microRNA 5692b and microRNA let-7d expression levels in children and adolescents with attention deficit hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder. Its etiology is not clearly understood yet, but neurobiological, genetic and environmental factors are shown to play a role. The relationship between ADHD and miRNAs has been studied quite recently, and few studies have been conducted up to now. In this study, peripheral blood expression levels of miR-5692b, miR-let-7d, miR-124-3p, miR-4447 and miR-107 of 30 children and adolescents with combined type ADHD were compared to 30 healthy controls to understand the roles of these miRNAs in the ADHD etiopathogenesis. Compared to controls, levels of miR-5692b (p = 0.006) were found higher and levels of miR-let-7d (p = 0.017) were found lower in the ADHD group. There was no significant difference in terms of miR-124-3p, miR-4447, and miR-107 levels between the groups. In conclusion, our findings support other studies suggesting the importance of miRNAs in the pathogenesis of ADHD. Regarding the regulatory role of miRNAs in gene regulation, their contribution to etiopathogenesis and heterogeneity of ADHD should be investigated further.

A Neurodevelopmental Model of Combined Pyrethroid and Chronic Stress Exposure.

Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders of childhood and previous studies indicate the dopamine system plays a major role in ADHD pathogenesis. Two environmental exposures independently associated with dopaminergic dysfunction and ADHD risk include exposure to deltamethrin, a pyrethroid insecticide, and chronic stress. We hypothesized that combined neurodevelopmental exposure to both deltamethrin and corticosterone (CORT), the major stress hormone in rodents, would result in additive changes within the dopamine system. To study this, we developed a novel dual exposure paradigm and exposed pregnant C57BL/6 dams to 3 mg/kg deltamethrin through gestation and weaning, and their offspring to 25 μg/mL CORT dissolved in the drinking water through adulthood. Midbrain RNA expression as well as striatal and cortical protein expression of key dopaminergic components were investigated, in addition to ADHD-like behavioral tasks and electrochemical dopamine dynamics via fast-scan cyclic voltammetry. Given the well-described sexual dimorphism of ADHD, males and females were assessed separately. Males exposed to deltamethrin had significantly decreased midbrain Pitx3 expression, decreased cortical tyrosine hydroxylase (TH) expression, increased activity in the Y maze, and increased dopamine uptake rate in the dorsal striatum. These effects did not occur in males exposed to CORT only, or in males exposed to both deltamethrin and CORT, suggesting that CORT may attenuate these effects. Additionally, deltamethrin- and CORT-exposed females did not display these dopaminergic features, which indicates these changes are sex-specific. Our results show dopaminergic changes from the RNA through the functional level. Moreover, these data illustrate the importance of testing multiple environmental exposures together to better understand how combined exposures that occur in certain vulnerable populations could affect similar neurodevelopmental systems, as well as the importance of studying sex differences of these alterations.

Positive effect of exogenous brain-derived neurotrophic factor on impaired neurite development and mitochondrial function in dopaminergic neurons derived from dental pulp stem cells from children with attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders and is characterized by impaired attention, hyperactivity, and impulsivity. While multiple etiologies are implicated in ADHD, its underlying mechanism(s) remain unclear. Although previous studies have suggested dysregulation of dopaminergic signals, mitochondria, and brain-derived neurotrophic factor (BDNF) in ADHD, few studies have reported these associations directly. Stem cells from human exfoliated deciduous teeth (SHED) can efficiently differentiate into dopaminergic neurons (DNs) and are thus a useful disease-specific cellular model for the study of neurodevelopmental disorders associated with DN dysfunction. This study aimed to elucidate the relationships between DNs, mitochondria, and BDNF in ADHD by analyzing DNs differentiated from SHED obtained from three boys with ADHD and comparing them to those from three typically developing boys. In the absence of exogenous BDNF in the cell culture media, DNs derived from boys with ADHD (ADHD-DNs) exhibited impaired neurite outgrowth and branching, decreased mitochondrial mass in neurites, and abnormal intracellular ATP levels. In addition, BDNF mRNA was significantly decreased in ADHD-DNs. Supplementation with BDNF, however, significantly improved neurite development and mitochondrial function in ADHD-DNs. These results suggest that ADHD-DNs may have impaired neurite development and mitochondrial function associated with insufficient production of BDNF, which may be improved by exogenous BDNF supplementation. Findings such as these, from patient-derived SHED, may contribute to the future development of treatment strategies for aberrant dopaminergic signaling, mitochondrial functioning, and BDNF levels implicated in ADHD pathogenesis.

Dehydroepiandrosterone sulfate, free testosterone, and sex hormone-binding globulin on susceptibility to attention-deficit/hyperactivity disorder

The neuroendocrine system may affect the pathophysiology of gender differences in attention deficit/hyperactivity disorder (ADHD). This study examines whether the relationships among dehydroepiandrosterone sulfate (DHEA-S), free testosterone, or sex hormone-binding globulin (SHBG) and ADHD presentations exhibit gender differences. A total of 113 boys and 35 girls with ADHD (all drug naïve) and 46 and 26 healthy control boys and girls, respectively, were recruited. Blood samples were obtained to measure the serum levels of DHEA-S, free testosterone, and SHBG in each child. The Swanson, Nolan, and Pelham Scale for ADHD Version IV (SNAP-IV) was used to evaluate behavioral symptoms and the Wechsler Intelligence Scale for Children–Fourth Edition (WISC-IV) and the Conners’ Continuous Performance Test (CPT) were utilized to assess neurocognitive functions. Patients with ADHD had lower DHEA-S levels than male and female healthy control subjects, and no significant differences were observed in free testosterone and SHBG levels between the patients and the controls. DHEA-S levels were negatively correlated with children’s impulsivity performance in the CPT. SHBG levels were negatively correlated with ADHD behavior symptoms among boys. Free testosterone levels were not significantly correlated with either ADHD clinical symptoms or neuropsychological functions. We propose that DHEA-S serves as a potential biomarker of ADHD and is consistently involved in the pathogenesis of ADHD in both boys and girls. SHBG may be involved in behaviors associated with ADHD in boys. Additional studies with basic scientific measures are warranted to elucidate the relationship between androgen hormones and clinical presentations of ADHD.

Antioxidant therapies in attention deficit hyperactivity disorder.

Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder among children and adults. Impulsivity, inattention, and hyperactivity are hallmark of ADHD. While ADHD is not on the autism spectrum, they are related in several ways as they have some overlapping symptoms. The pathogenesis of ADHD has so far remained enigmatic, however, there is some evidence suggesting critical association among ADHD and the level of oxidative stress which trigger cell membrane damage, changes in inner structure and function of proteins, as well as structural damage to DNA which eventually culminate into development of ADHD. Although stimulants as well as some classes of non-stimulants are used to ameliorate symptom of ADHD, various adverse effects have been associated with such compounds. To date, treatment of ADHD is done with a combination of medications, behavior modifications, psycho-education, family therapy and life-style changes. The American Academy of Pediatrics officially promote stimulant medications and/or behavior therapy as 'first line of therapy'. In addition to the presently therapeutic armamentarium, evidences are emerging on relevancy of natural products. There has been an interest on the therapeutic role of antioxidants in the treatment of ADHD. The present review aims to highlight the beneficiary role played by different antioxidants in mitigating the symptoms of ADHD.

M1 - FIVE NOVEL LOCI ASSOCIATED WITH ATTENTION-DEFICIT/HYPERACTIVITY DISORDER ARE REVEALED BY LEVERAGING POLYGENIC OVERLAP WITH EDUCATIONAL ATTAINMENT

Attention-Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental condition that affects about 5% of children and adolescents worldwide. Despite its high heritability little is known about underlying genetic factors. Among other things ADHD is tightly associated with educational failure. However, potential genetic overlap between ADHD and educational attainment has not been examined in detail so far. Exploiting epidemiological similarity between ADHD and educational attainment we aimed to improve discovery of ADHD-associated genetic factors and investigated genetic overlap between these phenotypes. We used ADHD data from the PGC (2064 trios, 896 cases, 2455 controls) and educational attainment data from the SSGAC (N=328917). To investigate polygenic overlap between ADHD and educational attainment we constructed fold-enrichment plots and conditional QQ plots in both directions: conditioning ADHD on educational attainment and vice versa. To explore the nature of the polygenic overlap and test a hypothesis that investigated traits correlate genetically we calculated correlations between z-scores of ADHD and educational attainment variants for nested strata of variants, representing subsets of SNPs with increasing significance of p-values in one of the traits. Additionally we supported this hypothesis by estimating genetic correlation between ADHD and educational attainment using LD score regression. We applied condFDR/conjFDR method to identify specific loci associated with ADHD and loci associated with both ADHD and educational attainment simultaneously. Consistency of effect directions for top association signals detected in our condFDR/conjFDR analyses was tested in the independent GWAS of ADHD symptoms from EAGLE consortium (N=17666). Using condFDR/conjFDR method we identified five novel loci associated with ADHD, three of these being shared between ADHD and educational attainment. Leading variants for four of five identified regions are located in introns of protein coding genes: KDM4A, MEF2C, PINK1, RUNX1T1, while the remaining one is an intergenic SNP on chromosome 2 at 2p24. Four of five loci have opposite directions of effect in ADHD and educational attainment and consistent directions of effect in the independent GWAS of ADHD symptoms from the EAGLE consortium. A hypothesis of polygenic overlap between ADHD and educational attainment was supported by significant genetic correlation (rg=-0.403, p=7.90E-8), consistent pleiotropic enrichment in conditional QQ plots, >10-fold mutual enrichment of SNPs associated with both traits and growing negative correlation of association z-scores for the nested SNP strata with increasing significance in both phenotypes. We found five novel loci associated with ADHD and provided evidence for a shared genetic basis between ADHD and educational attainment, implicating three genetic loci in this overlap. Four of five identified loci showed consistent effects in the independent data set of ADHD symptoms, and inverse correlation with educational attainment. The latter is in line with prior epidemiological and genetic studies. We belive that altogether these findings provide new insights into the relationship between ADHD and educational attainment, suggesting shared molecular genetic mechanisms. Further research is required to clarify the biological effects of the identified genetic variants and how these may influence educational attainment and ADHD pathogenesis.

The Effects of COMT Polymorphism on Cortical Thickness and Surface Area Abnormalities in Children with ADHD.

The catechol-O-methyltransferase (COMT) gene is associated with frontal cortex development and the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). However, how the COMT gene impacts brain structure and behavior in ADHD remains unknown. In the present study, we identify the effect of COMT on cortical thickness and surface area in children with ADHD and children with typically developing (TD) using a machine learning approach. In a sample of 39 children with ADHD and 34 age- and IQ-matched TD children, we found that cortical thickness and surface area differences were predominantly observed in the frontal cortex. Furthermore, a path analysis revealed that a COMT genotype affected abnormal development of the frontal cortex in terms of both cortical thickness and surface area and was associated with working memory changes in children with ADHD. Our study confirms that the role of COMT in ADHD is not restricted to the development of behavior but may also affect the cortical thickness and surface area. Thus, our findings may help to improve the understanding of the neuroanatomic basis for the relationship between the COMT genotype and ADHD pathogenesis.

Integrative analysis of genome-wide association study and chromosomal enhancer maps identified brain region related pathways associated with ADHD

Attention deficit/hyperactivity disorder (ADHD) is among the most common childhood onset psychiatric behavioral disorders, and the pathogenesis of ADHD is still unclear. Utilizing the latest genome wide association studies (GWAS) data and enhancer map, we explored the brain region related biological pathways associated with ADHD. The GWAS summary data of ADHD was driven from a published study, involving 20,183 ADHD cases and 35,191 healthy controls. The brain-related enhancer map was collected from ENCODE and Roadmap Epigenomics (ENCODE + Roadmap) including 489,581 enhancers. Firstly, the chromosomal enhancer maps of four brain regions were aligned with the ADHD GWAS summary data in order to obtain enhancer SNPs. Then the significant enhancers SNPs were subjected to the gene set enrichment analysis (GSEA) for identifying ADHD associated gene sets. A total of 866 pathways and 4 brain tissues were analyzed in this study. We detected several candidate genes for ADHD, such as AHI1, ALG2 and DNM1. We also detected several candidate biological pathways associated with ADHD, such as Reactome SEMA4D in semaphorin signaling and Reactome NCAM1 interactions. Our findings may provide a novel insight into the complex genetic mechanism of ADHD.

Serum Interleukin-6 Level in Children With Attention-Deficit Hyperactivity Disorder (ADHD).

Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioral disorder in children, but its specific etiology and pathophysiology are still incompletely understood. This case-control study aimed to measure the level of serum interleukin-6 (IL-6) as a predictor of the immunologic status in children with ADHD, and to study its correlation with severity of symptoms. 60 ADHD children who met the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, criteria for ADHD and 60 control children were subjected to complete history taking, clinical examination, and psychometric tests. Serum interleukin-6 of ADHD patients and control children was measured by enzyme-linked immunosorbent assay. The mean serum level of IL-6 was 22.35 (95% confidence interval [CI], 17.68-26.99) in ADHD patients, and it was 5.44 (95% CI, 4.81-6.06) in controls. A significantly higher level of IL-6 was reported in ADHD patients compared with controls ( P = .001). No significant correlation was found between serum IL-6 level and either the Intelligence Quotient (IQ) or the Conners' Parent Rating Scale score. Serum IL-6 values were significantly higher in ADHD patients compared to healthy control children. Increased production of IL-6 may play a role in the pathogenesis of ADHD.

Cross-species models of attention-deficit/hyperactivity disorder and autism spectrum disorder: lessons from CNTNAP2, ADGRL3, and PARK2.

Animal and cellular models are essential tools for all areas of biological research including neuroscience. Model systems can also be used to investigate the pathophysiology of psychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). In this review, we provide a summary of animal and cellular models for three genes linked to ADHD and ASD in human patients – CNTNAP2, ADGRL3, and PARK2. We also highlight the strengths and weaknesses of each model system. By bringing together behavioral and neurobiological data, we demonstrate how a cross-species approach can provide integrated insights into gene function and the pathogenesis of ADHD and ASD. The knowledge gained from transgenic models will be essential to discover and validate new treatment targets for these disorders.

Vitamin D's Molecular Action Mechanism in Attention-Deficit/ Hyperactivity Disorder: A Review of Evidence.

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous disorder characterized by hyperactivity, impulsivity and inattention. Children with ADHD have challenges with learning, behavior and psychosocial adjustments, sometimes retained into adulthood. The exact etiology of ADHD is unknown, and the pathophysiology of this disease is complex. Several hypotheses have been raised regarding ADHD pathogenesis, including serotonergic and catecholaminergic signalling pathway dysfunction, neurotropic-related factors, oxidative stress, or neuroinflammation. Vitamin D has an important protective effect against inflammation, oxidative stress and certain neurotrophic factors and neurotransmitter, as well as facilitating dopaminergic and serotonergic functions. Vitamin D levels in children with ADHD are lower than in healthy children, and thus may be involved in the pathogenesis of ADHD. These observations, therefore, confirm the neuroprotective role of vitamin D through multiple molecular mechanisms and can be considered as a promising target in understanding ADHD pathology. In this context, the present study reviews the molecular pathways of vitamin D in ADHD patients.

Blood Levels of Trace Elements in Children with Attention-Deficit Hyperactivity Disorder: Results from a Case-Control Study.

Some trace elements may participate in the pathogenesis of attention-deficit hyperactivity disorder (ADHD). This study aimed to investigate the trace element status of zinc (Zn), copper (Cu), iron (Fe), magnesium (Mg), and lead (Pb) in children with ADHD, and to compare them with normal controls. Associations between examined elements and SNAP-IV rating scores of ADHD symptoms were also assessed. Four hundred nineteen children with ADHD (8.8 ± 2.1years) and 395 matched normal controls (8.9 ± 1.7years) were recruited in the study. The concentrations of Zn, Fe, Cu, Mg, and Pb in the whole blood were measured by atomic absorption spectrometry. Lower zinc levels (P < 0.001) and the number out of normal ranges (P = 0.015) were found in children with ADHD when compared with the normal control group. The difference remained when adjusting the factor of BMI z-score. No significant between-group differences were found in levels of other elements. Zinc levels were negatively correlated with parent-rated scores of inattentive subscale of SNAP-IV (r = - 0.40) as well as with total score of SNAP-IV (r = - 0.24). Other significant associations were not observed. The present results indicated that there were alterations in blood levels of zinc, which was associated with the symptom scores of ADHD.

Effects of taurine on striatal dopamine transporter expression and dopamine uptake in SHR rats

Dopaminergic deficits in the prefrontal cortex and striatum have been attributed to the pathogenesis of attention-deficit hyperactivity disorder (ADHD). Our recent study revealed that high-dose taurine improves hyperactive behavior and brain-functional signals in SHR rats. This study investigates the effect of taurine on the SHR striatum by detecting the spontaneous alternation, DA transporter (DAT) level, dopamine uptake and brain-derived neurotrophic factor (BDNF) expression. A significant increase in the total arm entries was detected in both WKY and SHR rats fed with low-dose taurine but not in those fed with high-dose taurine. Notably, significantly increased spontaneous alternation was observed in SHR rats fed with high-dose taurine. Significantly higher striatal DAT level was detected in WKY rats fed with low-dose taurine but not in SHR rats, whereas significantly reduced striatal DAT level was detected in SHR rats fed with high-dose taurine but not in WKY rats. Significantly increased dopamine uptake was detected in the striatal synaptosomes of both WKY and SHR rats fed with low-dose taurine. Conversely, significantly reduced dopamine uptake was detected in the striatal synaptosomes of SHR rats fed with high-dose taurine. Accordingly, a negative correlation was detected between striatal dopamine uptake and spontaneous alternation in SHR rats fed with low or high-dose taurine. Significantly increased BDNF was detected in the striatum of both WKY and SHR rats fed with low or high-dose taurine. These findings indicate that different dosages of taurine have opposite effects on striatal DAT expression and dopamine uptake, suggesting high-dose taurine as a possible candidate for ADHD treatment.

The interaction between monoaminergic system and hypothalamic-pituitary-adrenal axis

Attention deficit hyperactivity disorder (ADHD) is one of the common neurodevelopmental disorders in childhood characterized by inattention, hyperactivity, impulsivity, cognitive impairment and learning difficulties and has a negative effect on children.The specific pathogenesis of ADHD is not fully clear.Recent studies have found that there are interactions between monoaminergic system and hypothalamic-pituitary-adrenal axis, in which the machanism is associated with transcription factors, such as Sp1、KLF11、R1.This article reviews the characteristics of the monoaminergic system and hypothalamic-pituitary-adrenal axis in attention deficit hyperactivity disorder, and the machanism with transcription factors. Key words: Attention deficit hyperactivity disorder; Monoaminergic system; Hypothalamic-pituitary-adrenal axis; Transcription factor

Generation of a human induced pluripotent stem cell (iPSC) line from a 51-year-old female with attention-deficit/hyperactivity disorder (ADHD) carrying a duplication of SLC2A3

Fibroblasts were isolated from a skin biopsy of a clinically diagnosed 51-year-old female attention-deficit/hyperactivity disorder (ADHD) patient carrying a duplication of SLC2A3, a gene encoding neuronal glucose transporter-3 (GLUT3). Patient fibroblasts were infected with Sendai virus, a single-stranded RNA virus, to generate transgene-free human induced pluripotent stem cells (iPSCs). SLC2A3-D2-iPSCs showed expression of pluripotency-associated markers, were able to differentiate into cells of the three germ layers in vitro and had a normal female karyotype. This in vitro cellular model can be used to study the role of risk genes in the pathogenesis of ADHD, in a patient-specific manner.

Attention-deficit/hyperactivity disorder associated with KChIP1 rs1541665 in Kv channels accessory proteins.

Attention-deficit/hyperactivity disorder (ADHD) is an early onset childhood neurodevelopmental disorder with high heritability. A number of genetic risk factors and environment factors have been implicated in the pathogenesis of ADHD. Genes encoding for subtypes of voltage-dependent K channels (Kv) and accessory proteins to these channels have been identified in genome-wide association studies (GWAS) of ADHD. We conducted a two-stage case–control study to investigate the associations between five key genes (KChIP4, KChIP1, DPP10, FHIT, and KCNC1) and the risk of developing ADHD. In the discovery stage comprising 256 cases and 372 controls, KChIP1 rs1541665 and FHIT rs3772475 were identified; they were further genotyped in the validation stage containing 328cases and 431 controls.KChIP1 rs1541665 showed significant association with a risk of ADHD at both stages, with CC vs TT odds ratio (OR) = 1.961, 95% confidence interval (CI) = 1.366–2.497, in combined analyses (P-FDR = 0.007). Moreover, we also found rs1541665 involvement in ADHD-I subtype (OR (95% CI) = 2.341(1.713, 3.282), and Hyperactive index score (P = 0.005) in combined samples.Intriguingly, gene-environmental interactions analysis consistently revealed the potential interactionsof rs1541665 collaboratingwith maternal stress pregnancy (Pmul = 0.021) and blood lead (Padd = 0.017) to modify ADHD risk. In conclusion, the current study provides evidence that genetic variants of Kv accessory proteins may contribute to the susceptibility of ADHD.Further studies with different ethnicitiesare warranted to produce definitive conclusions.

Attention-Deficit/Hyperactivity Disorder And Inflammation: What Does Current Knowledge Tell Us? A Systematic Review.

Attention-deficit/hyperactivity disorder (ADHD) is a complex condition that interferes with development and/or functioning. Our objective is to investigate the potential association between ADHD and inflammation. We conducted a systematic review of human studies measuring inflammatory markers in ADHD. The studies were identified by searching PUBMED, MEDLINE, EMBASE, PSYCHINFO, COCHRANE, and SCOPUS databases for peer-reviewed journals published until September 2016. We included cytokine gene expression and protein measured. Fourteen papers met the inclusion criteria. Seven studies evaluated the association of cytokine gene polymorphisms in ADHD, and six studies measured cytokines levels in blood. One study analyzed the presence of cytokines in cerebrospinal fluid in patients with ADHD. Altogether, these studies indicate a possible role of inflammation in ADHD pathogenesis, despite the significant heterogeneity and contradictory results. Evidence points to the association of ADHD with inflammatory processes, but more studies are warranted.

Alterations of Growth Factors in Autism and Attention-Deficit/Hyperactivity Disorder.

Growth factors (GFs) are cytokines that regulate the neural development. Recent evidence indicates that alterations in the expression level of GFs during embryogenesis are linked to the pathophysiology and clinical manifestations of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). In this concise review, we summarize the current evidence that supports the role of brain-derived neurotrophic factor, insulin-like growth factor 2, hepatocyte growth factor (HGF), glial-derived neurotrophic factor, nerve growth factor, neurotrophins 3 and 4, and epidermal growth factor in the pathogenesis of ADHD and ASD. We also highlight the potential use of these GFs as clinical markers for diagnosis and prognosis of these neurodevelopmental disorders.