Maternal selenium deficiency during pregnancy in association with autism and ADHD traits in children: The Odense Child Cohort.

BACKGROUND: Selenoproteins regulate pathways controlling neurodevelopment, e.g., redox signaling and thyroid hormone metabolism. However, studies investigating maternal selenium in relation to child neurodevelopmental disorders are scarce. METHODS: 719 mother-child pairs from the prospective population-based Odense Child Cohort study in Denmark were included. Three selenium biomarkers, i.e. concentrations of serum selenium, selenoprotein P (SELENOP), and activity of glutathione peroxidase 3 (GPX3), along with serum copper, zinc and iron were measured in early third trimester (at 28.9+/-0.8 weeks of pregnancy). ADHD and ASD traits in children were assessed systematically using the established Child Behaviour Checklist at 5 years of age, based on a Danish reference cohort with cut-off at 90th percentile. Multivariable regression models adjusted for biologically relevant confounders were applied. RESULTS: 155 of 719 (21.6 %) children had ASD traits and 59 of 719 (8.2 %) children had traits of ADHD at 5 years of age. In crude and adjusted models, all three selenium biomarkers associated inversely with ADHD traits. For ADHD, fully adjusted OR for 10 µg/L increment in selenium was 0.76 (95 % CI 0.60, 0.94), for one mg/L increment in SELENOP was 0.73 (0.56, 0.95), and for 10 U/L increment in GPx3 was 0.93 (0.87,1.00). Maternal total selenium was inversely associated with child ASD traits, OR per 10 µg/L increment was 0.85 (0.74, 0,98). SELENOP and GPx3 were not associated with ASD traits. The associations were specific to selenium, as other trace elements such as copper, zinc, or iron were not associated with the outcomes. CONCLUSIONS: The results provide coherent evidence for selenium deficiency as a risk factor for ADHD and ASD traits in an environment with borderline supply, the causality of which should be elucidated in a randomized controlled trial.

Functional Gastrointestinal Symptoms in Children with Autism and ADHD: Profiles of Hair and Salivary Cortisol, Serum Leptin Concentrations and Externalizing/Internalizing Problems.

BACKGROUND: Functional Gastrointestinal Disorders (FGIDs) present a higher prevalence in individuals with Neurodevelopmental Disorders (NDDs). The Stress System and the Gut-Brain axis (GBA) may mediate these relations. We aimed to assess the prevalence and profile of FGIDs in a clinical sample of children with Autism Spectrum Disorder (ASD) and Attention Deficit/Hyperactivity Disorder (ADHD) compared to typically developing children (TD) as well as to investigate possible relations between stress-related biomarkers and internalizing/externalizing problems in children with NDDS. METHODS: In total, 120 children, aged between 4 and 12 years old, formed three groups (N = 40, each): ADHD, ASD and TD. Salivary cortisol, hair cortisol and serum leptin were measured. RESULTS: The ASD group had more FGID problems than the TD group (p = 0.001). The ADHD and ASD groups had higher total internalizing/externalizing problems than the TD group (p < 0.0001, p < 0.0001, p = 0.005, respectively). Children with FGIDs showed more total, internalizing and externalizing problems compared to children without FGIDs (p < 0.0001, p < 0.0001, p = 0.041, respectively). The ADHD group showed lower AUCg values (p < 0.0001), while the hair cortisol was higher for the TD group (p < 0.0001). CONCLUSION: In conclusion, children with NDDs had more FGID symptoms and present higher internalizing and externalizing problems. Children with ADHD and FGIDs had more internalizing problems compared to those without FGIDs. No differences in stress-related biomarkers were shown to differentiate children with NDDs with and without FGIDs. Future prospective studies including a greater number of children may elucidate the biological pathways linking these comorbidities.

Expression Patterns of miRNAs in Egyptian Children with ADHD: Clinical Study with Correlation Analysis.

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 miR-34c-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.

Increased Serum Terminal Complements Complex Levels in Attention Deficit Hyperactivity Disorder Children.

Background: Attention deficit hyperactivity disorder (ADHD) is a widespread neuropsychiatric disorder in both children and adolescents, which is associated with social isolation and poor academic performance. Complement proteins are regarded as a major player in inflammation and disease development for several neuropsychiatric diseases such as schizophrenia and bipolar diseases. As clarified by previous data, increased levels of complement molecules and other immunological markers as cytokines were demonstrated in these disorders. Limited studies have investigated complement proteins particularly terminal complement complex or membrane attack complex (C5b-9) among ADHD patients. The present research aims to elucidate the association between C5b-9 complex protein and ADHD. Methods: This is a cross-sectional study. Sera were collected from Al-Hussain Teaching Medical City in Holy Karbala, Iraq, during 2019-2020. Sera were tested for C5-b9 using commercial kits by enzyme-linked immunosorbent assay (ELISA). Results: In 90 participants included in the study, a significant increment in C5b-9 levels among ADHD patients (P=0.019) was observed. Patients with positive C5b-9 levels had a 2.76 times higher risk of developing ADHD than control subjects. The diagnostic utility for C5b-9 was statistically significant with 71.11% sensitivity, 55.6% specificity, and a high negative predictive value (97.3%). Conclusion: The study concluded elevation of the C5b-9 terminal complements complex levels in ADHD patients, which could point to the association of complement proteins as inflammatory markers with the ADHD disease process.

The impact of Toxocara-seropositivity on attention and motor skills in children with attention-deficit hyperactivity disorder.

BACKGROUND: The study aims to compare neurological soft signs and executive functions between Toxocara-seropositive and seronegative groups in children with attention-deficit/hyperactivity disorder. METHODS: The study included 60 boys with ADHD, aged 7-12. After blood samples were taken, the Stroop Color Word Test and Judgment of Line Orientation test (JLOT) were implemented to measure executive functions. Neurological soft signs were evaluated with Physical and Neurological Examination for Subtle Signs (PANESS). RESULTS: Serological tests were positive for Toxocara antibodies in 20 cases. There was no significant difference between Toxocara seropositive and seronegative regarding age, socioeconomic status, developmental stages, and ADHD severity. However, Toxocara-seropositive children had higher Stroop time and Stroop interference scores and lower JLOT scores than Toxocara-seronegative children. Furthermore, Toxocara-seropositive children exhibited more neurological soft signs, such as gait and station abnormalities, dysrhythmia, and a longer total time in timed movements compared to Toxocara-seronegative children. CONCLUSION: Our study indicates a link between Toxocara-seropositivity and impaired neurological soft signs and executive functions in ADHD. Further research is needed to understand ADHD mechanisms, develop practical treatments considering immunological factors, and thoroughly evaluate how Toxocara seropositivity affects executive functions and motor skills in children with ADHD.

Brain-derived neurotrophic factor (BDNF) levels in children and adolescents before and after stimulant use a systematic review and metanalysis.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder associated with cognitive, social, and academic impairment. Neurotrophins, particularly brain-derived neurotrophic factor (BDNF), have been implicated in the pathophysiology of ADHD and response to stimulant treatment. This review aims to investigate the relationship between BDNF levels in ADHD before and after treatment with stimulants in childhood. METHODS: This systematic review followed PRISMA-P guidelines and included 19 studies from PubMed, EMBASE, Cochrane, Capes Periodic, and Lilacs databases. The studies were evaluated for risk of bias and level of evidence. RESULTS: There was no significant difference in peripheral BDNF levels in ADHD children before or after methylphenidate treatment. Additionally, there was no statistically significant difference in BDNF levels between children with ADHD and controls. DISCUSSION: Understanding the role of BDNF in ADHD may provide insight into the disorder's pathophysiology and facilitate the development of biological markers for clinical use. CONCLUSION: Our findings suggest that BDNF levels are not significantly affected by methylphenidate treatment in ADHD children and do not differ from controls. SYSTEMATIC REVIEW REGISTRATION: "Brain-derived neurotrophic factor (BDNF) levels in children and adolescents before and after stimulant use: a systematic review". Number CRD42021261519.

Pharmacokinetics, Safety, and Tolerability of SHP465 Mixed Amphetamine Salts After Administration of Multiple Daily Doses in Children Aged 4-5 Years with Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: Given the limited treatment options for younger children with attention-deficit/hyperactivity disorder (ADHD), a clinical study for SHP465 treatment was warranted. OBJECTIVES: We aimed to evaluate the pharmacokinetics, safety, and tolerability of SHP465 mixed amphetamine salts (MAS) 6.25 mg after multiple once-daily doses in children aged 4-5 years with ADHD. METHODS: In this open-label multicenter study, SHP465 MAS 6.25 mg once daily was administered for 28 days to children aged 4-5 years with ADHD; baseline ADHD Rating Scale-5 total score ≥ 28 (boys) or ≥ 24 (girls) and Clinical Global Impression-Severity scale score ≥ 4. Blood samples were collected in the pharmacokinetic-rich group predose on day 1 week 1 and day 7 week 4 (predose, postdose at 2, 5, 8, 12, 16, 24, and 48 hours); and in the pharmacokinetic-sparse group predose on day 1 weeks 1, 2, and 3 and 24 hours postdose on day 7 week 4 . Key pharmacokinetic parameters included maximum plasma drug concentration (Cmax), plasma trough drug concentration, time to Cmax during a dosing interval (tmax), area under the concentration-time curve from time 0 to time of last collected sample, area under the concentration-time curve over the dosing interval (24 h) at steady state (AUCtau,ss), first-order rate constant associated with the terminal phase of elimination, terminal half-life (t1/2), total clearance of drug from plasma after oral administration, and apparent volume of distribution at steady state. Safety endpoints included treatment-emergent adverse events and vital signs. RESULTS: Mean ± standard deviation age and body mass index of 24 participants (66.7% male) were 4.8 ± 0.41 years and 17.2 ± 3.18 kg/m2, respectively. The most common ADHD was the combined presentation (91.7%); ratings were 50% markedly ill and 45.8% moderately ill on the Clinical Global Impression-Severity scale. Plasma d-amphetamine and l-amphetamine steady state was attained by predose on treatment day 8, consistent with the half-life. Peak steady-state plasma concentration (median tmax) for both d-amphetamine and l-amphetamine occurred at 7.92 h postdose on day 7 week 4 and thereafter declined monoexponentially, with a geometric mean t1/2 of 10.4 and 12.3 h for d-amphetamine and l-amphetamine, respectively. For both d-amphetamine and l-amphetamine, Cmax and AUCtau,ss were comparable between children aged 4 years (n = 3) and children aged 5 years (n = 8) regardless of sex. In total, 14 treatment-emergent adverse events were reported by 45.8% (11/24) of participants. Five treatment-emergent adverse events, reported for four (16.7%) participants, were considered treatment related; affect lability occurred in two (8.3%) participants, and insomnia, accidental overdose, and increased blood pressure each occurred in one (4.2%) participant. CONCLUSIONS: In children aged 4-5 years with ADHD, following multiple once-daily administrations of SHP465 MAS 6.25 mg, the pharmacokinetic profile of plasma d-amphetamine and l-amphetamine was generally consistent among participants. Between-individual variability of plasma d-amphetamine and l-amphetamine steady-state exposure was low to moderate. SHP465 MAS was generally well tolerated in this study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03327402 (31 October, 2017).

The lowest effective plasma concentration of atomoxetine in pediatric patients with attention deficit/hyperactivity disorder: A non-randomized prospective interventional study.

BACKGROUND: Atomoxetine (ATX) is used as a first-line, non-stimulant treatment for attention-deficit/hyperactivity disorder (ADHD), although no studies have systematically examined the relationship between plasma concentration and clinical efficacy. We conducted this non-randomized prospective interventional study to examine the relationship between plasma concentration of ATX and clinical efficacy. METHODS: Forty-three ADHD pediatric patients received ATX, and the steady-state through plasma concentration of the last daily dose that was maintained for at least 4 weeks were determined by high-performance liquid chromatography. RESULTS: The receiver operating characteristic curve suggested that when plasma concentration exceeded 64.60 ng/mL, scores on the ADHD-Rating Scale improved by 50% or more (P = .14). Although 6 of the 8 final responders were unresponsive at the initial dose (.72 ±â€Š.04 mg/kg [mean ±â€Šstandard deviation]), they responded after increasing the ATX dose to the final dose (1.52 ±â€Š.31 mg/kg). Excluding 7 outlier participants, the concentration was 83.3 ±â€Š32.3 ng/mL in 7 responders and was significantly higher than 29.5 ±â€Š23.9 ng/mL (P < .01) for the 29 non-responders. CONCLUSIONS: These results suggest that a minimum effective plasma concentration of ATX is required to achieve sufficient clinical efficacy. We hypothesized a mechanism that results in the realization of a clinical effect when the plasma concentration exceeds a certain threshold in the potential response group, whereas will not improve even if the plasma concentration is increased in the unqualified non-responder group.

PLS-DA Model for the Evaluation of Attention Deficit and Hyperactivity Disorder in Children and Adolescents through Blood Serum FTIR Spectra.

Attention deficit and hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders of childhood. It affects ~10% of the world's population of children, and about 30-50% of those diagnosed in childhood continue to show ADHD symptoms later, with 2-5% of adults having the condition. Current diagnosis of ADHD is based on the clinical evaluation of the patient, and on interviews performed by clinicians with parents and teachers of the children, which, together with the fact that it shares common symptoms and frequent comorbidities with other neurodevelopmental disorders, makes the accurate and timely diagnosis of the disorder a difficult task. Despite the large effort to identify reliable biomarkers that can be used in a clinical environment to support clinical diagnosis, this goal has never been achieved hitherto. In the present study, infrared spectroscopy was used together with multivariate statistical methods (hierarchical clustering and partial least-squares discriminant analysis) to develop a model based on the spectra of blood serum samples that is able to distinguish ADHD patients from healthy individuals. The developed model used an approach where the whole infrared spectrum (in the 3700-900 cm-1 range) was taken as a holistic imprint of the biochemical blood serum environment (spectroscopic biomarker), overcoming the need for the search of any particular chemical substance associated with the disorder (molecular biomarker). The developed model is based on a sensitive and reliable technique, which is cheap and fast, thus appearing promising to use as a complementary diagnostic tool in the clinical environment.

The study of Tau and phospho Tau protein levels in attention deficit and hyperactivity disorder

Background/aim: Attention deficit and hyperactivity disorder (ADHD) is a widespread neurodevelopmental disorder that begins in childhood and has negative consequences throughout adult life. The etiology and pathogenesis of ADHD are still unclear. Tau protein is a soluble microtubule-related protein expressed by neurons and localized in the cytoplasm as well as axons. Tau protein provides stability of microtubule in two ways: phosphorylation and isoforms. The excessive phosphorylation of Tau separates the protein from the microtubule, thus making it unstable. In this study, we aimed to investigate whether there is a relationship between serum Tau protein and phospho Tau (p-Tau181) levels and ADHD occurrence. Materials and methods: This study included 26 male children aged 7­12 years with newly diagnosed ADHD, who had previously not used any medication for ADHD, and 26 male healthy children. Serum Tau and p-Tau181 concentrations were performed by enzyme- linked immunosorbent assay (ELISA). Results: In patients, the Tau levels were not significantly different from those of the controls; the p-Tau181 levels were significantly higher than those of the controls. Conclusion: We concluded that high p-Tau181 might be associated with the progression of ADHD and cognitive changes in ADHD.

Assessment of Exposure to Mycotoxins in Spanish Children through the Analysis of Their Levels in Plasma Samples.

In this study, we present, for the first time in Spain, the levels of 19 mycotoxins in plasma samples from healthy and sick children (digestive, autism spectrum (ASD), and attention deficit hyperactivity (ADHD) disorders) (n = 79, aged 2-16). The samples were analyzed by liquid chromatography-mass spectrometry (triple quadrupole) (LC-MS/MS). To detect Phase II metabolites, the samples were reanalyzed after pre-treatment with ß-glucuronidase/arylsulfatase. The most prevalent mycotoxin was ochratoxin A (OTA) in all groups of children, before and after enzyme treatment. In healthy children, the incidence of OTA was 92.5% in both cases and higher than in sick children before (36.7% in digestive disorders, 50% in ASD, and 14.3% in ADHD) and also after the enzymatic treatment (76.6 % in digestive disorders, 50% in ASD, and 85.7% in ADHD). OTA levels increased in over 40% of healthy children after enzymatic treatment, and this increase in incidence and levels was also observed in all sick children. This suggests the presence of OTA conjugates in plasma. In addition, differences in OTA metabolism may be assumed. OTA levels are higher in healthy children, even after enzymatic treatment (mean OTA value for healthy children 3.29 ng/mL, 1.90 ng/mL for digestive disorders, 1.90 ng/mL for ASD, and 0.82 ng/mL for ADHD). Ochratoxin B appears only in the samples of healthy children with a low incidence (11.4%), always co-occurring with OTA. Sterigmatocystin (STER) was detected after enzymatic hydrolysis with a high incidence in all groups, especially in sick children (98.7% in healthy children and 100% in patients). This supports glucuronidation as a pathway for STER metabolism in children. Although other mycotoxins were studied (aflatoxins B1, B2, G1, G2, and M1; T-2 and HT-2 toxins; deoxynivalenol, deepoxy-deoxynivalenol, 3-acetyldeoxynivalenol, 15-acetyldeoxynivalenol; zearalenone; nivalenol; fusarenon-X; neosolaniol; and diacetoxyscirpenol), they were not detected either before or after enzymatic treatment in any of the groups of children. In conclusion, OTA and STER should be highly considered in the risk assessment of mycotoxins. Studies concerning their sources of exposure, toxicokinetics, and the relationship between plasma levels and toxic effects are of utmost importance in children.

Efficacy of Polyunsaturated Fatty Acids (PUFAs) on Impulsive Behaviours and Aggressiveness in Psychiatric Disorders.

It is the focus of increasing interest to investigate the effects of long-chain n-3 and long-chain n-6 polyunsaturated fatty acids (LC n-3 PUFAs; LC n-6 PUFAs) on psychiatric symptoms in a transdiagnostic perspective. There is some evidence that low levels of LC n-3 PUFAs and a higher ratio of LC n-6 to LC n-3 PUFAs in plasma and blood cells are associated with aggressive and impulsive behaviours. Therefore, implementation of LC n-3 PUFAs may produce positive effects on hostility, aggression, and impulsivity in both psychiatric and non-psychiatric samples across different stages of life. A possible mechanism of action of LC n-3 PUFAs in conditions characterized by a high level of impulsivity and aggression is due to the effect of these compounds on the serotonin system and membrane stability. Studies that evaluated the effects of LC n-3 PUFAs on impulsivity and aggressiveness indicated that addition of rather low doses of these agents to antipsychotic treatment might reduce agitation and violent behaviours in psychosis, attention deficit hyperactivity disorder, personality disorders, and impulsive control and conduct disorders. The present review is aimed at examining and discussing available data from recent trials on this topic.

Association between serum levels of glial cell line-derived neurotrophic factor and inattention in adult patients with attention deficits/hyperactivity disorder.

Glial cell line-derived neurotrophic factor (GDNF) may play an important role in attention. We investigated the association between serum GDNF levels and clinical status in unmedicated adults with attention deficit/hyperactivity disorder (ADHD) (n = 16) and healthy controls (n = 33); the levels were comparable between the ADHD and control groups (107.2 ± 31.7 vs. 110.5 ± 40.0 pg/mL, respectively; p = 0.77). In the ADHD group, higher GDNF serum levels were associated with severe subjective inattention (r = 0.528, p = 0.035). These preliminary results suggest that the serum GDNF level may not be a suitable biomarker for adult ADHD, although it may be associated with the pathophysiology of persistent inattention in adult ADHD.

Ubiquinone Levels as a Marker of Antioxidant System in Children with Attention Deficit Hyperactivity Disorder.

The aims of this study are to compare serum ubiquinone levels in children with attention deficit hyperactivity disorder (ADHD) with healthy controls and to investigate the correlation between ubiquinone levels of children with ADHD and their ADHD symptoms. Twenty-seven children who are 6-12 years old age with attention deficit hyperactivity disorder having clinically normal intelligence and 23 children with clinically normal intelligence and no psychiatric disorder of similar age and sex who referred to Ankara University School of Medicine Department of Child and Adolescent Psychiatry were included in this study. All children were diagnosed by same researcher using the Semi-Structured Clinical Interview for DSM-IV Scale for Affective Disorders and Schizophrenia Interview for School Children-Now and for the Life-Long Version (K-SADS-PL). Parents and teachers of the children completed the Conners Parent Rating Scale Revised Long Form (CPRS-LF) and Conners Teacher Rating Scale Revised Long Form (CTRS-LF). There were no statistically significant differences regarding the age, gender, and sociodemographic data of the groups. Serum ubiquinone levels of the ADHD group were significantly lower than the control group. We did not find any correlation between ubiquinone levels and clinical values. Since ubiquinone levels are lower in children with ADHD compared with controls, we suggest that decreased antioxidant levels may play a role in ADHD pathogenesis by disrupting oxidative balance.

Elevated neutrophil-to-lymphocyte ratio in children and adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVE: Inflammation is reported to play a substantial role in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). Neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) are inexpensive and potentially interesting biomarkers of inflammation. In this cross-sectional and retrospective study, we investigated the relationship between NLR, PLR and ADHD. METHODS: This study consisted of 100 children and adolescents with ADHD (85 of those receiving psychopharmacological treatment), and 99 physically and mentally healthy children. RESULTS: The mean NLR and PLR were significantly higher in patients than in controls. There was no significant difference between patients who received psychopharmacological treatment for ADHD and patient that did not with regard to NLR and PLR. No associations were found between NLR and PLR and ADHD symptom severity. The significance of NLR is not influenced by medication use, age and sex. CONCLUSIONS: Our findings suggest that NLR and PLR may be inflammation biomarkers in children and adolescents with ADHD. Moreover, the significance of NLR is not influenced by medication use, age and sex. Prospective studies that address alterations in NLR and PLR and other pro-inflammatory cytokines following ADHD treatment may provide additional information about the inflammatory mechanisms in ADHD.Key pointsThe mean NLR and PLR were significantly higher in patients than in controls.The significance of NLR is not influenced by medication use, age and sex.No associations were found between NLR and PLR and ADHD symptom severity.Prospective studies that address alterations in NLR and PLR and other pro-inflammatory cytokines following psychopharmacological treatment of ADHD may provide additional information about the inflammatory mechanisms in ADHD.

Brain iron concentrations in the pathophysiology of children with attention deficit/hyperactivity disorder: a systematic review.

CONTEXT: Attention deficit/hyperactivity disorder (ADHD) is a neurological disorder associated with iron dysregulation in children. Although previous focus was on examining systemic iron status, brain iron content may be a more reliable biomarker of the disorder. OBJECTIVE: This systematic review examines whether children with ADHD have lower serum as well as brain iron concentrations, compared with healthy control subjects (HCS). DATA SOURCES: A systematic literature search was conducted in Medline via PubMed, the Cochrane Library, Web of Science, Embase. and Ovid for papers published between 2000 and June 7, 2019. DATA EXTRACTION: Studies were included if the mean difference of iron concentration, measured as serum iron, serum ferritin, or brain iron, between children with ADHD and HCS was an outcome measure. DATA ANALYSIS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Risks of bias within and between studies were assessed using the quality assessment tools of the National Institutes of Health. Of 599 records screened, 20 case-control studies met the inclusion criteria. In 10 of 18 studies in which serum ferritin concentration was assessed, and 2 of 10 studies that assessed serum iron, a significant difference between children with ADHD and HCS was observed. Results of systemic iron levels were inconsistent. In 3 studies in which brain iron concentration was assessed, a statistically significant, lower thalamic iron concentration was found in children with ADHD than in HCS. CONCLUSION: The evidence, though limited, reveals that brain iron rather than systemic iron levels may be more associated with the pathophysiology of ADHD in children. Larger, longitudinal, magnetic resonance imaging studies are needed to examine any correlations of iron deficiency in specific brain regions and symptoms of ADHD.

Serum zonulin and claudin-5 levels in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: This study aimed to investigate serum zonulin and claudin-5 levels of children and adolescents with attention-deficit/hyperactivity disorder (ADHD) and healthy controls by controlling the parameters such as age, sex and body mass index (BMI) percentile which are known to affect these parameters. METHOD: A total of 80 treatment-naive children and adolescents with ADHD and 40 healthy volunteer controls aged 8-12 years were enrolled in this study. The severities of ADHD symptoms were assessed via parent- and teacher-rated questionnaires. The severity of anxiety and depression symptoms of the children were assessed by the self-report inventories. Serum levels of zonulin and claudin-5 were measured using commercial enzyme-linked immunosorbent assay kits. RESULTS: The multivariate analysis of covariance (MANCOVA) revealed a significant main effect of groups in the serum zonulin and claudin-5 levels, an effect that was independent of age, sex and BMI percentile. Significant differences were found between the study groups in terms of serum log-claudin-5 levels. However, there was no significant difference between the study groups in terms of serum zonulin levels. CONCLUSION: These findings provide additional evidence for dysregulation of the blood-brain barrier, especially abnormalities in claudin-5 function, which may be involved in the aetiology of ADHD.Key pointsADHD is one of the most common neurodevelopmental disorders of childhood. Although ADHD is quite common, its aetiology has yet to be fully explained.In recent years, studies on the relationship between intestinal and blood-brain brain barrier permeability and psychiatric disorders have increased.In our study, serum claudin-5 levels were higher in the ADHD group compared to the control group, while serum zonulin levels did not differ between the groups.

Proinflammatory mediators and their associations with medication and comorbid traits in children and adults with ADHD.

Peripheral immune activation can influence neurodevelopment and is increased in autism, but is less explored in attention deficit hyperactivity disorder (ADHD). Patients with ADHD often display comorbid autism traits and gastrointestinal (GI) symptoms. Plasma protein levels of two acute phase reactants, C-reactive protein (CRP) and serum amyloid A (SAA), and two endothelial adhesion molecules, soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1), which share important roles in inflammation, were analyzed in 154 patients with ADHD and 61 healthy controls. Their associations with ADHD diagnosis, severity, medication and comorbid autistic symptoms, emotion dysregulation and GI symptoms were explored. The ADHD patients had increased levels of sICAM-1 and sVCAM-1 compared to healthy controls (p = 8.6e-05, p = 6.9e-07, respectively). In children with ADHD, the sICAM-1 and sVCAM-1 levels were higher among those with ADHD medication than among children (p = 0.0037, p = 0.0053, respectively) and adults (p = 3.5e-09, p = 1.9e-09, respectively) without ADHD medication. Among the adult ADHD patients, higher sICAM-1 levels were associated with increased comorbid autistic symptoms in the domains attention to detail and imagination (p = 0.0081, p = 0.00028, respectively), and higher CRP levels were associated with more GI symptoms (p = 0.014). sICAM-1 and sVCAM-1 levels were highly correlated with each other, and so were CRP and SAA levels. To conclude, vascular inflammatory activity may be overrepresented in ADHD, with elevated sICAM-1 and sVCAM-1 levels and this may in children be a consequence of current ADHD medication, and in adults relate to increased comorbid autistic symptoms. Replication is warranted.

Thiols and ceruloplasmin levels in serum of children with attention deficit hyperactivity disorder: A cross-sectional study.

Attention deficit hyperactivity disorder (ADHD) is a childhood onset disorder with well-known findings that include impulsivity, hyperactivity, and inattention. This study aims to explore the relationship between the levels of ceruloplasmin, native thiol, total thiol, and disulfide and ADHD by comparing case and control groups. The study case group comprised 50 children aged 6-16 years who had been diagnosed with ADHD. The control group included 47 healthy children. Clinical interviews were conducted and the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version Turkish Adaptation and the Conners Parent Rating Scale were administered. Additionally, blood samples were taken and native thiol, total thiol, disulfide, and ceruloplasmin levels measured. In the ADHD group, the mean native thiol, total thiol, and disulfide levels were significantly lower than the control group. There was no significant difference between the ADHD and control groups in ceruloplasmin levels. Total thiol and native thiol levels were inversely correlated with scores on the Conners Inattention and Hyperactivity subscales; total thiol was negatively correlated with the ADHD index. Thiol-disulfide homeostasis was impaired in ADHD children and was related to symptom severity. Oxidative stress balance may play a role in ADHD.