BDNF, proBDNF and proBDNF/BDNF ratio with electroencephalographic abnormalities in children with attention deficit hyperactivity disorder: Possible relations to cognition and severity.

Attention deficit hyperactivity disorder (ADHD) with and without subclinical epileptogenic discharges (SED) have been suggested to negatively affect cognitive abilities of children with ADHD. The role of brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in ADHD is in need of being investigated. The aims were to evaluate the levels of serum BDNF, proBDNF and the proBDNF/BDNF ratio in addition to the potential impacts of SED on the children's cognitive abilities and the severity of ADHD. The included participants with ADHD were 30 children with normal electroencephalogram (EEG) (G1) and 30 children with SED (G2), together with 30 healthy children (G3). The cognitive abilities and severity of the disorder were evaluated. The biochemical measures were determined by ELISA. The presence of coexisting SED and nocturnal enuresis has led to a deleterious effect on cognitive processes but not on the severity. The focal epileptogenic discharge was the most common among children in G2. The levels of BDNF in Groups 1 and 2 were less than those in G3. The higher proBDNF/BDNF ratio could be related to the low BDNF levels rather than high proBDNF levels. The findings of this study highlight the importance of investigating the presence of SED and nocturnal enuresis in children with ADHD. Targeting strengthening of cognitive abilities in children with coexisting ADHD and SED is advised. The role of proBDNF in the pathophysiology of ADHD needs further investigation.

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.

Childhood Apraxia of Speech: Exploring Gluten Sensitivity and Changes in Glutamate and Gamma-Aminobutyric Acid Plasma Levels.

BACKGROUND: Individuals with childhood apraxia of speech (CAS) were reported to have genetic variations related to gluten sensitivity and some neuroanatomic changes, which could be associated with alterations in neurotransmitters levels such as glutamate and gamma-aminobutyric acid (GABA). The aim was to measure the levels of antigliadin immunoglobulin A (IgA) antibody, glutamate, and GABA in the plasma of children with CAS compared with children with delayed language development (DLD) and neurotypical (NT) children. METHODS: The participants (N = 120) were in three groups: Group I for CAS (N = 30), Group II for DLD (N = 60), and Group III for NT (N = 30). The abilities of children in Groups I and II were evaluated. The plasma levels of antigliadin IgA, glutamate, and GABA were determined by enzyme-linked immunosorbent assay. RESULTS: The intelligence quotient and expressive language age in Group I were low compared with Group II (P = 0.001; 0.004). The levels of antigliadin IgA and glutamate in Group I were higher compared with the other two groups, whereas the level of GABA was lower (P < 0.0001). An imbalance between glutamate and GABA was found in Group I. In Group II, no measures differed from NTs except lower GABA levels (P = 0.0007). CONCLUSIONS: The elevated levels of antigliadin IgA antibody and glutamate demonstrated high sensitivity and specificity, differentiating children with CAS from children with DLD and NT children. The low levels of GABA contributed to the imbalance between the excitatory and inhibitory neurotransmitters' levels detected in children with CAS.

Efficacy of Laser Acupuncture for Children With Autism Spectrum Disorder: Clinical, Molecular, and Biochemical Study.

BACKGROUND: Low-level laser acupuncture (LLLA) biostimulation could contribute to improving the symptoms and communication of children manifesting autism spectrum disorder (ASD). Photobiomodulation might influence the level of brain-derived neurotrophic factor (BDNF) and miR-320 expression. The aim was to investigate the influence of LLLA biostimulation on the severity, language abilities, BDNF levels, and miR-320 in a sample of children with ASD. METHODS: The participants with ASD (N = 30) were randomly divided equally into groups: Group I received LLLA therapy twice a week for 12 sessions and Group II did not receive it. Assessments of the severity, language abilities, BDNF level by enzyme-linked immunosorbent assay, and miR-320 expression by reverse transcriptase quantitative polymerase chain reaction were performed before and after the intervention. A comparison between ASD cases (N = 30) before starting the therapy and neurotypical children (N = 15) regarding miR-320 expression was performed. RESULTS: Following the intervention, the severity of ASD was reduced and language performance was elevated in both groups. The improvement in Group I was higher with (P = 0.002; 0.03). The plasma BDNF level was reduced only in Group I (P < 0.001). The expression level of miR-320 in Group I did not show a change (P = 0.641). A significant difference in miR-320 expression between children with ASD and the neurotypical group (P = 0.000) was observed. CONCLUSION: This study introduces LLLA therapy as a safe and promising therapeutic procedure for improving the core manifestations and communication abilities and for modulating BDNF levels in children with ASD. The reduced expression of miR-320 showed a good diagnostic value in children with ASD.

BDNF Val66Met Polymorphism: Suggested Genetic Involvement in Some Children with Learning Disorder.

Brain-derived neurotrophic factor (BDNF) plays an essential role in neuronal survival, especially in areas responsible for memory and learning. The BDNF Val66Met polymorphism has been described as a cognitive modifier in people with neuropsychiatric disorders. BDNF levels have been found to be low in children with learning disorder (LD). However, Val66Met polymorphism has not been studied before in such children. The aim was to investigate the presence of BDNF val66Met polymorphism in a group of children with specific LD and to verify its impact on their cognitive abilities. The participants in this cross-sectional study (N = 111) were divided into two groups: one for children with LD and the other for neurotypical (NT) ones. Children with LD (N = 72) were diagnosed according to the DSM-5 criteria. Their abilities were evaluated using Stanford-Binet Intelligence Scale, dyslexia assessment test, Illinois Test of Psycholinguistic Abilities, and phonological awareness test. Genotyping of BDNF Val66Met polymorphism was performed for all participants. The frequency of the Met allele was 26% among children with LD (6 children had homozygous, 26 had heterozygous genotype). The percentage of participants with deficits in reading, writing, and phonemic segmentation was higher in Met allele carriers when compared to non-Met allele carriers in LD group. The frequency of Met allele among NT children was 3.85% (0 homozygous, 3 children had heterozygous genotype) (p = 0.00001). The high frequency of Val66Met polymorphism among children with LD introduces the BDNF gene as a genetic modifier of learning performance in some children who manifest specific learning disorder (developmental dyslexia).

Differential expression of cystathionine beta synthase in adolescents with Down syndrome: impact on adiposity.

Purpose: Obesity is more prevalent among people with Down Syndrome (DS) compared to general population. In this pilot study, we investigated the effect of cystathionine beta-synthase (CBS) overdosage on the regulation of transsulfuration pathway and the obesity phenotype in fifty adolescents (25 obese/overweight and 25 lean) with trisomy 21. Methods: The transcriptional levels of CBS in leukocytes and its translational levels in plasma were quantified using real time polymerase chain reaction and enzyme-linked immunosorbent assay respectively. Meanwhile, ultra performance liquid chromatography tandem mass spectrometry was used to determine the plasma concentrations of methionine, homocysteine, cystathionine and cysteine. Fasting plasma lipid profiles were assessed by colorimetric assays. The anthropometric measurements and indices of all subjects were recorded. Results: Both DS groups had comparable levels of CBS transcripts (p = 0.2734). The plasma levels of the enzyme were significantly higher in the lean DS cases (p = 0.0174) compared to the obese/overweight participants. Total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, methionine, homocysteine, cystathionine and cysteine showed similar plasma levels in both groups. However, the plasma cysteine levels exceeded the normal range in all DS cases. We reported a statistically significant inverse association between CBS enzyme levels and weight (r= - 0.3498, p = 0.0128), hip circumference (r= - 0.3584, p = 0.0106), body mass index (r= - 0.3719, p = 0.0078) and body adiposity index (r= - 0.3183, p = 0.0243). Conclusions: Our data suggests that the high concentrations of CBS enzyme together with cysteine modulate the DS obesity presumably through increased hydrogen sulfide production which has recently showed anti-adiposity effects.

Kynurenine and oxidative stress in children having learning disorder with and without attention deficit hyperactivity disorder: possible role and involvement.

BACKGROUND: The etiological and pathophysiological factors of learning disorder (LD) and attention deficit hyperactivity disorder (ADHD) are currently not well understood. These disorders disrupt some cognitive abilities. Identifying biomarkers for these disorders is a cornerstone to their proper management. Kynurenine (KYN) and oxidative stress markers have been reported to influence some cognitive abilities. Therefore, the aim was to measure the level of KYN and some oxidative stress indicators in children with LD with and without ADHD and to investigate their correlations with the abilities of children with LD. METHODS: The study included 154 participants who were divided into 3 groups: one for children who have LD (N = 69); another for children with LD and ADHD (N = 31); and a group for neurotypical (NT) children (N = 54). IQ testing, reading, writing, and other ability performance evaluation was performed for children with LD. Measuring plasma levels of KYN, malondialdehyde, glutathione peroxidase, and superoxide dismutase by enzyme-linked immunosorbent assay was performed for all participants. RESULTS: Some IQ measures and learning skills differed between the first two groups. The biochemical measures differed between children with LD (with and without ADHD) and NT children (p < 0.001). However, the biochemical measures did not show a significant statistical difference between the first two groups. KYN and glutathione peroxidase levels were correlated with one-minute writing and at-risk quotient, respectively (p = 0.03;0.04). KYN and malondialdehyde showed the highest sensitivity and specificity values. CONCLUSION: These biochemical measures could be involved or have a role in the abilities' performance of children with specific learning disorder.

Impact of Bisphenol A on Gonadotropic Hormone Levels in Children with Autism Spectrum Disorders.

Early developmental exposures to endocrine disruptors including bisphenol A (BPA) may affects the body's endocrine system producing adverse neurologic, reproductive, cardiovascular, metabolic, and immune effects in humans. Many studies show the effect of BPA on human reproduction at lower concentrations than that of the safety limit recommendations. However, limited studies have been associated between environmental exposure of BPA and gonadotropic hormone levels in children with autism spectrum disorders (ASDs). This study was done to evaluate association between the serum levels of hormones; follicle-stimulating (FSH), inhibin B (INHB), and estradiol (E2) and BPA in 49 ASD children compared with 40 healthy control children. Serum levels of FSH, INHB, and E2 were lower in ASD group than that of control. Correlations between BPA and FSH, INHB, and E2 within autistic children were not significant. The observed results revealed that BPA may cause endocrine dysfunction in ASD children.

Combined neurotoxic effects of cannabis and nandrolone decanoate in adolescent male rats.

Polydrug use among adolescence is a widespread phenomenon and has increased in the last few years. In particular, most nandrolone decanoate (Nan) abusers combine its use with cannabis (Can); thus, studying the consequences of this combination in adolescent subjects is important because potentiation of their effects may increase their neurotoxicity. The present study was designed to study the neurotoxic effects of Nan and Can, alone and in combination, in adolescent male rats by studying the behavioural, biochemical, and histopathological effects. Nan (15 mg/kg, s.c.) and Can (20 mg/kg, s.c.) were given alone or in combination to rats once daily for one month. The combined administration of Can and Nan induced learning and spatial memory deficits, hypo-locomotion, anxiety and aggression in adolescent rats as evidenced by the Morris water maze, open field, elevated plus maze, and defensive aggression tests. In parallel, rats treated with the combination showed severe deleterious effects in the hippocampal and prefrontal cortex (PFC) neural architecture along with a decrease in brain-derived neurotropic factor. Furthermore, combined administration of Can and Nan increased oxidative stress (significantly increased malondialdehyde and nitric oxide levels and reduced glutathione content), elevated brain pro-inflammatory cytokines (tumour necrosis factor alpha and interleukin 1 beta), and upregulated caspase-3, caspase-8, and caspase-9 mRNA expression and cytochrome c levels. In conclusion, abuse of both Can and Nan conferred greater neurotoxic effects than either drug alone that were at least partially attributed to oxidative stress, inflammation, and intrinsic and extrinsic apoptosis in the hippocampus and PFC of rats.

Investigating the influence of ubiquinone blood level on the abilities of children with specific learning disorder.

BACKGROUND: Ubiquinone has antioxidant properties and has been linked to cognitive performance in some neuropsychiatric disorders. Its role in specific learning disorder manifestations has not been previously investigated. Therefore, the aim of this study was to measure the blood levels of ubiquinone in a group of children with specific learning disorder in comparison to typically developing children and to investigate the correlation between ubiquinone levels in children with specific learning disorder and some of their intellectual capabilities, reading, spelling and writing performance. METHODS: The study included 71 native Arabic speaking children: 31 in the specific learning disorder group and 40 in the typically developing (TD) group. The abilities of the children with specific learning disorder were evaluated by the Stanford-Binet Intelligence Scale-4th edition, the Dyslexia Assessment Test, and the Illinois Test of Psycholinguistic Abilities. The level of ubiquinone was measured in both groups by ELISA. Correlation between some aptitudes of children with specific learning disorder and the ubiquinone level was performed. RESULTS: The blood levels of ubiquinone in the children with specific learning disorder group were less than those in the TD group. Correlation analysis revealed a significant positive correlation between ubiquinone and the scores of backward digit span abilities. CONCLUSIONS: Ubiquinone has a role in the auditory working memory performance of children with specific learning disorder (with impairment in reading). The decreased levels of ubiquinone in this sample of children with specific learning disorder could have participated in the pathogenesis of this disorder.

Cognitive Function and Heat Shock Protein 70 in Children With Temporal Lobe Epilepsy.

We conducted the present study to examine cognitive function and serum heat shock protein 70 levels among children with temporal lobe epilepsy. The Stanford-Binet Intelligence Test was carried out to examine cognitive function in 30 children with temporal lobe epilepsy and 30 controls. Serum heat shock protein 70 levels were determined with an enzyme-linked immunosorbent assay. The epilepsy group had significantly lower cognitive function testing scores and significantly higher serum heat shock protein 70 levels than the control group; there were significant negative correlations between serum heat shock protein 70 levels and short-term memory and composite scores. Children with uncontrolled seizures had significantly lower verbal reasoning scores and significantly higher serum heat shock protein 70 levels than children with controlled seizures. Children with temporal lobe epilepsy have cognitive dysfunction and elevated levels of serum heat shock protein 70, which may be considered a stress biomarker.

Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy.

Autism spectrum disorders are a genetically heterogeneous constellation of syndromes characterized by impairments in reciprocal social interaction. Available somatic treatments have limited efficacy. We have identified inactivating mutations in the gene BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) in consanguineous families with autism, epilepsy, and intellectual disability. The encoded protein is responsible for phosphorylation-mediated inactivation of the E1α subunit of branched-chain ketoacid dehydrogenase (BCKDH). Patients with homozygous BCKDK mutations display reductions in BCKDK messenger RNA and protein, E1α phosphorylation, and plasma branched-chain amino acids. Bckdk knockout mice show abnormal brain amino acid profiles and neurobehavioral deficits that respond to dietary supplementation. Thus, autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome.

Reduced serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D in Egyptian children with autism.

OBJECTIVE: The aim of this study was to investigate the potential role of vitamin D in autism through serum level assessment. DESIGN: This was a case-controlled cross-sectional study. SETTING: The study was conducted at the Out-patient Clinic for "Children with Special Needs" at the Medical Services Unit of the National Research Centre in Cairo, Egypt. SUBJECTS: Seventy (70) children with autism diagnosed according to the DSM-IV criteria of the American Psychiatric Association were recruited for this study. The mean age +/- standard deviation (SD) of the patients was 5.3 +/- 2.8 years. Controls included 42 age-matched randomly selected healthy children of the same socioeconomic status (mean age +/- SD, 6.1 +/- 1.8 years). METHODS: Circulating levels of both forms of vitamin D (25(OH)D and 1,25(OH)(2)D) and serum calcium were measured for all subjects. Associations between vitamin D status, birth season, and clinical characteristics of autism were examined. RESULTS: Children with autism had significantly lower 25(OH)D (p < 0.00001) and 1,25(OH)(2)D (p < 0.005) as well as lower calcium (p < 0.0001) serum values than the controls. A significant positive correlation was obtained between 25(OH)D and calcium (correlation coefficient r = 0.309, p < 0.01) within the children with autism. No significant difference was found on comparison of birth month and season of birth between children with autism and healthy controls. Furthermore, associations linking parental consanguinity or convulsions with vitamin D could not be established. CONCLUSIONS: Serum values of 25(OH)D in the children with autism of this study could classify them as being "vitamin D inadequate," which lends support to the hypothesis that autism is a vitamin D deficiency disorder.

Homocysteine and oxidative stress in Egyptian children with Down syndrome.

OBJECTIVE: To assess homocysteine, folic acid and vitamin B12, trace element levels and oxidant/antioxidant status in Down syndrome (DS) mothers and children. DESIGN AND METHODS: 42 mothers with previous history of bearing DS baby with karyotypically confirmed full trisomy 21 were included. 48 healthy mothers with their healthy children were considered as control. Serum B12, folic acid, total homocysteine (tHcy), vitamins E and C, TBARS and trace elements were estimated. RESULTS: DS mothers showed higher levels of tHCy, lower levels of folic acid and vitamin B12 than controls. tHCy and folic acid concentrations were significantly decreased, while vitamin B12 exhibited a slight decrease in DS children versus control. Vitamins E and C, zinc and copper levels were markedly reduced in DS mothers. By contrast, TBARS showed significant elevation in them. Furthermore, DS children had severe reduction of vitamin C and zinc levels relative to healthy children. However, vitamin E showed slight reduction and TBARS displayed a slight rise in DS children. CONCLUSION: Abnormal folic acid-homocysteine metabolism is a potent marker to identify women at risk for having DS child and it also exposes them to oxidant/antioxidant imbalance.